text:
Merit Health Batesville West Batesville, MS - 5.7 miles from Courtland155 Keating Road
Batesville, MS 38606
An Addiction Treatment Specialist is standing by now to help you find an effective treatment program that fits your needs and insurance/financial requirements.
What Payment Options Does the Rehab Offer?
If you are worried that you cannot accept addiction treatment services because you have no insurance cover and do not qualify for state or federal help, you should consider finding other ways to pay for your recovery.
Some drug rehabs actually offer scholarships to some of their needy patients. You can find out if the rehab that you are interested in has such a program to see if they will be able to help you overcome your addiction without asking for too much money.
Does The Rehab Offer an Aftercare Program?
Addiction can come with devastating consequences both in the short and long term. If you are looking to recover fully from it, you may want to enroll in an addiction treatment program in Courtland that offers aftercare planning and programming services.
Although rehab can offer you the supportive and healthy environment that will help you repair all the damage your addiction caused, it is important that you continue trying to overcome this condition even after the rehab period.
For this reason, it is highly recommended that you look for a rehab center that has a stable aftercare program in place, or one that can point you to various after-treatment support service providers.
Do They Offer Relapse Prevention Techniques?
Addiction is a chronic and relapsing disease according to ASAM - the American Society of Addiction Medicine. As such, it comes with physical, emotional, social, biological, and behavioral aspects.
Additionally, the rates of relapse are quite high even among people who have been through formal addiction treatment and rehabilitation program. For this reason, you need to ensure that the drug rehab in Courtland that you participate in will teach you relapse prevention techniques to reduce this risk.
There are so many types of treatment methods and service settings to choose from when it comes to addiction treatment that it can be hard to know what treatment would be best for you or your loved one.
It can be extremely helpful to speak with a counselor who is familiar with all the different types of rehabs that are available.
USNoDrugs has certified, caring counselors that can guide you through the process of finding an addiction treatment program that fits all your needs.
If you would like to speak with one of our counselors, call 1-888-852-7453 and we will help you through each step.
All calls are toll-free, and our services are completely confidential and free of charge.
We can help you find the best rehab program that fits your specific needs.
Free Assessment • 100% Confidential
We provide a free service to help you find the right drug or alcohol rehab program in your area, contact us now!
For immediate assistance call us now to speak with one of our Treatment Specialists.
Available 24/71-888-852-7453
Fill out the Help Request Form and one of our Treatment Specialists will respond shortly.
Response time will vary.Help Request Form
Courtland, MS does not have a local alcohol and drug rehab program. However, there are a number of nearby treatment centers in cities near you.
You can find inpatient alcohol and drug treatment programs in Batesville, MS & Senatobia, MS:
If you're looking for outpatient drug treatment facilities, there are some located in Batesville, MS:
Most individuals need some type of drug and alcohol detox before starting treatment. You can find detox facilities in Oxford, MS & Tutwiler, MS:


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Custom Kitchen & Bathroom Design Build Contractor in Brandermill, VA
With 80 distinctive neighborhoods, Brandermill is the second best place to live in Chesterfield County, right behind Woodlake. This relatively new family-friendly area boasts parks, walking paths, boating facilities, top-rated schools, The Green Market, and easy access to shopping and freeways. There's a sense of community that brings everyone together. Blending a modern, 21st century lifestyle with the great outdoors, Brandermill is back-road enough to avoid traffic, but contemporary enough to make it an incredible place to live.
Although Brandermill is one of Virginia's more recent residential developments, your home could be as much as 40 years old. Is it everything you'd like it to be, or could it use a little TLC? Maybe your kitchen or bathrooms are in need of some updates—or repair work. That's when you call us at Leo Lantz Construction.
We work with homeowners throughout Brandermill when they want to upgrade their home. Whether you need your kitchen or bathroom renovated, a window or door replacement, or are considering aging-in-place remodeling, Leo Lantz Construction can handle both the design and building of any project.
What Is Aging In Place?
As people are living longer, more and more want to stay in their homes longer rather than move in with adult children or downsize completely into an assisted living facility. Aging in place not only makes that possible, it makes it safer and easier to stay home while eliminating the risks that you may have.
Simple modifications that can help you stay in your home as you grow older include rooms such as:
- Kitchen
- Bathroom
- Exterior
- Bedroom
We can make these same modifications in any part of your house to increase safety, usability and comfort. Making changes now, before they're needed, will make life easier when the time comes.
Leo Lantz Construction specializes in home renovation for older homes. We'll take care of your Brandermill home like it was our own. Contact us today at (804) 262-3360 to schedule your free consultation.

subset: commoncrawl


text: fetchProvidence Primitive Baptist Church | SermonAudio My Church My History My Favorite Broadcasters My Favorite Speakers My Favorite Sermons My Favorite Videos My Favorite Series Notification Manager Sign in or signup Radio Streams SA Radio24/7 Radio Stream VCY America24/7 Radio Stream IDSOLOprovidencepbcCODE #15164 My Favorite Things HomeNews, SITEEvents | Local | BlogsNew Audio | Video | ClipsBroadcastersChurch FinderWebcast LIVE NOW!Sermons by BibleSermons by CategorySermons by TopicSermons by SpeakerSermons by DateStaff PicksComments, ALL -23 secTop SermonsDaily LogPhotosStoresOnline BibleHymnalDaily ReadingOur ServicesSermon DashboardNEWMembers Only Providence Primitive Baptist Church Andy Carter and Nathan Pitney | Falkner, Mississippi Contact Info | Edit Email MY FAVORITEAdd to Favorites | MyChurch PHONE662-643-5034 ADDRESSProvidence Primitive Baptist Church20840 Hwy 15 NFalkner, MS 38629 Podcast + Codes XML Podcast Feed Apple iTunes Blog-Only Feed (RSS)SERMONS EMBED | InfoSermons EmbedMobile Apps | Info iPhone + iPad Android Devices Kindle Fire Tablet Amazon Fire TV ROKU TV Apple TV Chromecast Apple Watch Kindle Reader Listen LineEnjoy sermons from this broadcasteron a variety of mobile devices.MyChurch: providencepbc | SetMyChurch Code#: 15164 Home About Sermons Blog Events Photos Guest Links Store eDocs Welcome to our spot on sermonaudio.com | edit page 6 Basic Information Introduction ( nothing to say | edit page ) Service Times Sunday Morning 10:00 AM -12:00 PMWednesday Evening 7:00 PM - 8:00 PM Speakers Primary Speaker:Andy CarterPitney, Nathan 3 sermons | new!Harris, Jeff 1 sermons | new!-- sermons by speaker --Carter, Andy 2Harris, Jeff 1Pitney, Nathan 3 Attendance 1-100 Bible Version KJV Type Church Total Sermons 6 Member Since October 2019 Contact Information SA Website www.sermonaudio.com/providencepbc Code ID 15164 Solo Site www.sermonaudio.com/solo/providencepbc Contact 662-643-5034 Location Falkner, Mississippi Country USA Address Providence Primitive Baptist Church20840 Hwy 15 NFalkner, MS 38629 Mailing Labels Print Avery #5164 Labels for Gospel of John Personal Edition Business Cards Order Business Cards[ More Info ] Billboards Advertise your church on billboards!Our unique partnerships with billboard companies now make it easier than ever. Magherafelt, N. IrelandMagherafelt Free Presbyterian ChurchPlay! | More Today's Featured | more Bob VincentJesus' Will and TestamentBitter FruitSunday ServiceSermons by Bob and OthersPlay! | MP3 | RSSNot Ashamed of Gentile SaintsJohn Pittman Hey Text! Featured | add | more E. A. JohnstonLordship Or HellEvangelism AwakeningCamp MeetingPlay! | MP3Drew McKeownServing With Purpose (Luke 9)Fearless in FaithDrew McKeownPlay! | MP3Dr. James M. PhillipsWhich Bible is The Best,..Dr. Jim on Mission FieldDiscover The Word With Dr...Video!Play! | MP4Joelee ChamberlainChristmas for ChildrenHolidaysChildren's Bible AudiosPlay! | MP3Stephen MacKenzieReformed HypocrisyReformation ConfessionsFishers of Men Bible...Video!Play! | MP4Sponsor:Kept Pure in All Ages: Text ConferenceMarch 27-28, 2020 with Dr. Jeffrey T. Riddle at Five Solas Church (Reedsburg, WI)https://www.keptpure.comSponsor:Kept Pure in All Ages: Text ConferenceMarch 27-28, 2020 with Dr. Jeffrey T. Riddle at Five Solas Church (Reedsburg, WI)https://www.keptpure.comSermon: We Don't Need a Better LawyerJohn Pittman Hey Our SPONSORS | more SPONSOR | 2,500+SPONSORAdd Now | view all ads Today's Quote The greatness of a man's power is the measure of his surrender. ... William Booth Gospel of John Cities | Local | Personal MOBILE iPhone + iPad Church App Watch Android Church App Fire Tablet Wear Chromecast TV Apple TV Android TV ROKU TV Amazon Fire TV Amazon Echo Kindle Reader HELP Knowledgebase Broadcasters Listeners Q&A Uploading Sermons Uploading Videos Webcasting Tips & Tricks YouTube Screencasts 2-MINUTE TIPS FOLLOW Weekly Newsletter Staff Picks Feed SA Newsroom New! RSS | Twitter | Facebook SERVICES Dashboard | Info Cross Publish New! Audio | Video | Podcast Sermon Player | Video New! Church Finder | Info Mobile & Apps Live Webcasting Listen Line Events Support Transcription | PowerClips Billboards | Biz Cards Solo Sites Favorites | QR Codes Online Donations 24x7 Radio Stream INTEGRATION Embed Codes Goodies WordPress Twitter Facebook Logos | e-Sword | BLB JSON API BATCH Transfer Agent Protected Podcasts Auto-Upload Sermons Upload via FTP Upload via Dropbox Picasa ABOUT US The largest and most trusted library of audio sermons from conservative churches and ministries worldwide. Our Services | Articles of Faith Broadcast With Us Earn SA COINS! Advertising | Local Ads CONTACT email@example.com Privacy Policy | Support Us | Stories


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Area > Bermondsey > Melior St
Melior St
8 Melior Street Bermondsey, SE1 3QP
Located a stone's throw from London Bridge station. Melior St is a small cosy venue with a lovely minimalist and industrial look and feel. If you want to stay for the evening they offer some fantastic homemade food with their own craft beer by 'Lost Rivers Brewery' named after the historical rivers that run under lost London.
We recommend the chef's £5 sandwich deal for lunch.
No external food or drink in this venue.
What's on offer
- Dog Friendly
- Kitchen
- Wifi
- Tea & Coffee
- Events
- Bar
- Busy Evenings
- Lunch
- Private Hire
- Stay For Dinner
- Cocktails
- Quiet Atmosphere
- Craft Beers
- Breakfast
Getting here
Show your booking on arrival and ask the manager on duty to take you to your desk.
8 Melior Street, Bermondsey, London, SE1 3QP
AndCo opening hours
- Monday10:00 AM – 05:00 PM
- Tuesday10:00 AM – 05:00 PM
- Wednesday10:00 AM – 05:00 PM
- Thursday10:00 AM – 05:00 PM
- Friday10:00 AM – 05:00 PM


text:
[email protected]
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Come meet us at The Special Operations Forces Industry Conference (SOFIC) and see a live demonstration of our tactical breaching solutions.
The Special Operations Forces Industry Conference (SOFIC) is the premier conference for the SOF community to interact with industry and to collaborate on the challenges, initiatives, and way-ahead in delivering the most cutting-edge capabilities into the hands of SOF operators.
Our booth number is 1818 under the Israeli Ministry of Defense (SIBAT) pavilion.
Please let us know if you would like to schedule a meeting at [email protected] and we will set a live demonstration just for you.
Date: 21 – 23 May 2019
Location: Tampa Convention Center | TAMPA, FL


text:
§ Mrs. Joyce Butler
asked the Secretary of State for Education and Science if she will list the consumer protection bodies she consults when she is seeking the opinion of consumers on matters covered by her Department.
§ Mrs. Thatcher
My Department is not concerned with the sale or purchase of goods or services in the commonly accepted sense. I consult local education authorities and other interested bodies in education matters as I judge appropriate.


text:
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GR-12 Hott +3XG +3A + Vario
Product Details
With the GRAUPNER HoTT 2.4 GHz technology, the receiver has a new Hopping Telemetry Transmission high-frequency unit with state-of-the-art components and software. Without add-on sensors, the parameters receiver voltage and temperature, signal strength, altitude and vario-information are transmitted.
3-axis gyro:
Stabilization of the model aircraft in difficult wind conditions for up to 3 axes
Natural flight behaviour thanks to proportional gyro offset adjustment
Very good stabilization for tight flight figures
Thanks to the 3-axis gyro, even aerobatic models that are difficult to master can be flown very comfortably; simplifying aerobatic flight extremely
Flight figures can be flown very tightly
Simple adjustment of gyro assignment
Adjustment of the parameters via the HoTT telemetry
Altitude sensor for vario-function and altitude
Temperature range : -15 ... +70 °C
Antenna length : 145 mm
All-up weight, approx.: 8 g
Frequency : 2400 ... 2483.5 MHz
Range approx. : 2000 m
Dimensions (LxWxH): 36 x 21 x 10 mm
Modulation: 2.4 GHz FHSS
Charging rate : 70 mA
Operating voltage : (2,5) 3,6 ... 8,4 V
|Article reference
Some alternatives
- GR-12 HOTT receiver€58.15 €48.06
- GR-12SH+ HoTT€31.50 €26.03
- GR-24 PRO receiver 3 Axis Gyro€161.80 €133.72
- GR-12L light Receiver€38.01 €31.41
- GR-18 +3xG+3A + Vario HoTT€127.50 €105.37
- GR-32 HOTT receiver€119.90 €99.09
- GR-24 HOTT receiver€96.90 €80.08
- GR-16 HOTT receiver€67.80 €56.03
Spare Parts
- RX Antenne 300mm HOTT€5.95 €4.92
- RX Antenne 2.4Ghz 150mm HOTT€4.95 €4.09


text:
PR-39, a proline/arginine-rich peptide antibiotic, has been purified from pig intestine and later shown to originate in the bone marrow. Intending to isolate a clone for a human counterpart to PR-39, we synthesized a PCR probe derived from the PR-39 gene. However, when this probe was used to screen a human bone marrow cDNA library, eight clones were obtained with information for another putative human peptide antibiotic, designated FALL-39 after the first four residues. FALL-39 is a 39-residue peptide lacking cysteine and tryptophan. All human peptide antibiotics previously isolated (or predicted) belong to the defensin family and contain three disulfide bridges. The clone for prepro-FALL-39 encodes a cathelin-like precursor protein with 170 amino acid residues. We have postulated a dibasic processing site for the mature FALL-39 and chemically synthesized the putative peptide. In basal medium E, synthetic FALL-39 was highly active against Escherichia coli and Bacillus megaterium. Residues 13-34 in FALL-39 can be predicted to form a perfect amphiphatic helix, and CD spectra showed that medium E induced 30% helix formation in FALL-39. RNA blot analyses disclosed that the gene for FALL-39 is expressed mainly in human bone marrow and testis.
The plant-derived steroid, digoxin, a specific inhibitor of Na,K-ATPase, has been used for centuries in the treatment of heart disease. Recent studies demonstrate the presence of a digoxin analog, ouabain, in mammalian tissue, but its biological role has not been elucidated. Here, we show in renal epithelial cells that ouabain, in doses causing only partial Na,K-ATPase inhibition, acts as a biological inducer of regular, low-frequency intracellular calcium ([Ca2+](i)) oscillations that elicit activation of the transcription factor, NF-KB. Partial inhibition of Na,K-ATPase using low extracellular K+ and depolarization of cells did not have these effects. Incubation of cells in Ca2+-free media, inhibition of voltage-gated calcium channels, inositol triphosphate receptor antagonism, and redistribution of actin to a thick layer adjacent to the plasma membrane abolished [Ca2+](i) oscillations, indicating that they were caused by a concerted action of inositol triphosphate receptors and capacitative calcium entry via plasma membrane channels. Blockade of ouabain-induced [C-a2+](i) oscillations prevented activation of NF-kappaB. The results demonstrate a new mechanism for steroid signaling via plasma membrane receptors and underline a novel role for the steroid hormone, ouabain, as a physiological inducer of [Ca2+](i) oscillations involved in transcriptional regulation in mammalian cells.
We study the performance of stochastic local search algorithms for random instances of the K-satisfiability (K-SAT) problem. We present a stochastic local search algorithm, ChainSAT, which moves in the energy landscape of a problem instance by never going upwards in energy. ChainSAT is a focused algorithm in the sense that it focuses on variables occurring in unsatisfied clauses. We show by extensive numerical investigations that ChainSAT and other focused algorithms solve large K-SAT instances almost surely in linear time, up to high clause-to-variable ratios a; for example, for K = 4 we observe linear-time performance well beyond the recently postulated clustering and condensation transitions in the solution space. The performance of ChainSAT is a surprise given that by design the algorithm gets trapped into the first local energy minimum it encounters, yet no such minima are encountered. We also study the geometry of the solution space as accessed by stochastic local search algorithms.
Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins over-expressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of a-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.
MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca2+ it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. TheMUC2-N aggregates were dissolved by removing Ca2+ and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion.
Oxides with the cubic fluorite structure, e.g., ceria (CeO2), are known to be good solid electrolytes when they are doped with cations of lower valence than the host cations. The high ionic conductivity of doped ceria makes it an attractive electrolyte for solid oxide fuel cells, whose prospects as an environmentally friendly power source are very promising. In these electrolytes, the current is carried by oxygen ions that are transported by oxygen vacancies, present to compensate for the lower charge of the dopant cations. Ionic conductivity in ceria is closely related to oxygen-vacancy formation and migration properties. A clear physical picture of the connection between the choice of a dopant and the improvement of ionic conductivity in ceria is still lacking. Here we present a quantum-mechanical first-principles study of the influence of different trivalent impurities on these properties. Our results reveal a remarkable correspondence between vacancy properties at the atomic level and the macroscopic ionic conductivity. The key parameters comprise migration barriers for bulk diffusion and vacancy-dopant interactions, represented by association (binding) energies of vacancy-dopant clusters. The interactions can be divided into repulsive elastic and attractive electronic parts. In the optimal electrolyte, these parts should balance. This finding offers a simple and clear way to narrow the search for superior dopants and combinations of dopants. The ideal dopant should have an effective atomic number between 61 (Pm) and 62 (Sm), and we elaborate that combinations of Nd/Sm and Pr/Gd show enhanced ionic conductivity, as compared with that for each element separately.
Ca shows an interesting high-pressure phase transformation sequence, but, despite similar physical properties at high pressure and affinity in the electronic structure with its neighbors in the periodic table, no complex phase has been identified for Ca so far. We predict an incommensurate high-pressure phase of Ca from first principle calculations and describe a procedure of estimating incommensurate structure parameters by means of electronic structure calculations for periodic crystals. Thus, by using the ab initio technique for periodic structures, one can get not only reliable information about the electronic structure and structural parameters of an incommensurate phase, but also identify and predict such phases in new elements.
Expanding the repertoire of molecularly diverse neurons in the human nervous system is paramount to characterizing the neuronal networks that underpin sensory processing. Defining neuronal identities is particularly timely in the human olfactory system, whose structural differences from nonprimate macrosmatic species have recently gained momentum. Here, we identify clusters of bipolar neurons in a previously unknown outer "shell" domain of the human olfactory tract, which express secretagogin, a cytosolic Ca2+ binding protein. These "shell" neurons are wired into the olfactory circuitry because they can receive mixed synaptic inputs. Unexpectedly, secretagogin is often coexpressed with polysialylated-neural cell adhesion molecule, beta-III-tubulin, and calretinin, suggesting that these neurons represent a cell pool that might have escaped terminal differentiation into the olfactory circuitry. We hypothesized that secretagogin-containing "shell" cells may be eliminated from the olfactory axis under neurodegenerative conditions. Indeed, the density, but not the morphological or neurochemical integrity, of secretagogin-positive neurons selectively decreases in the olfactory tract in Alzheimer's disease. In conclusion, secretagogin identifies a previously undescribed cell pool whose cytoarchitectonic arrangements and synaptic connectivity are poised to modulate olfactory processing in humans.
Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
The current best membrane-protein topology-prediction methods are typically based on sequence statistics and contain hundreds of parameters that are optimized on known topologies of membrane proteins. However, because the insertion of transmembrane helices into the membrane is the outcome of molecular interactions among protein, lipids and water, it should be possible to predict topology by methods based directly on physical data, as proposed >20 years ago by Kyte and Doolittle. Here, we present two simple topology-prediction methods using a recently published experimental scale of position-specific amino acid contributions to the free energy of membrane insertion that perform on a par with the current best statistics-based topology predictors. This result suggests that prediction of membrane-protein topology and structure directly from first principles is an attainable goal, given the recently improved understanding of peptide recognition by the translocon.
A significant improvement in molecular hydrogen uptake properties is revealed by our ab initio calculations for Li-decorated metal-organic framework 5. We have found that two Li atoms are strongly adsorbed on the surfaces of the six-carbon rings, one on each side, carrying a charge of +0.9e per Li atom. Each Li can cluster three H-2 molecules around itself with a binding energy of 12 kJ (mol H-2)(-1). Furthermore, we show from ab initio molecular dynamics simulations with a hydrogen loading of 18 H2 per formula unit that a hydrogen uptake of 2.9 wt % at 200 K and 2.0 wt % at 300 K is achievable. To our knowledge, this is the highest hydrogen storage capacity reported for metal-organic framework 5 under such thermodynamic conditions.
The most characteristic feature of domestic animals is their change in behavior associated with selection for tameness. Here we show, using high-resolution brain magnetic resonance imaging in wild and domestic rabbits, that domestication reduced amygdala volume and enlarged medial prefrontal cortex volume, supporting that areas driving fear have lost volume while areas modulating negative affect have gained volume during domestication. In contrast to the localized gray matter alterations, white matter anisotropy was reduced in the corona radiata, corpus callosum, and the subcortical white matter. This suggests a compromised white matter structural integrity in projection and association fibers affecting both afferent and efferent neural flow, consistent with reduced neural processing. We propose that compared with their wild ancestors, domestic rabbits are less fearful and have an attenuated flight response because of these changes in brain architecture.
During invasion, cells breach basement membrane (BM) barriers with actin-rich protrusions. It remains unclear, however, whether actin polymerization applies pushing forces to help break through BM, or whether actin filaments play a passive role as scaffolding for targeting invasive machinery. Here, using the developmental event of anchor cell (AC) invasion in Caenorhabditis elegans, we observe that the AC deforms the BM and underlying tissue just before invasion, exerting forces in the tens of nanonewtons range. Deformation is driven by actin polymerization nucleated by the Arp2/3 complex and its activators, whereas formins and cross-inkers are dispensable. Delays in invasion upon actin regulator loss are not caused by defects in AC polarity, trafficking, or secretion, as appropriate markers are correctly localized in the AC even when actin is reduced and invasion is disrupted. Overall force production emerges from this study as one of the main tools that invading cells use to promote BM disruption in C. elegans.
Observing and controlling molecular motion and in particular rotation are fundamental topics in physics and chemistry. To initiate ultrafast rotation, one needs a way to transfer a large angular momentum to the molecule. As a showcase, this was performed by hard X-ray C1s ionization of carbon monoxide accompanied by spinning up the molecule via the recoil "kick" of the emitted fast photoelectron. To visualize this molecular motion, we use the dynamical rotational Doppler effect and an X-ray "pump-probe" device offered by nature itself: the recoil-induced ultrafast rotation is probed by subsequent Auger electron emission. The time information in our experiment originates from the natural delay between the C1s photoionization initiating the rotation and the ejection of the Auger electron. From a more general point of view, time-resolved measurements can be performed in two ways: either to vary the "delay" time as in conventional time-resolved pump-probe spectroscopy and use the dynamics given by the system, or to keep constant delay time and manipulate the dynamics. Since in our experiment we cannot change the delay time given by the core-hole lifetime tau, we use the second option and control the rotational speed by changing the kinetic energy of the photoelectron. The recoil-induced rotational dynamics controlled in such a way is observed as a photon energy-dependent asymmetry of the Auger line shape, in full agreement with theory. This asymmetry is explained by a significant change of the molecular orientation during the core-hole lifetime, which is comparable with the rotational period.
The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a four-stage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that similar to 6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interestingly, the majority of these genes are down-regulated, linking malignant transformation to dedifferentiation. The up-regulated genes are mainly components that control cellular proliferation, whereas the down-regulated genes consist of proteins exposed on or secreted from the cell surface. As many of the identified gene products control basic cellular functions that are defective in cancers, the data provide candidates for follow-up studies to investigate their functional roles in tumor formation. When we further compared the expression levels of four of the identified proteins in clinical cancer cohorts, similar differences were observed between benign and cancer cells, as in the cell model. This shows that this comprehensive demonstration of the molecular changes underlying malignant transformation is a relevant model to study the process of tumor formation.
It is well known that prokaryotic life can withstand extremes of temperature, pH, pressure, and radiation. Little is known about the proliferation of prokaryotic life under conditions of hyperacceleration attributable to extreme gravity, however. We found that living organisms can be surprisingly proliferative during hyperacceleration. In tests reported here, a variety of microorganisms, including Gram-negative Escherichia coli, Paracoccus denitrificans, and Shewanella amazonensis; Gram-positive Lactobacillus delbrueckii; and eukaryotic Saccharomyces cerevisiae, were cultured while being subjected to hyperaccelerative conditions. We observed and quantified robust cellular growth in these cultures across a wide range of hyperacceleration values. Most notably, the organisms P. denitrificans and E. coli were able to proliferate even at 403,627 × g. Analysis shows that the small size of prokaryotic cells is essential for their proliferation under conditions of hyperacceleration. Our results indicate that microorganisms cannot only survive during hyperacceleration but can display such robust proliferative behavior that the habitability of extraterrestrial environments must not be limited by gravity.
Failures of government policies often provoke opposite reactions from citizens; some call for a reversal of the policy, whereas others favor its continuation in stronger form. We offer an explanation of such polarization, based on a natural bimodality of preferences in political and economic contexts and consistent with Bayesian rationality.
Striatal spiny projection neurons (SPNs) receive convergent excitatory synaptic inputs from the cortex and thalamus. Activation of spatially clustered and temporally synchronized excitatory inputs at the distal dendrites could trigger plateau potentials in SPNs. Such supralinear synaptic integration is crucial for dendritic computation. However, how plateau potentials interact with subsequent excitatory and inhibitory synaptic inputs remains unknown. By combining computational simulation, two-photon imaging, optogenetics, and dual-color uncaging of glutamate and GABA, we demonstrate that plateau potentials can broaden the spatiotemporal window for integrating excitatory inputs and promote spiking. The temporal window of spiking can be delicately controlled by GABAergic inhibition in a cell-type–specific manner. This subtle inhibitory control of plateau potential depends on the location and kinetics of the GABAergic inputs and is achieved by the balance between relief and reestablishment of NMDA receptor Mg2+ block. These findings represent a mechanism for controlling spatiotemporal synaptic integration in SPNs.
Water oxidation catalysts are essential components of light-driven water splitting systems, which could convert water to H-2 driven by solar radiation (H2O + h nu -> 1/2O(2) + H-2). The oxidation of water (H2O -> 1/2O(2) + 2H(+) + 2e(-)) provides protons and electrons for the production of dihydrogen (2H(+) + 2e(-) -> H-2), a clean-burning and high-capacity energy carrier. One of the obstacles now is the lack of effective and robust water oxidation catalysts. Aiming at developing robust molecular Ru-bda (H(2)bda = 2,2'-bipyridine-6,6'-dicarboxylic acid) water oxidation catalysts, we carried out density functional theory studies, correlated the robustness of catalysts against hydration with the highest occupied molecular orbital levels of a set of ligands, and successfully directed the synthesis of robust Ru-bda water oxidation catalysts. A series of mononuclear ruthenium complexes [Ru(bda)L-2] (L = pyridazine, pyrimidine, and phthalazine) were subsequently synthesized and shown to effectively catalyze Ce-IV-driven [Ce-IV = Ce(NH4)(2()NO3)(6)] water oxidation with high oxygen production rates up to 286 s(-1) and high turnover numbers up to 55,400.
Working memory capacity, the maximum number of items that we can transiently store in working memory, is a good predictor of our general cognitive abilities. Neural activity in both dorsolateral prefrontal cortex and posterior parietal cortex has been associated with memory retention during visuospatial working memory tasks. The parietal cortex is thought to store the memories. However, the role of the dorsolateral prefrontal cortex, a top-down control area, during pure information retention is debated, and the mechanisms regulating capacity are unknown. Here, we propose that a major role of the dorsolateral prefrontal cortex in working memory is to boost parietal memory capacity. Furthermore, we formulate the boosting mechanism computationally in a biophysical cortical microcircuit model and derive a simple, explicit mathematical formula relating memory capacity to prefrontal and parietal model parameters. For physiologically realistic parameter values, lateral inhibition in the parietal cortex limits mnemonic capacity to a maximum of 2-7 items. However, at high loads inhibition can be counteracted by excitatory prefrontal input, thus boosting parietal capacity. Predictions from the model were confirmed in an fMRI study. Our results show that although memories are stored in the parietal cortex, interindividual differences in memory capacity are partly determined by the strength of prefrontal top-down control. The model provides a mechanistic framework for understanding top-down control of working memory and specifies two different contributions of prefrontal and parietal cortex to working memory capacity.
CDK8 (cyclin-dependent kinase 8), along with CycC, Med12, and Med13, form a repressive module (the Cdk8 module) that prevents RNA polymerase II (pol II) interactions with Mediator. Here, we report that the ability of the Cdk8 module to prevent pol II interactions is independent of the Cdk8-dependent kinase activity. We use electron microscopy and single-particle reconstruction to demonstrate that the Cdk8 module forms a distinct structural entity that binds to the head and middle region of Mediator, thereby sterically blocking interactions with pol II.
Two one-sided conservation form difference approximations to a scalar one-dimensional convex conservation law are introduced. These are respectively of first- and second-order accuracy and each has the minimum possible band-width. They are nonlinearly stable, they converge only to solutions satisfying the entropy condition, and they have sharp monotone profiles. No such stable approximation of order higher than two is possible. Dimensional splitting algorithms are constructed and used to approximate the small-disturbance equation of transonic flow. These approximations are also nonlinearly stable and without nonphysical limit solutions.
Reported here is direct imaging (and diffraction) by using 4D ultrafast electron microscopy (UEM) with combined spatial and temporal resolutions. In the first phase of UEM, it was possible to obtain snapshot images by using timed, single-electron packets; each packet is free of space-charge effects. Here, we demonstrate the ability to obtain sequences of snapshots ("movies") with atomic-scale spatial resolution and ultrashort temporal resolution. Specifically, it is shown that ultrafast metal-insulator phase transitions can be studied with these achieved spatial and temporal resolutions. The diffraction (atomic scale) and images (nanometer scale) we obtained manifest the structural phase transition with its characteristic hysteresis, and the time scale involved (100 fs) is now studied by directly monitoring coordinates of the atoms themselves.
MHC-I epitope presentation to CD8(+) T cells is directly dependent on peptide loading and selection during antigen processing. However, the exact molecular bases underlying peptide selection and binding by MHC-I remain largely unknown. Within the peptide-loading complex, the peptide editor tapasin is key to the selection of MHC-I-bound peptides. Here, we have determined an ensemble of crystal structures of MHC-I in complex with the peptide exchange-associated dipeptide GL, as well as the tapasin-associated scoop loop, alone or in combination with candidate epitopes. These results combined with mutation analyses allow us to propose a molecular model underlying MHC-I peptide selection by tapasin. The N termini of bound peptides most probably bind first in the N-terminal and middle region of the MHC-I peptide binding cleft, upon which the peptide C termini are tested for their capacity to dislodge the tapasin scoop loop from the F pocket of the MHC-I cleft. Our results also indicate important differences in peptide selection between different MHC-I alleles.
In palladium-catalyzed alkylations of allylic acetates with malonate as nucleophile, catalysts with oxazoline ligands bearing hydroxymethyl substituents in 4-position have been shown by density functional theory computations to undergo a conformational change on nucleophilic attack, which is accompanied by reduction of Pd(II) to Pd(0). The conformations of the Pd(0) complexes were shown to be governed by the presence of a hydrogen bond with the metal center acting as a hydrogen bond acceptor. The conformational change, which is absent in catalysts with O-alkylated analogs, largely affects the enantioselectivity of the catalytic process. This process is a previously uninvestigated example of where this type of weak hydrogen bond has been shown to influence the stereochemistry of a chemical reaction.
Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.
The large vascular meristem of poplar trees with its highly organized secondary xylem enables the boundaries between different developmental zones to be easily distinguished. This property of wood-forming tissues allowed us to determine a unique tissue-specific transcript profile for a well defined developmental gradient. RNA was prepared from different developmental stages of xylogenesis for DNA microarray analysis by using a hybrid aspen unigene set consisting of 2,995 expressed sequence tags. The analysis revealed that the genes encoding lignin and cellulose biosynthetic enzymes, as well as a number of transcription factors and other potential regulators of xylogenesis, are under strict developmental stage-specific transcriptional regulation.
Biological organization depends on a sensitive balance of noncovalent interactions, in particular also those involving interactions between ions. Ion-pairing is qualitatively described by the law of "matching water affinities." This law predicts that cations and anions (with equal valence) form stable contact ion pairs if their sizes match. We show that this simple physical model fails to describe the interaction of cations with (molecular) anions of weak carboxylic acids, which are present on the surfaces of many intra- and extracellular proteins. We performed molecular simulations with quantitatively accurate models and observed that the order K(+) < Na(+) < Li(+) of increasing binding affinity with carboxylate ions is caused by a stronger preference for forming weak solvent-shared ion pairs. The relative insignificance of contact pair interactions with protein surfaces indicates that thermodynamic stability and interactions between proteins in alkali salt solutions is governed by interactions mediated through hydration water molecules.
Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to similar to 30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.
Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1. Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain-or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.
We show that the three most relevant magnetic properties (magnetic moment, critical temperature, and interlayer exchange coupling) of metallic multilayers can be reproduced with good accuracy by first principles theory, provided that the picture of atomically sharp interfaces is abandoned and one allows instead for both interface alloying and interface roughness. The interface of a metallic multilayer (exemplified by the Fe/V system) is demonstrated to, at best, have interdiffusion essentially over two to three atomic layers on each side of the interface. Our conclusions are the result of combining experimental work with theoretical modeling, and we argue that this approach is the best avenue to obtain accurate information about the interface quality of metallic multilayers.
Despite its long history of use and abuse in human culture, the molecular basis for alcohol action in the brain is poorly understood. The recent determination of the atomic-scale structure of GLIC, a prokaryotic member of the pentameric ligand-gated ion channel (pLGIC) family, provides a unique opportunity to characterize the structural basis for modulation of these channels, many of which are alcohol targets in brain. We observed that GLIC recapitulates bimodal modulation by n-alcohols, similar to some eukaryotic pLGICs: methanol and ethanol weakly potentiated proton-activated currents in GLIC, whereas n-alcohols larger than ethanol inhibited them. Mapping of residues important to alcohol modulation of ionotropic receptors for glycine, γ-aminobutyric acid, and acetylcholine onto GLIC revealed their proximity to transmembrane cavities that may accommodate one or more alcohol molecules. Site-directed mutations in the pore-lining M2 helix allowed the identification of four residues that influence alcohol potentiation, with the direction of their effects reflecting α-helical structure. At one of the potentiation-enhancing residues, decreased side chain volume converted GLIC into a highly ethanol-sensitive channel, comparable to its eukaryotic relatives. Covalent labeling of M2 positions with an alcohol analog, a methanethiosulfonate reagent, further implicated residues at the extracellular end of the helix in alcohol binding. Molecular dynamics simulations elucidated the structural consequences of a potentiation-enhancing mutation and suggested a structural mechanism for alcohol potentiation via interaction with a transmembrane cavity previously termed the "linking tunnel." These results provide a unique structural model for independent potentiating and inhibitory interactions of n-alcohols with a pLGIC family member.
According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-β (Aβ) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Aβ assemblies is accompanied by a conformational change toward a high content of β-structure. Here, we report the solution structure of Aβ(1–40) in complex with the phage-display selected affibody protein ZAβ3, a binding protein of nanomolar affinity. Bound Aβ(1–40) features a β-hairpin comprising residues 17–36, providing the first high-resolution structure of Aβ in β conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar Aβ. ZAβ3 stabilizes the β-sheet by extending it intermolecularly and by burying both of the mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity. Consequently, ZAβ3 acts as a stoichiometric inhibitor of Aβ fibrillation. The selected Aβ conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates.
There is an increasing demand for biotech-based production of recombinant proteins for use as pharmaceuticals in the food and feed industry and in industrial applications. Yeast Saccharomyces cerevisiae is among preferred cell factories for recombinant protein production, and there is increasing interest in improving its protein secretion capacity. Due to the complexity of the secretory machinery in eukaryotic cells, it is difficult to apply rational engineering for construction of improved strains. Here we used highthroughput microfluidics for the screening of yeast libraries, generated by UV mutagenesis. Several screening and sorting rounds resulted in the selection of eight yeast clones with significantly improved secretion of recombinant α-amylase. Efficient secretion was genetically stable in the selected clones. We performed wholegenome sequencing of the eight clones and identified 330 mutations in total. Gene ontology analysis of mutated genes revealed many biological processes, including some that have not been identified before in the context of protein secretion. Mutated genes identified in this study can be potentially used for reverse metabolic engineering, with the objective to construct efficient cell factories for protein secretion. The combined use of microfluidics screening and whole-genome sequencing to map the mutations associated with the improved phenotype can easily be adapted for other products and cell types to identify novel engineering targets, and this approach could broadly facilitate design of novel cell factories.
The core extends from the depth of 2,900 km to the center of the Earth and is composed mainly of an iron-rich alloy with nickel, with 10% of the mass comprised of lighter elements like hydrogen, but the exact composition is uncertain. We present a quantum mechanical first-principles study of the dynamical stability of FeH phases and their phonon densities of states at high pressure. Our free-energy calculations reveal a phonon-driven stabilization of dhcp FeH at low pressures, thus resolving the present contradiction between experimental observations and theoretical predictions. Calculations reveal a complex phase diagram for FeH under pressure with a dhcp -> hcp -> fcc sequence of structural transitions.
Prostaglandins (PG) are bioactive lipids produced from arachidonic acid via the action of cyclooxygenases and terminal PG synthases. Microsomal prostaglandin E synthase 1 (MPGES1) constitutes an inducible glutathione-dependent integral membrane protein that catalyzes the oxidoreduction of cyclooxygenase derived PGH(2) into PGE(2). MPGES1 has been implicated in a number of human diseases or pathological conditions, such as rheumatoid arthritis, fever, and pain, and is therefore regarded as a primary target for development of novel antiinflammatory drugs. To provide a structural basis for insight in the catalytic mechanism, we determined the structure of MPGES1 in complex with glutathione by electron crystallography from 2D crystals induced in the presence of phospholipids. Together with results from site-directed mutagenesis and activity measurements, we can thereby demonstrate the role of specific amino acid residues. Glutathione is found to bind in a U-shaped conformation at the interface between subunits in the protein trimer. It is exposed to a site facing the lipid bilayer, which forms the specific environment for the oxidoreduction of PGH(2) to PGE(2) after displacement of the cytoplasmic half of the IN-terminal transmembrane helix. Hence, insight into the dynamic behavior of MPGES1 and homologous membrane proteins in inflammation and detoxification is provided.
The activation of plastic deformation mechanisms determines the mechanical behavior of crystalline materials. However, the complexity of plastic deformation and the lack of a unified theory of plasticity have seriously limited the exploration of the full capacity of metals. Current efforts to design high-strength structural materials in terms of stacking fault energy have not significantly reduced the laborious trial and error works on basic deformation properties. To remedy this situation, here we put forward a comprehensive and transparent theory for plastic deformation of face-centered cubic metals. This is based on a microscopic analysis that, without ambiguity, reveals the various deformation phenomena and elucidates the physical fundaments of the currently used phenomenological correlations. We identify an easily accessible single parameter derived from the intrinsic energy barriers, which fully specifies the potential diversity of metals. Based entirely on this parameter, a simple deformation mode diagram is shown to delineate a series of convenient design criteria, which clarifies a wide area of material functionality by texture control.
Transmembrane helices are generally believed to insert into membranes based on their hydrophobicity. Nevertheless, there are important exceptions where polar residues have great functional importance, for instance the S4 helix of voltage-gated ion channels. It has been shown experimentally that insertion can be accomplished by hydrophobic counterbalance, predicting an arginine insertion cost of only 2.5 kcal/mol, compared with 14.9 kcal/mol in cyclohexane. Previous simulations of pure bilayers have produced values close to the pure hydrocarbon, which has lead to spirited discussion about the experimental conditions. Here, we have performed computer simulations of models better mimicking biological membranes by explicitly including protein helices at mass fractions from 15% to 55%, as well as an actual translocon. This has a striking effect on the solvation free energy of arginine. With some polar residues present, the solvation cost comes close to experimental observation at approximately 30% mass fraction, and negligible at 40%. In the presence of a translocon in the membrane, the cost of inserting arginine next to the lateral gate can be as low as 3-5 kcal/mol. The effect is mainly due to the extra helices making it easier to retain hydration water. These results offer a possible explanation for the discrepancy between the in vivo hydrophobicity scale and computer simulations and highlight the importance of the high protein contents in membranes. Although many membrane proteins are stable in pure bilayers, such simplified models might not be sufficiently accurate for insertion of polar or charged residues in biological membranes.
The composition and the structure of the Earth's solid inner core are still unknown. Iron is accepted to be the main component of the core. Lately, the body-centered cubic (bcc) phase of iron was suggested to be present in the inner core, although its stability at core conditions is still in discussion. The higher density of pure iron compared with that of the Earth's core indicates the presence of light element(s) in this region, which could be responsible for the stability of the bcc phase. However, so far, none of the proposed composition models were in full agreement with seismic observations. The solubility of magnesium in hexagonal Fe has been found to increase significantly with increasing pressure, suggesting that Mg can also be an important element in the core. Here, we report a first-principles density functional study of bcc Fe-Mg alloys at core pressures and temperatures. We show that at core conditions, 5-10 atomic percent Mg stabilizes the bcc Fe both dynamically and thermodynamically. Our calculated density, elastic moduli, and sound velocities of bcc Fe-Mg alloys are consistent with those obtained from seismology, indicating that the bcc-structured Fe-Mg alloy is a possible model for the Earth's inner core.
Some of the most remarkable materials in nature are made from proteins. The properties of these materials are closely connected to the hierarchical assembly of the protein building blocks. In this perspective, amyloid-like protein nanofibrils (PNFs) have emerged as a promising foundation for the synthesis of novel bio-based materials for a variety of applications. Whereas recent advances have revealed the molecular structure of PNFs, the mechanisms associated with fibril-fibril interactions and their assembly into macroscale structures remain largely unexplored. Here, we show that whey PNFs can be assembled into microfibers using a flow-focusing approach and without the addition of plasticizers or cross-linkers. Microfocus small-angle X-ray scattering allows us to monitor the fibril orientation in the microchannel and compare the assembly processes of PNFs of distinct morphologies. We find that the strongest fiber is obtained with a sufficient balance between ordered nanostructure and fibril entanglement. The results provide insights in the behavior of protein nanostructures under laminar flow conditions and their assembly mechanism into hierarchical macroscopic structures.
We demonstrate the use of surface-enhanced Raman spectroscopy (SERS) as an excellent tool for identifying the binding site of small molecules on a therapeutically important protein. As an example, we show the specific binding of the common antihypertension drug felodipine to the oncogenic Aurora A kinase protein via hydrogen bonding interactions with Tyr-212 residue to specifically inhibit its activity. Based on SERS studies, molecular docking, molecular dynamics simulation, biochemical assays, and point mutation-based validation, we demonstrate the surface-binding mode of this molecule in two similar hydrophobic pockets in the Aurora A kinase. These binding pockets comprise the same unique hydrophobic patches that may aid in distinguishing human Aurora A versus human Aurora B kinase in vivo. The application of SERS to identify the specific interactions between small molecules and therapeutically important proteins by differentiating competitive and noncompetitive inhibition demonstrates its ability as a complementary technique. We also present felodipine as a specific inhibitor for oncogenic Aurora A kinase. Felodipine retards the rate of tumor progression in a xenografted nude mice model. This study reveals a potential surface pocket that may be useful for developing small molecules by selectively targeting the Aurora family kinases.
Metallization of pure solid hydrogen is of great interest, not least because it could lead to high-temperature superconductivity, but it continues to be an elusive goal because of great experimental challenges. Hydrogen-rich materials, in particular, CH4, SiH4, and GeH4, provide an opportunity to study related phenomena at experimentally achievable pressures, and they too are expected to be high-temperature superconductors. Recently, the emergence of a metallic phase has been observed in silane for pressures just above 60 GPa. However, some uncertainty exists about the crystal structure of the discovered metallic phase. Here, we show by way of elimination, that a single structure that possesses all of the required characteristics of the experimentally observed metallic phase of silane from a pool of plausible candidates can be identified. Our density functional theory and GW calculations show that a structure with space group P4/nbm is metallic at pressures > 60 GPa. Based on phonon calculations, we furthermore demonstrate that the P4/nbm structure is dynamically stable at > 43 GPa and becomes the ground state at 97 GPa when zero-point energy contributions are considered. These findings could lead the way for further theoretical analysis of metallic phases of hydrogen-rich materials and stimulate experimental studies.
The long-standing prediction that hydrogen can assume a metallic state under high pressure, combined with arguments put forward more recently that this state might even be superconducting up to high temperatures, continues to spur tremendous research activities toward the experimental realization of metallic hydrogen. These efforts have however so far been impeded by the enormous challenges associated with the exceedingly large required pressure. Hydrogen-dense materials, of the MH4 form ( where M can be, e. g., Si, Ge, or Sn) or of the MH3 form ( with M being, e. g., Al, Sc, Y, or La), allow for the rather exciting opportunity to carry out a proxy study of metallic hydrogen and associated high-temperature superconductivity at pressures within the reach of current techniques. At least one experimental report indicates that a superconducting state might have been observed already in SiH4, and several theoretical studies have predicted superconductivity in pressurized hydrogen-rich materials; however, no systematic dependence on the applied pressure has yet been identified so far. In the present work, we have used first-principles methods in an attempt to predict the superconducting critical temperature (T-c) as a function of pressure ( P) for three metal-hydride systems of the MH3 form, namely ScH3, YH3, and LaH3. By comparing the obtained results, we are able to point out a general trend in the T-c-dependence on P. These gained insights presented here are likely to stimulate further theoretical studies of metallic phases of hydrogen-dense materials and should lead to new experimental investigations of their superconducting properties.
New important applications of copper metal, e.g., in the areas of hydrogen production, fuel cell operation, and spent nuclear fuel disposal, require accurate knowledge of the physical and chemical properties of stable and metastable copper compounds. Among the copper(I) compounds with oxygen and hydrogen, cuprous oxide Cu(2)O is the only one stable and the best studied. Other such compounds are less known (CuH) or totally unknown (CuOH) due to their instability relative to the oxide. Here we combine quantum-mechanical calculations with experimental studies to search for possible compounds of monovalent copper. Cuprous hydride (CuH) and cuprous hydroxide (CuOH) are proved to exist in solid form. We establish the chemical and physical properties of these compounds, thereby filling the existing gaps in our understanding of hydrogen- and oxygen-related phenomena in Cu metal.
The complex and unusual high-pressure phase transition of III-A (i.e. Al, Ga, and In) metals have been investigated in the last several decades because of their interesting periodic table position between the elements having metallic and covalent bonding. Our present first principles-based electronic structure calculations and experimental investigation have revealed the unusual distortion in face-centered cubic (f.c.c.) phase of the heavy element thallium (Tl) induced by the high pressure. We have predicted body-centered tetragonal (b.c.t) phase at 83 GPa using an evolutionary algorithm coupled with ab initio calculations, and this prediction has been confirmed with a slightly distorted parameter (√2 x a - c)/c lowered by 1% using an angle-dispersive X-ray diffraction technique. The density functional theory (DFT)-based calculations suggest that s-p mixing states and the valence-core overlapping of 6s and 5d states play the most important roles for the phase transitions along the pathway h.c.p → f.c.c. → b.c.t.
First principles-based electronic structure calculations of super-hard iron tetraboride (FeB4) under high pressure have been undertaken in this study. Starting with a "conventional" superconducting phase of this material under high pressure leads to an unexpected phase transition toward a semiconducting one. This transition occurred at 53.7 GPa, and this pressure acts as a demarcation between two distinct crystal symmetries, metallic orthorhombic and semiconducting tetragonal phases, with Pnnm and I4(1)/acd space groups, respectively. In this work, the electron-phonon coupling-derived superconducting T-c has been determined up to 60 GPa and along with optical band gap variation with increasing pressure up to 300 GPa. The dynamic stability has been confirmed by phonon dispersion calculations throughout this study.
The vertebrate central nervous system is organized in modules that independently execute sophisticated tasks. Such modules are flexibly controlled and operate with a considerable degree of autonomy. One example is locomotion generated by spinal central pattern generator networks (CPGs) that shape the detailed motor output. The level of activity is controlled from brainstem locomotor command centers, which in turn, are under the control of the basal ganglia. By using a biophysically detailed, full-scale computational model of the lamprey CPG (10,000 neurons) and its brainstem/forebrain control, we demonstrate general control principles that can adapt the network to different demands. Forward or backward locomotion and steering can be flexibly controlled by local synaptic effects limited to only the very rostral part of the network. Variability in response properties within each neuronal population is an essential feature and assures a constant phase delay along the cord for different locomotor speeds.


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Key Dates and Deadlines. CGU operates on a priority deadline cycle. Applicants are strongly encouraged to submit complete applications by the priority dates in.
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Here are the details for Snaylham House Cottage ideal for a cottage holiday in Rye, East Sussex. To book or find out more please use the Booking Info or Availability buttons below.
Open plan living room with French doors/dining room with kitchen area. Double bedroom with 6ft zip and link bed (can be twin). Shower room with toilet.
Once a stable to the main house, Snaylham House Cottage is now tastefully converted holiday accommodation in the grounds of the owners home. It lies on a quiet leafy farm track on the 1066 Country Walk with far reaching views over the Brede Valley. The Cinque Port town of Rye, with its cobbles and fascinating shops, Winchelsea with its medieval gates, Battle and Tenterden are all within easy reach. National Trust properties close by include Smallhythe, Bodiam Castle and Sissinghurst Gardens. Camber provides miles of golden sand dunes. Shop 2 miles, public house and restaurant 1 mile.
Sea within 5 miles Short StaysThis Susssex cottage can be booked for a short break Easy Walking Access Pets are not permitted at this cottage
Price: £ from 303.3
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Snaylham House Cottage
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As you can see Snaylham House Cottage is located in a great location. The perfect base for any holiday around Rye. And well suited to explore the whole of
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Tribute bands sadden me
Tribute bands have their place. There's no doubting that it's nice to see a song you know and love being performed note perfect, such as the excellent Italian band The Watch (pictured), but it saddens me that this very talented band - who perform Genesis covers as well as their own material - pulled such a large crowd at the Wesley Centre tonight, and yet had they been performing their own material instead of Genesis covers I would expect the crowd to shrink to about a quarter of that which was in tonight.
Without original bands, where would the tribute bands be?


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Scoring Summary
Game Leaders
Team Stats
Shots (on goal)
Corner Kicks
PDF Box Score
ATHENS, Ohio â The Ohio womenâs soccer team (2-7-1, 0-3 MAC) returned to Athens on Friday (Sept. 30) for some Mind-American Conference action, falling to Western Michigan (8-3-0, 2-1 MAC) by the final of 2-0.
âFirst of all, Western Michiganâs a really good team,â head coach Aaron Rodgers said. âThey won our league two of the last three years. We knew that if you let them get on the front foot early, it's going to be really difficult. So we just talked at halftime about tactical things, but it wasn't anything super magical, it was more of our effort and our energy out there and our willingness to battle a little bit more and win first balls. Play quicker, we had to play quicker, we had to have a little quicker movement. You know, tactically, we talked about playing in behind their outside backs a little bit more, which we did and we started to create some chances from that.â
Western Michigan opened the game with the first three shots of the game, with its best chance coming in the sixth minute when keeper Erin Beurket (Milford, Ohio) was forced to make a diving save to her right side.
The Broncos would strike first in the 24th minute when Tiffany Buckler scored off a rebound into the bottom right corner, giving Western Michigan a 1-0 lead.
Remi Eades (New Albany, Ohio) would get the first shot for Ohio in the 22nd minute when Eades would get in a one-on-one match up with a WMU defender and would fire a powerful kick to the net, forcing the Bronco keeper to make a save.
The Broncos would get two more shots, with Beurket making another save in the 24th minute. In the 38th minute, Western Michigan would add another goal when Buckler would score with a chip shot over Beurket into the upper right corner, giving the Broncos a 2-0 lead.
Ohio would enter the half trailing 2-0 with WMU outshooting the Bobcats 15-1 and Beurket making six saves in the first half.
Western Michigan would start the second half off with the first shot, which would be saved by keeper Taylor Smith (Uniontown, Ohio), who entered the game at the start of the half. WMU would get the next three shots, forcing Smith to make three more saves entering the 56th minute.
Ohioâs first shot of the half would come in the 59th minute when Courtney Daugerdas (Libertyville, Ill.) would get free into the open field and force the Bronco keeper to make a save.
Ohio would register the next shot of the game in the 73rd minute when Sydney Leckie (Medina, Ohio) would beat the defender down the middle and take a shot from the left side of the net, forcing the WMU keeper to make another save.
The Bobcats would register their third corner kick in the 76th minute, which would result in Mollie Whitacre (Perrysburg, Ohio) getting a shot off, but it would go wide.
Leckie would register the final shot of the game for the Bobcats, when in the 89th minute she would force the WMU keeper to make a save from the right side once again. However, the Bobcats would run out of time and the Broncos would come away with the 2-0 win.
Overall, The Bobcats registered five shots with four of them on goal. Eades, Whitacre, and Daugerdas would register one shot, while Leckie would record two shots, both of them on goal.
In goal, Beurket would play 45 minutes, allowing two goals and register six saves. Smith would enter the game to start of the second half and would not allow a goal in 45 minutes of play. She also registered four saves.
âIt was really just an energy thing,â Rodgers said. âWe were very flat in the first half, but we came back really strong in the second half and we talked about it at the end of the game. We just have to put those two halves together and if we do that against one of the best teams in the league and weâre right there. Weâve got to make that change for Sunday.â
The Bobcats return to action Sunday, Oct. 2 when they take on Northern Illinois. First touch is set for 1 p.m. at Chessa Field.


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The year is 291 CE, and a generation has passed since the tumultuous events of the Three Kingdoms period began. Despite the tripartite division of power which brought the conflict to a stalemate, and the brief unification of the kingdoms under the Jin dynasty, civil war is no more than a heartbeat away.
For the Jin is a dynasty divided. Its many ruling princes are hungry for greater power, each with ambitions – and methods – of their own. Eight stand above all others… will they rally to their emperor and empress? Or carve a legacy for themselves that will echo through the ages?


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