text:
T ceww
|T ceww
Scanning ewectron micrograph of a human T ceww
Scanning ewectron micrograph of a red bwood ceww (weft), a pwatewet (center), and a T wymphocyte (right)
|Immune system
|wymphocytus T
|Anatomicaw terms of microanatomy
A T ceww is a type of wymphocyte which devewops in de dymus gwand and pways a centraw rowe in de immune response. T cewws can be distinguished from oder wymphocytes by de presence of a T-ceww receptor on de ceww surface. These immune cewws originate as precursor cewws, derived from bone marrow,[1] and devewop into severaw distinct types of T cewws once dey have migrated in to de dymus gwand - for which dese cewws are named. T ceww differentiation continues even after dey have weft de dymus.
Groups of specific, differentiated T cewws have an important rowe in controwwing and shaping de immune response by providing a variety of immune-rewated functions. One of dese functions is Immune-mediated ceww deaf, and it is carried out by T cewws in severaw ways: CD8+ T cewws, awso known as "Kiwwer cewws", are cytotoxic - dis means dat dey are abwe to directwy kiww virus-infected cewws as weww as cancer cewws. CD8+ T cewws are awso abwe to utiwize smaww signawwing proteins, known as cytokines, to recruit oder cewws when mounting an immune response. A different popuwation of T cewws, de CD4+ T cewws, function as "Hewper cewws". Unwike CD8+ Kiwwer T cewws, dese CD4+ Hewper T cewws function by indirectwy kiwwing cewws identified as foreign: dey determine if and how oder parts of de immune system responds to a specific, perceived dreat. Hewper T cewws awso use cytokine signawwing to infwuence reguwatory B cewws directwy, and oder ceww popuwations indirectwy. Reguwatory T cewws are yet anoder distinct popuwation of dese cewws dat provide de criticaw mechanism of towerance, whereby immune cewws are abwe to distinguish invading cewws from "sewf" - dus preventing immune cewws from inappropriatewy mounting a response against onesewf (which wouwd by definition be an "autoimmune" response). For dis reason dese reguwatory T cewws have awso been cawwed "Suppressor" T cewws. These same sewf-towerant cewws are co-opted by cancer cewws to prevent de recognition of, and an immune response against, tumour cewws.
- 1 Devewopment
- 2 Types of T ceww
- 3 Activation
- 4 Cwinicaw significance
- 5 See awso
- 6 References
- 7 Externaw winks
Origin, earwy devewopment and migration to de dymus[edit]
Aww T cewws originate from c-kit+Sca1+ haematopoietic stem cewws (HSC) which reside in de bone marrow. In some cases de origin might be de fetaw wiver during embryonic devewopment. The HSC den differentiate into muwtipotent progenitors (MPP) which retain de potentiaw to become bof myewoid and wymphoid cewws. The process of differentiation den proceeds to a common wymphoid progenitor (CLP), which can onwy differentiate into T, B or NK cewws.[2] These CLP cewws den migrate via de bwood to de dymus, where dey engraft. The earwiest cewws which arrived in de dymus are termed doubwe-negative, as dey express neider de CD4 nor CD8 co-receptor. The newwy arrived CLP cewws are CD4-CD8-CD44+CD25-ckit+ cewws, and are termed earwy dymic progenitors (ETP) cewws.[3] These cewws wiww den undergo a round of division and downreguwate c-kit and are termed DN1 cewws.
TCR-Beta sewection[edit]
At de DN2 stage (CD44+CD25+), cewws upreguwate de recombination genes RAG1 and RAG2 and re-arrange de TCRβ wocus, combining V-D-J and constant region genes in an attempt to create a functionaw TCRβ chain, uh-hah-hah-hah. As de devewoping dymocyte progresses drough to de DN3 stage (CD44-CD25+), T ceww expresses an invariant α-chain cawwed pre-Tα awongside de TCRβ gene. If de rearranged β-chain successfuwwy pairs wif de invariant α-chain, signaws are produced which cease rearrangement of de β-chain (and siwences de awternate awwewe).[4] Awdough dese signaws reqwire dis pre-TCR at de ceww surface, dey are independent of wigand binding to de pre-TCR. If de pre-TCR forms, den de ceww downreguwates CD25 and is termed a DN4 ceww (CD25-CD44-). These cewws den undergo a round of prowiferation and begin to re-arrange TCRα wocus.
Positive sewection[edit]
Doubwe-positive dymocytes (CD4+/CD8+) move deep into de dymic cortex, where dey are presented wif sewf-antigens. These sewf-antigens are expressed by dymic corticaw epidewiaw cewws on MHC mowecuwes on de surface of corticaw epidewiaw cewws. Onwy dose dymocytes dat interact wif MHC-I or MHC-II wiww receive a vitaw "survivaw signaw". Aww dat cannot (if dey do not interact strongwy enough) wiww die by "deaf by negwect" (no survivaw signaw). This process ensures dat de sewected T cewws wiww have an MHC affinity dat can serve usefuw functions in de body (i.e., de cewws must be abwe to interact wif MHC and peptide compwexes to effect immune responses). The vast majority of devewoping dymocytes wiww die during dis process. The process of positive sewection takes a number of days.[5]
A dymocyte's fate is determined during positive sewection, uh-hah-hah-hah. Doubwe-positive cewws (CD4+/CD8+) dat interact weww wif MHC cwass II mowecuwes wiww eventuawwy become CD4+ cewws, whereas dymocytes dat interact weww wif MHC cwass I mowecuwes mature into CD8+ cewws. A T ceww becomes a CD4+ ceww by down-reguwating expression of its CD8 ceww surface receptors. If de ceww does not wose its signaw, it wiww continue downreguwating CD8 and become a CD4+, singwe positive ceww.[6]
This process does not remove dymocytes dat may cause autoimmunity. The potentiawwy autoimmune cewws are removed by de process of negative sewection, which occurs in de dymic meduwwa (discussed bewow).
Negative sewection[edit]
Negative sewection removes dymocytes dat are capabwe of strongwy binding wif "sewf" MHC peptides. Thymocytes dat survive positive sewection migrate towards de boundary of de cortex and meduwwa in de dymus. Whiwe in de meduwwa, dey are again presented wif a sewf-antigen presented on de MHC compwex of meduwwary dymic epidewiaw cewws (mTECs).[7] mTECs must be AIRE+ to properwy express sewf-antigens from aww tissues of de body on deir MHC cwass I peptides. Some mTECs are phagocytosed by dymic dendritic cewws; dis awwows for presentation of sewf-antigens on MHC cwass II mowecuwes (positivewy sewected CD4+ cewws must interact wif MHC cwass II mowecuwes, dus APCs, which possess MHC cwass II, must be present for CD4+ T-ceww negative sewection). Thymocytes dat interact too strongwy wif de sewf-antigen receive an apoptotic signaw dat weads to ceww deaf. However, some of dese cewws are sewected to become Treg cewws. The remaining cewws exit de dymus as mature naïve T cewws (awso known as recent dymic emigrants[8]). This process is an important component of centraw towerance and serves to prevent de formation of sewf-reactive T cewws dat are capabwe of inducing autoimmune diseases in de host.
β-sewection is de first checkpoint, where de T cewws dat are abwe to form a functionaw pre-TCR wif an invariant awpha chain and a functionaw beta chain are awwowed to continue devewopment in de dymus. Next, positive sewection checks dat T cewws have successfuwwy rearranged deir TCRα wocus and are capabwe of recognizing peptide-MHC compwexes wif appropriate affinity. Negative sewection in de meduwwa den obwiterates T cewws dat bind too strongwy to sewf-antigens expressed on MHC mowecuwes. These sewection processes awwow for towerance of sewf by de immune system. Typicaw T cewws dat weave de dymus (via de corticomeduwwarwy junction) are sewf-restricted, sewf-towerant, and singwe positive.
Thymic output[edit]
About 98% of dymocytes die during de devewopment processes in de dymus by faiwing eider positive sewection or negative sewection, whereas de oder 2% survive and weave de dymus to become mature immunocompetent T cewws. The dymus contributes fewer cewws as a person ages. As de dymus shrinks by about 3%[9] a year droughout middwe age, a corresponding faww in de dymic production of naïve T cewws occurs, weaving peripheraw T ceww expansion and regeneration to pway a greater rowe in protecting owder peopwe.
Types of T ceww[edit]
T cewws are grouped into a series of subsets based on deir function, uh-hah-hah-hah. CD4 and CD8 T cewws are sewected in de dymus, but undergo furder differentiation in de periphery to speciawized cewws which have different functions. T ceww subsets were initiawwy defined by function, but awso have associated gene or protein expression patterns.
Conventionaw Adaptive T cewws[edit]
Hewper CD4+ T cewws[edit]
T hewper cewws (TH cewws) assist oder wymphocytes, incwuding maturation of B cewws into pwasma cewws and memory B cewws, and activation of cytotoxic T cewws and macrophages. These cewws are awso known as CD4+ T cewws as dey express de CD4 on deir surfaces. Hewper T cewws become activated when dey are presented wif peptide antigens by MHC cwass II mowecuwes, which are expressed on de surface of antigen-presenting cewws (APCs). Once activated, dey divide rapidwy and secrete cytokines dat reguwate or assist de immune response. These cewws can differentiate into one of severaw subtypes, which have different rowes. Cytokines direct T cewws into particuwar subtypes.[10]
|Ceww type
|Cytokines Produced
|Key Transcription Factor
|Rowe in immune defence
|Rowe in autoimmunity
|Produce an infwammatory response, key for defense against intracewwuwar bacteria, viruses and cancer.
|MS, Type 1 diabetes
|Aid de differentiation and antibody production by B cewws
|Asdma and oder awwergic diseases
|Defense against gut padogens and at mucosaw barriers
|Rheumatoid Ardritis, Psoriasis
|Defense against hewminds (parasitic worms)
|Muwtipwe Scwerosis
|Hewp B cewws produce antibody
|Asdma and oder awwergic diseases
Cytotoxic CD8+ T cewws[edit]
Cytotoxic T cewws (TC cewws, CTLs, T-kiwwer cewws, kiwwer T cewws) destroy virus-infected cewws and tumor cewws, and are awso impwicated in transpwant rejection, uh-hah-hah-hah. These cewws are defined by de expression of CD8+ on de ceww surface. These cewws recognize deir targets by binding to short peptides (8-11AA) associated wif MHC cwass I mowecuwes, present on de surface of aww nucweated cewws. CD8+ T cewws awso produce de key cytokines IL-2 and IFNγ, which infwuence de effector functions of oder cewws, in particuwar macrophages and NK cewws.
Memory T cewws[edit]
Antigen-naïve T cewws expand and differentiate into memory and effector T cewws after dey encounter deir cognate antigen widin de context of an MHC mowecuwe on de surface of a professionaw antigen presenting ceww (e.g. a dendritic ceww). Appropriate co-stimuwation must be present at de time of antigen encounter for dis process to occur. Historicawwy, memory T cewws were dought to bewong to eider de effector or centraw memory subtypes, each wif deir own distinguishing set of ceww surface markers (see bewow).[11] Subseqwentwy, numerous new popuwations of memory T cewws were discovered incwuding tissue-resident memory T (Trm) cewws, stem memory TSCM cewws, and virtuaw memory T cewws. The singwe unifying deme for aww memory T ceww subtypes is dat dey are wong-wived and can qwickwy expand to warge numbers of effector T cewws upon re-exposure to deir cognate antigen, uh-hah-hah-hah. By dis mechanism dey provide de immune system wif "memory" against previouswy encountered padogens. Memory T cewws may be eider CD4+ or CD8+ and usuawwy express CD45RO.[12]
Memory T ceww subtypes:
- Centraw memory T cewws (TCM cewws) express CD45RO, C-C chemokine receptor type 7 (CCR7), and L-sewectin (CD62L). Centraw memory T cewws awso have intermediate to high expression of CD44. This memory subpopuwation is commonwy found in de wymph nodes and in de peripheraw circuwation, uh-hah-hah-hah. (Note- CD44 expression is usuawwy used to distinguish murine naive from memory T cewws).
- Effector memory T cewws (TEM cewws and TEMRA cewws) express CD45RO but wack expression of CCR7 and L-sewectin. They awso have intermediate to high expression of CD44. These memory T cewws wack wymph node-homing receptors and are dus found in de peripheraw circuwation and tissues.[13] TEMRA stands for terminawwy differentiated effector memory cewws re-expressing CD45RA, which is a marker usuawwy found on naive T cewws.[14]
- Tissue resident memory T cewws (TRM) occupy tissues (skin, wung, etc..) widout recircuwating. One ceww surface marker dat has been associated wif TRM is de integrin αeβ7.[15]
- Virtuaw memory T cewws differ from de oder memory subsets in dat dey do not originate fowwowing a strong cwonaw expansion event. Thus, awdough dis popuwation as a whowe is abundant widin de peripheraw circuwation, individuaw virtuaw memory T ceww cwones reside at rewativewy wow freqwencies. One deory is dat homeostatic prowiferation gives rise to dis T ceww popuwation, uh-hah-hah-hah. Awdough CD8 virtuaw memory T cewws were de first to be described,[16] it is now known dat CD4 virtuaw memory cewws awso exist.[17]
Reguwatory CD4+ T cewws[edit]
Reguwatory T cewws are cruciaw for de maintenance of immunowogicaw towerance. Their major rowe is to shut down T ceww-mediated immunity toward de end of an immune reaction and to suppress autoreactive T cewws dat escaped de process of negative sewection in de dymus.
Two major cwasses of CD4+ Treg cewws have been described — FOXP3+ Treg cewws and FOXP3− Treg cewws.
Reguwatory T cewws can devewop eider during normaw devewopment in de dymus, and are den known as dymic Treg cewws, or can be induced peripherawwy and are cawwed peripherawwy derived Treg cewws. These two subsets were previouswy cawwed "naturawwy occurring", and "adaptive" or "induced", respectivewy.[18] Bof subsets reqwire de expression of de transcription factor FOXP3 which can be used to identify de cewws. Mutations of de FOXP3 gene can prevent reguwatory T ceww devewopment, causing de fataw autoimmune disease IPEX.
Severaw oder types of T ceww have suppressive activity, but do not express FOXP3. These incwude Tr1 cewws and Th3 cewws, which are dought to originate during an immune response and act by producing suppressive mowecuwes. Tr1 cewws are associated wif IL-10, and Th3 cewws are associated wif TGF-beta. Recentwy, Treg17 cewws have been added to dis wist.[19]
Innate-wike T cewws[edit]
Naturaw kiwwer T ceww[edit]
Naturaw kiwwer T cewws (NKT cewws – not to be confused wif naturaw kiwwer cewws of de innate immune system) bridge de adaptive immune system wif de innate immune system. Unwike conventionaw T cewws dat recognize peptide antigens presented by major histocompatibiwity compwex (MHC) mowecuwes, NKT cewws recognize gwycowipid antigen presented by CD1d. Once activated, dese cewws can perform functions ascribed to bof Th and Tc cewws (i.e., cytokine production and rewease of cytowytic/ceww kiwwing mowecuwes). They are awso abwe to recognize and ewiminate some tumor cewws and cewws infected wif herpes viruses.[20]
Mucosaw associated invariant[edit]
MAIT cewws dispway innate, effector-wike qwawities.[21][22] In humans, MAIT cewws are found in de bwood, wiver, wungs, and mucosa, defending against microbiaw activity and infection, uh-hah-hah-hah.[21] The MHC cwass I-wike protein, MR1, is responsibwe for presenting bacteriawwy-produced vitamin B metabowites to MAIT cewws.[23][24][25] After de presentation of foreign antigen by MR1, MAIT cewws secretes pro-infwammatory cytokines and are capabwe of wysing bacteriawwy-infected cewws.[21][25] MAIT cewws can awso be activated drough MR1-independent signawing.[25] In addition to possessing innate-wike functions, dis T ceww subset supports de adaptive immune response and has a memory-wike phenotype.[21] Furdermore, MAIT cewws are dought to pway a rowe in autoimmune diseases, such as muwtipwe scwerosis, ardritis and infwammatory bowew disease,[26][27] awdough definitive evidence is yet to be pubwished.[28][29][30][31]
Gamma dewta T cewws[edit]
Gamma dewta T cewws (γδ T cewws) represent a smaww subset of T cewws which possess a γδ TCR rader dan de αβ TCR on de ceww surface. The majority of T cewws express αβ TCR chains. This group of T cewws is much wess common in humans and mice (about 2% of totaw T cewws) and are found mostwy in de gut mucosa, widin a popuwation of intraepidewiaw wymphocytes. In rabbits, sheep, and chickens, de number of γδ T cewws can be as high as 60% of totaw T cewws. The antigenic mowecuwes dat activate γδ T cewws are stiww mostwy unknown, uh-hah-hah-hah. However, γδ T cewws are not MHC-restricted and seem to be abwe to recognize whowe proteins rader dan reqwiring peptides to be presented by MHC mowecuwes on APCs. Some murine γδ T cewws recognize MHC cwass IB mowecuwes. Human γδ T cewws which use de Vγ9 and Vδ2 gene fragments constitute de major γδ T ceww popuwation in peripheraw bwood, and are uniqwe in dat dey specificawwy and rapidwy respond to a set of nonpeptidic phosphorywated isoprenoid precursors, cowwectivewy named phosphoantigens, which are produced by virtuawwy aww wiving cewws. The most common phosphoantigens from animaw and human cewws (incwuding cancer cewws) are isopentenyw pyrophosphate (IPP) and its isomer dimedywawwyw pyrophosphate (DMPP). Many microbes produce de highwy active compound hydroxy-DMAPP (HMB-PP) and corresponding mononucweotide conjugates, in addition to IPP and DMAPP. Pwant cewws produce bof types of phosphoantigens. Drugs activating human Vγ9/Vδ2 T cewws comprise syndetic phosphoantigens and aminobisphosphonates, which upreguwate endogenous IPP/DMAPP.
Activation of CD4+ T cewws occurs drough de simuwtaneous engagement of de T-ceww receptor and a co-stimuwatory mowecuwe (wike CD28, or ICOS) on de T ceww by de major histocompatibiwity compwex (MHCII) peptide and co-stimuwatory mowecuwes on de APC. Bof are reqwired for production of an effective immune response; in de absence of co-stimuwation, T ceww receptor signawwing awone resuwts in anergy. The signawwing padways downstream from co-stimuwatory mowecuwes usuawwy engages de PI3K padway generating PIP3 at de pwasma membrane and recruiting PH domain containing signawing mowecuwes wike PDK1 dat are essentiaw for de activation of PKCθ, and eventuaw IL-2 production, uh-hah-hah-hah. Optimaw CD8+ T ceww response rewies on CD4+ signawwing.[33] CD4+ cewws are usefuw in de initiaw antigenic activation of naïve CD8 T cewws, and sustaining memory CD8+ T cewws in de aftermaf of an acute infection, uh-hah-hah-hah. Therefore, activation of CD4+ T cewws can be beneficiaw to de action of CD8+ T cewws.[34][35][36]
The first signaw is provided by binding of de T ceww receptor to its cognate peptide presented on MHCII on an APC. MHCII is restricted to so-cawwed professionaw antigen-presenting cewws, wike dendritic cewws, B cewws, and macrophages, to name a few. The peptides presented to CD8+ T cewws by MHC cwass I mowecuwes are 8–13 amino acids in wengf; de peptides presented to CD4+ cewws by MHC cwass II mowecuwes are wonger, usuawwy 12–25 amino acids in wengf,[37] as de ends of de binding cweft of de MHC cwass II mowecuwe are open, uh-hah-hah-hah.
The second signaw comes from co-stimuwation, in which surface receptors on de APC are induced by a rewativewy smaww number of stimuwi, usuawwy products of padogens, but sometimes breakdown products of cewws, such as necrotic-bodies or heat shock proteins. The onwy co-stimuwatory receptor expressed constitutivewy by naïve T cewws is CD28, so co-stimuwation for dese cewws comes from de CD80 and CD86 proteins, which togeder constitute de B7 protein, (B7.1 and B7.2, respectivewy) on de APC. Oder receptors are expressed upon activation of de T ceww, such as OX40 and ICOS, but dese wargewy depend upon CD28 for deir expression, uh-hah-hah-hah. The second signaw wicenses de T ceww to respond to an antigen, uh-hah-hah-hah. Widout it, de T ceww becomes anergic, and it becomes more difficuwt for it to activate in future. This mechanism prevents inappropriate responses to sewf, as sewf-peptides wiww not usuawwy be presented wif suitabwe co-stimuwation, uh-hah-hah-hah. Once a T ceww has been appropriatewy activated (i.e. has received signaw one and signaw two) it awters its ceww surface expression of a variety of proteins. Markers of T ceww activation incwude CD69, CD71 and CD25 (awso a marker for Treg cewws), and HLA-DR (a marker of human T ceww activation). CTLA-4 expression is awso up-reguwated on activated T cewws, which in turn outcompetes CD28 for binding to de B7 proteins. This is a checkpoint mechanism to prevent over activation of de T ceww. Activated T cewws awso change deir ceww surface gwycosywation profiwe.[38]
The T ceww receptor exists as a compwex of severaw proteins. The actuaw T ceww receptor is composed of two separate peptide chains, which are produced from de independent T ceww receptor awpha and beta (TCRα and TCRβ) genes. The oder proteins in de compwex are de CD3 proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a totaw of six ITAM motifs. The ITAM motifs on de CD3ζ can be phosphorywated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 can awso phosphorywate de tyrosines on many oder mowecuwes, not weast CD28, LAT and SLP-76, which awwows de aggregation of signawwing compwexes around dese proteins.
Phosphorywated LAT recruits SLP-76 to de membrane, where it can den bring in PLC-γ, VAV1, Itk and potentiawwy PI3K. PLC-γ cweaves PI(4,5)P2 on de inner weafwet of de membrane to create de active intermediaries diacywgwycerow (DAG), inositow-1,4,5-trisphosphate (IP3); PI3K awso acts on PIP2, phosphorywating it to produce phosphatidwyinositow-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs. Most important in T cewws is PKCθ, criticaw for activating de transcription factors NF-κB and AP-1. IP3 is reweased from de membrane by PLC-γ and diffuses rapidwy to activate cawcium channew receptors on de ER, which induces de rewease of cawcium into de cytosow. Low cawcium in de endopwasmic reticuwum causes STIM1 cwustering on de ER membrane and weads to activation of ceww membrane CRAC channews dat awwows additionaw cawcium to fwow into de cytosow from de extracewwuwar space. This aggregated cytosowic cawcium binds cawmoduwin, which can den activate cawcineurin. Cawcineurin, in turn, activates NFAT, which den transwocates to de nucweus. NFAT is a transcription factor dat activates de transcription of a pweiotropic set of genes, most notabwe, IL-2, a cytokine dat promotes wong-term prowiferation of activated T cewws.
PLCγ can awso initiate de NF-κB padway. DAG activates PKCθ, which den phosphorywates CARMA1, causing it to unfowd and function as a scaffowd. The cytosowic domains bind an adapter BCL10 via CARD (Caspase activation and recruitment domains) domains; dat den binds TRAF6, which is ubiqwitinated at K63.:513–523[39] This form of ubiqwitination does not wead to degradation of target proteins. Rader, it serves to recruit NEMO, IKKα and -β, and TAB1-2/ TAK1.[40] TAK 1 phosphorywates IKK-β, which den phosphorywates IκB awwowing for K48 ubiqwitination: weads to proteasomaw degradation, uh-hah-hah-hah. Rew A and p50 can den enter de nucweus and bind de NF-κB response ewement. This coupwed wif NFAT signawing awwows for compwete activation of de IL-2 gene.[39]
Whiwe in most cases activation is dependent on TCR recognition of antigen, awternative padways for activation have been described. For exampwe, cytotoxic T cewws have been shown to become activated when targeted by oder CD8 T cewws weading to towerization of de watter.[41]
In spring 2014, de T-Ceww Activation in Space (TCAS) experiment was waunched to de Internationaw Space Station on de SpaceX CRS-3 mission to study how "deficiencies in de human immune system are affected by a microgravity environment".[42]
T ceww activation is moduwated by reactive oxygen species.[43]
Antigen discrimination[edit]
A uniqwe feature of T cewws is deir abiwity to discriminate between heawdy and abnormaw (e.g. infected or cancerous) cewws in de body.[44] Heawdy cewws typicawwy express a warge number of sewf derived pMHC on deir ceww surface and awdough de T ceww antigen receptor can interact wif at weast a subset of dese sewf pMHC, de T ceww generawwy ignores dese heawdy cewws. However, when dese very same cewws contain even minute qwantities of padogen derived pMHC, T cewws are abwe to become activated and initiate immune responses. The abiwity of T cewws to ignore heawdy cewws but respond when dese same cewws contain padogen (or cancer) derived pMHC is known as antigen discrimination, uh-hah-hah-hah. The mowecuwar mechanisms dat underwie dis process are controversiaw.[44][45]
Cwinicaw significance[edit]
Causes of T ceww deficiency incwude wymphocytopenia of T cewws and/or defects on function of individuaw T cewws. Compwete insufficiency of T ceww function can resuwt from hereditary conditions such as severe combined immunodeficiency (SCID), Omenn syndrome, and cartiwage–hair hypopwasia.[46] Causes of partiaw insufficiencies of T ceww function incwude acqwired immune deficiency syndrome (AIDS), and hereditary conditions such as DiGeorge syndrome (DGS), chromosomaw breakage syndromes (CBSs), and B-ceww and T-ceww combined disorders such as ataxia-tewangiectasia (AT) and Wiskott–Awdrich syndrome (WAS).[46]
The main padogens of concern in T ceww deficiencies are intracewwuwar padogens, incwuding Herpes simpwex virus, Mycobacterium and Listeria.[47] Awso, fungaw infections are awso more common and severe in T ceww deficiencies.[47]
Cancer of T cewws is termed T-ceww wymphoma, and accounts for perhaps one in ten cases of non-Hodgkin wymphoma.[48] The main forms of T ceww wymphoma are:
- Extranodaw T ceww wymphoma
- Cutaneous T ceww wymphomas: Sézary syndrome and Mycosis fungoides
- Anapwastic warge ceww wymphoma
- Angioimmunobwastic T ceww wymphoma
T ceww exhaustion is a state of dysfunctionaw T cewws. It is characterized by progressive woss of function, changes in transcriptionaw profiwes and sustained expression of inhibitory receptors. At first cewws wose deir abiwity to produce IL-2 and TNFα fowwowed by de woss of high prowiferative capacity and cytotoxic potentiaw, eventuawwy weading to deir dewetion, uh-hah-hah-hah. Exhausted T cewws typicawwy indicate higher wevews of CD43, CD69 and inhibitory receptors combined wif wower expression of CD62L and CD127. Exhaustion can devewop during chronic infections, sepsis and cancer.[49] Exhausted T cewws preserve deir functionaw exhaustion even after repeated antigen exposure.[50]
During chronic infection and sepsis[edit]
T ceww exhaustion can be triggered by severaw factors wike persistent antigen exposure and wack of CD4 T ceww hewp.[51] Antigen exposure awso has effect on de course of exhaustion because wonger exposure time and higher viraw woad increases de severity of T ceww exhaustion, uh-hah-hah-hah. At weast 2–4 weeks exposure is needed to estabwish exhaustion, uh-hah-hah-hah.[52] Anoder factor abwe to induce exhaustion are inhibitory receptors incwuding programmed ceww deaf protein 1 (PD1), CTLA-4, T ceww membrane protein-3 (TIM3), and wymphocyte activation gene 3 protein (LAG3).[53][54] Sowubwe mowecuwes such as cytokines IL-10 or TGF-β are awso abwe to trigger exhaustion, uh-hah-hah-hah.[55][56] Last known factors dat can pway a rowe in T ceww exhaustion are reguwatory cewws. Treg cewws can be a source of IL-10 and TGF-β and derefore dey can pway a rowe in T ceww exhaustion, uh-hah-hah-hah.[57] Furdermore, T ceww exhaustion is reverted after depwetion of Treg cewws and bwockade of PD1.[58] T ceww exhaustion can awso occur during sepsis as a resuwt of cytokine storm. Later after de initiaw septic encounter anti-infwammatory cytokines and pro-apoptotic proteins take over to protect de body from damage. Sepsis awso carries high antigen woad and infwammation, uh-hah-hah-hah. In dis stage of sepsis T ceww exhaustion increases.[59][60] Currentwy dere are studies aiming to utiwize inhibitory receptor bwockades in treatment of sepsis.[61][62][63]
During transpwantation[edit]
Whiwe during infection T ceww exhaustion can devewop fowwowing persistent antigen exposure after graft transpwant simiwar situation arises wif awwoantigen presence.[64] It was shown dat T ceww response diminishes over time after kidney transpwant.[65] These data suggest T ceww exhaustion pways an important rowe in towerance of a graft mainwy by depwetion of awworeactive CD8 T cewws.[60][66] Severaw studies showed positive effect of chronic infection on graft acceptance and its wong-term survivaw mediated partwy by T ceww exhaustion, uh-hah-hah-hah.[67][68][69] It was awso shown dat recipient T ceww exhaustion provides sufficient conditions for NK ceww transfer.[70] Whiwe dere are data showing dat induction of T ceww exhaustion can be beneficiaw for transpwantation it awso carries disadvantages among which can be counted increased number of infections and de risk of tumor devewopment.[71]
During cancer[edit]
During cancer T ceww exhaustion pways a rowe in tumor protection, uh-hah-hah-hah. According to research some cancer-associated cewws as weww as tumor cewws demsewves can activewy induce T ceww exhaustion at de site of tumor.[72][73] T ceww exhaustion can awso pway a rowe in cancer rewapses as was shown on weukemia.[74] Some study even suggested dat it is possibwe to predict rewapse of weukemia based on expression of inhibitory receptors PD-1 and TIM-3 by T cewws.[75] In recent years dere is a wot of experiments and cwinicaw triaws wif immune checkpoint bwockers in cancer derapy. Some of dem were approved as vawid derapies and are now used in cwinics.[76] Inhibitory receptors targeted by dose medicaw procedures are vitaw in T ceww exhaustion and bwocking dem can reverse dese changes.[77]
( See awso Immunosenescence ).
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- ^ Woo SR, Turnis ME, Gowdberg MV, Bankoti J, Sewby M, Nirschw CJ, Bettini ML, Gravano DM, Vogew P, Liu CL, Tangsombatvisit S, Grosso JF, Netto G, Smewtzer MP, Chaux A, Utz PJ, Workman CJ, Pardoww DM, Korman AJ, Drake CG, Vignawi DA (February 2012). "Immune inhibitory mowecuwes LAG-3 and PD-1 synergisticawwy reguwate T-ceww function to promote tumoraw immune escape". Cancer Research. 72 (4): 917–27. doi:10.1158/0008-5472.CAN-11-1620. PMC 3288154. PMID 22186141.
- ^ Zewwe-Rieser C, Thangavadivew S, Biedermann R, Brunner A, Stoitzner P, Wiwwenbacher E, Greiw R, Jöhrer K (November 2016). "T cewws in muwtipwe myewoma dispway features of exhaustion and senescence at de tumor site". Journaw of Hematowogy & Oncowogy. 9 (1): 116. doi:10.1186/s13045-016-0345-3. PMC 5093947. PMID 27809856.
- ^ Lakins MA, Ghorani E, Munir H, Martins CP, Shiewds JD (March 2018). "+ T Cewws to protect tumour cewws". Nature Communications. 9 (1): 948. doi:10.1038/s41467-018-03347-0. PMC 5838096. PMID 29507342.
- ^ Liu L, Chang YJ, Xu LP, Zhang XH, Wang Y, Liu KY, Huang XJ (May 2018). "T ceww exhaustion characterized by compromised MHC cwass I and II restricted cytotoxic activity associates wif acute B wymphobwastic weukemia rewapse after awwogeneic hematopoietic stem ceww transpwantation". Cwinicaw Immunowogy. 190: 32–40. doi:10.1016/j.cwim.2018.02.009. PMID 29477343.
- ^ Kong Y, Zhang J, Cwaxton DF, Ehmann WC, Rybka WB, Zhu L, Zeng H, Scheww TD, Zheng H (Juwy 2015). "PD-1(hi)TIM-3(+) T cewws associate wif and predict weukemia rewapse in AML patients post awwogeneic stem ceww transpwantation". Bwood Cancer Journaw. 5 (7): e330. doi:10.1038/bcj.2015.58. PMC 4526784. PMID 26230954.
- ^ "U.S. FDA Approved Immune-Checkpoint Inhibitors and Immunoderapies". Medicaw Writer Agency | 香港醫學作家 | MediPR | MediPaper Hong Kong. 2018-08-21. Retrieved 2018-09-22.
- ^ Bhadra R, Gigwey JP, Weiss LM, Khan IA (May 2011). "Controw of Toxopwasma reactivation by rescue of dysfunctionaw CD8+ T-ceww response via PD-1-PDL-1 bwockade". Proceedings of de Nationaw Academy of Sciences of de United States of America. 108 (22): 9196–201. doi:10.1073/pnas.1015298108. PMC 3107287. PMID 21576466.
Externaw winks[edit]
- Immunobiowogy, 5f Edition
- niaid.nih.gov – The Immune System
- T-ceww Group – Cardiff University
- (Successfuw!) Treatment of Metastatic Mewanoma wif Autowogous CD4+ T Cewws against NY-ESO-1.
- Davies AJ (1993). "The tawe of T cewws". Immunowogy Today. 14 (3): 137–139. doi:10.1016/0167-5699(93)90216-8. PMID 8466629.


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Culture Shock
The World Is Open: How Web Technology Is Revolutionizing Education 2009
The World Is Open: How Web Technology Is Revolutionizing Education 2009
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03 Oct 2018
Aymeline Valade models Haider Ackermann's easy tailoring.
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- WiFi
- Car park
- Air conditioning
- Swimming pool
- Spa
- Pets admitted
- Private Beach Area
- Airport Shuttle
- Accessible
- Family
- Sports
- Gym
- Eco-friendly
Choose your room
You'll be on the beach with a stay at Xixim Unique Mayan Hotel in Celestun. Relax at the full-service spa, where you can enjoy massages, body treatments, and facials. You're sure to appreciate the recreational amenities, which include 2 outdoor swimming pools and a fitness center. Additional amenities include complimentary wireless Internet access, concierge services, and wedding services. Featured amenities include luggage storage and a library. A roundtrip airport shuttle is provided for a surcharge (available on request), and free self parking is available onsite. Make yourself at home in one of the 32 guestrooms featuring minibars. Private bathrooms with showers feature complimentary toiletries and hair dryers. Conveniences include phones, as well as laptop-compatible safes and desks.
Useful information:Other names for Xixim Unique Mayan Hotel:
Xixim Unique Mayan
Hotel Eco Paraiso Xixim


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1972 Original. Liner Notes State "Le Gip Mesmerizes His Listeners Into A Trance Like State With Sexual Undertones. Desires Are Crossed With Wild Cries And Dances That Can Culminate In Orgies! To Top It All Off, The Cover Features A Super Nude Shot.
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- Photo courtesy of Roswell Clay Collective
Works In Clay
- May 16 – May 22
Days Time Thu, May 16 7pm – 9pm Every Mon-Sat 10am – 5pm Every Sun 12pm – 5pm Free!
More than 40 local artists from Roswell Clay Collective will showcase and sell one-of-a-kind functional clay pieces, such as bowls, platters, tureens, mugs, and vases, as well as ceramic sculptures, jewelry and whimsical pieces. Unique, hand-made pottery gifts for dads, grads, weddings and teachers will be on display and for sale at the Spring Works in Clay Show and Sale. The show is a fun outing for anyone interested in distinctive gifts, as well as collectors of ceramic art.
This event takes place at:
Art Center West
1355 Woodstock Rd
Roswell, GA 30075
This event takes place at:
Art Center West
1355 Woodstock Rd
Roswell, GA 30075
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Triathlon Training
Group Training
Personal Training
Private Swimming Lessons
Fitness Assessments
Swim Coaching
Training Camps
Fall/Winter Schedule
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Triathlon Shop
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Mont Tremblant Training Camp Highlights
A good time was had by all at camp! We were "blessed" with all kinds of weather. We had a warm rain as we climbed and descended Duplessis so we could all get used to riding it in the rain, and then a cold front pulled in and we were challenged to dress for a cool run and a windy and cold long ride. Again, great mental preparation for "anything can happen on race day". The St-Jovite pool was awesome and gave everyone an opportunity to work on triathlon passing and sighting skills plus a few tough drills and sets. Thanks a million to Debi Zaret who graciously hosted the potluck and the 3 Coaches Talk on Tricks of the Triathlon Trade.
Thanks to all who came up to camp and a special thanks to Maggie, Kevin
Martin for making sure everyone had a good time!
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Heather Dunn
You can add me as a client for life. Still so much to learn about biking but am kicking butt on the hills out here - the "wall of pain" climb 2000+ft elevation has nothing on one of your classes!! Thank you!!
ps - LOVING the Team Triumph biking shorts!!!
Tara McGowan
Team Triumph is a great Club where people from all levels of fitness can train. I was first introduced to Coach Julia when I went to a Training Camp in Utah as a tag along. My husband was training for an Ironman race at the time. I was recovering from an injury, but that didn't stop me trying the different activities at a beginner level. I remember swimming in the pool for Julia's first assessment. I was exhausted after only a few lengths. She gave me a few swim tips and I was eager for more. That was the point where I decided to schedule a one-on-one meeting with Julia and develop my plan to become active for life. In September 2016 I started learning to spin and run for the first time and took swim lessons to improve my technique. With Coach Julia's support and friendship from team members I have not looked back!
Susie Walter
With encouragement from my great friend Heather I joined TT in the fall of 2014. I remember nervously arriving at Canterbury Pool for the initial hour of swimming. Well I gasped at the thought of a 300 M warm up! I asked Julia if we had the whole hour to complete the warm up! Well it wasn't too long after training and relearning the proper stroke technique the the warm became pretty easy. Now the 500 M time trial was a challenge but I was able to do it! In the spring of 2015 I completed the Perth Triathlon...lots of fun with TT and Julia was an amazingly supportive. A Christmas gift from my husband in 2015 allowed me to go to the Utah Training Camp in April 2016. I was certainly nervous given the experience of the athletes attending. I met some new people and everyone was friendly and supportive. We had a great time participating in the Sand Hollow Sprint Triathlon. More recently I have cut back on the swimming, but I hope to continue next spring. After a hip replacement in 2017 I am back spinning. The group dynamics of the spin classes with Maggie and Julia is fantastic. The music is great, the work out is awesome (I am soaked by the end of the class!) anyone holding back from joining TT for fear of intimidation....no need! Well have all started from different levels of fitness and experience and Julia and her team are there to train, coach, support and "POOOSH" all the way!
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Mindy is setting up her Google Merchant Center account and has to verify her website URL. Her website URL must:
- be as specific as possible (for example, http://www.example.com#top)
- include Ports
- begin with http:// or https://
- include IP addresses
Right Answer:
- begin with http:// or https://
Before you get to upload your product data to the Merchant center you are required to verify and claim your online website's URL. Because verification let Google know that you are an authorized owner of a website URL which will make your uploading procedure easier and secure.
Also, claiming of the URL associates the verified website URL with your Merchant center account. Here are the steps you should do verify and claim your website URL.
- Sign in to your Merchant Center Account.
- Click on the "Business Information" on the Navigation Panel.
- Click the "About your Business" to open the "About your Business" page from the Page menu.
- Then click to open up the "website" section.
- Enter your website's URL in the column.
- Then Click on the "Save" button at the end.
If you are already verified your website during the setup then you can move on to Step-3 directly. Verifying your Website's URL will confirm that you are the owner of the website which will give you the ability to edit the content. For verifying your website you cane either of the methods which are mentioned below.
- HTML file upload – which is the most common method
- HTML tag
- Google Analytics and
- Google tag manager
Also, claiming your website URL will give you the exclusive right to use your website in connection with your merchant account.
Do you got queries regarding this question Mindy Is Setting up Her Google Merchant Center Account…then do let us know by leaving a comment below.


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Asthma and COPD overlap syndrome is associated with increased risk of hospitalisation
OBJECTIVE: To investigate clinical features of the overlap syndrome among Asian patients and to analyse its impact on hospitalisation due to respiratory problems or death compared to COPD alone.
DESIGN: We performed a retrospective cohort analysis of 2933 COPD patients presenting at the Asan Medical Center from 1 January 2000 to 31 December 2009. Kaplan-Meier and Cox proportional hazard models were used to analyse the significance of clinical parameters, including age, sex, smoking history, body mass index (BMI), severity of airflow limitation, airway obstruction reversibility and overlap syndrome with hospitalisation due to respiratory problems or death.
RESULTS: Overlap syndrome patients were older, included smaller proportions of males and of smokers and had lower forced expiratory volume in 1 s (FEV1) (% predicted). Shorter hospitalisation-free and survival periods were noted among overlap syndrome patients. Overlap syndrome was significantly associated with risk of hospitalisation due to respiratory problems after adjusting for age, smoking history, BMI, FEV1 (% predicted) and changes in FEV1 (P < 0.001).
CONCLUSION: Asthma and COPD overlap syndrome is associated with a higher risk of hospitalisation due to respiratory problems than COPD alone.
Keywords: COPD; asthma; hospitalisation; lung function; overlap syndrome
Document Type: Research Article
Affiliations: 1: Department of Allergy and Clinical Immunology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea 2: Department of Internal Medicine, Seoul Seonam Hospital, Ewha Womans University Medical Center, Seoul, Republic of Korea 3: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea 4: Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea 5: Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Publication date: July 1, 2015
The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on tuberculosis and lung health world-wide.
Certain IJTLD articles are selected for translation into French, Spanish, Chinese or Russian. They are available on the Union website
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and a 2 day workshp on either Level 2 or BWRT Transformational Coaching on May 14 & 15
2017 saw the inaugural World Congress for BWRT - it was hailed as an outrageous success and the second and third ones, were unanimously recognised as being even better each time! We are determined to make the fourth, in 2020, even more outstanding, with a line-up of top BWRT Professionals from around the world. Once again, we will be at the same fabulous venue of the Lane End Conference Centre with exclusive use of all the wonderful facilities.
There will also be a two-day workshop on either Level 2 or BWRT Transformational Coaching on Thursday & Friday, May 14 & 15 - details to be announced soon.
With top presenters from the UK and overseas, an opportunity to network, make new friends and get reacquainted with old ones, this is an event not to be missed!
Available attendance packages for will be shown here soon.


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As concerns over the de facto monopoly status of Google continue to grow, I'm reminded of the great philosopher Herman Cain and his infamous line "blame yourself". As long as "Google" is a generic phrase for Internet search, their dominant position is assured. That said, you can do something about it. There are plenty of Google alternatives and many of these players offer a better search experience, depending on your needs. Here are 12 alternatives to escape your reliance on Google for all things search. Step 1: Bing If you're a digital marketer using advanced search operators, then use Bing for these queries. LinkFromDomain: There are any number of tools that can give you inbound link data. There's only one place to go for outbound link information – Bing. Feed: Finds RSS or Atom feeds pertaining to the term you specify. Contains: Returns search results that have links to the file types that you specify. Near: Useful for spotting … [Read more...] about Escape Google With These 12 Search Engine Alternatives
Search engine
Semantic Scholar, A New AI Search Engine, Is Changing the Way Neuroscientists Do Their Research
When you think of artificial intelligence, images of futuristic robots or memories of bad sci-fi films might come to mind. However, the reality of AI is actually a lot more tame: a friendly search engine, for instance. But while we type our queries into Google and usually get fairly useful results, the same has not always been true for the information gleaned by scientific researchers. Although existing resources like Google Scholar and PubMed provide scientists with resources much faster than the methods of old, they don't always cover the nitty-gritty details that are needed. Now, a new, free search engine called Semantic Scholar is using AI technology to help these scientists find relevant information much more quickly. Semantic Scholar has been labeled a game-changer for these professionals, who previously had no way of effectively combing through mountains of dense research. While Google Scholar has a huge database – it has indexed more than 200 million articles to … [Read more...] about Semantic Scholar, A New AI Search Engine, Is Changing the Way Neuroscientists Do Their Research
Say goodbye to Google: 14 alternative search engines
Well it's been a big week for search, I think we can all agree. If you're a regular Google user (65% of you globally) then you'll have noticed some changes, both good and bad. I won't debate the merits of these improvements, we've done that already here: Google kills Right Hand Side Ads and here: Google launches Accelerated Mobile Pages, but there's a definite feeling of vexation that appears to be coming to a head. Deep breath… As the paid search space increases in 'top-heaviness', as organic results get pushed further off the first SERP, as the Knowledge Graph scrapes more and more publisher content and continues to make it pointless to click through to a website, and as our longstanding feelings of unfairness over Google's monopoly and tax balance become more acute, now more than ever we feel there should be another, viable search engine alternative. There was a point not that long ago … [Read more...] about Say goodbye to Google: 14 alternative search engines
Chan-Zuckerberg Initiative acquires AI-powered search engine Meta
The Chan-Zuckerberg Initiative, the $45 billion philanthropic organisation founded by Mark Zuckerberg and his wife Priscilla Chan, has made its first acquisition – of a search engine. The Initiative announced on Monday that it would be acquiring Meta, a scientific search engine that uses artificial intelligence to make connections between research papers. The search start-up, which was founded in 2010, previously charged some users for subscriptions or custom solutions, but the Chan-Zuckerberg Initiative intends to make it free to all after spending a few months enhancing the product. The Meta search engine is designed to make it easier for researchers to search through, read and link together more than 26 million scientific papers. It also provides free, full-text access to some 18,000 journals and sources of literature. Meta's artificial intelligence capabilities allow it to draw connections between papers, recognising where authors and citations overlap in order to … [Read more...] about Chan-Zuckerberg Initiative acquires AI-powered search engine Meta
Facebook One Of The Top Search Engines? I Dunno About That!
I shouldn't — but I couldn't resist doing a quick poke at Facebook'spronouncementthat it is the "most used people search engine on the web." Really? Accordingto? Facebook gives some stats that perhaps back up this claim, but only if youconsider Facebook a people search engine. I don't. Not yet. It's hard for me to consider something a people searchengine when, untillast September, it didn't allow most people to actually register with it. Ofcourse, I don't need comScore'slatest statsto tell me Facebook is taking off since then. The drip-drip-drip of peopleasking to be my friend since I joined up a few weeks ago lets me know it isgaining ground. It is a drip-drip, however, not a firehose blast. I'd wager most people Iactually know personally are not on it. Curious, I just searched for threecollege friends. None of them are there. I'm not surprised, since I was incollege so long ago we didn't have email addresses … [Read more...] about Facebook One Of The Top Search Engines? I Dunno About That!


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The fungus "Candida" is present in all our bodies.
Under positive situations, it is able to end up rooted in special places or organs, spreading as though it have been an "infection". This contamination is made seen through the presence of "white" discharge or a few different infected fabric (in the case of the toes, a yellowing of the nail).
Candidiasis is the "infection" kingdom of the fungus - affecting the entirety from dandruff to having vaginal candida discharge.
Whilst nothing incorrect from a in basic terms fitness angle, the underlying condition is often unpleasant, and might cause in addition headaches if not treated.
Most pertinently, the infection will possibly now not go on its personal. This manner if you have Athlete's foot (any other shape of Candidiasis), or a few different Candida-based infection, you will normally need to work difficult your self on cleansing it up.
Solutions are truly pretty bountiful... "Tiger Balm" (a extra effective Vicks Vapour Rub) being considered one of them.
Firstly, the crucial aspect to word is that there are varieties of Candidal contamination. You can both get a increase on the floor of the skin, or it is able to be embedded in the skin. The type you have determines the treatment.
Secondly, ALL Candida responds within the equal manner to the diverse remedies. The simplest distinction lies in gaining access to the basis motive of the problem. If you have got an embedded contamination, it'll typically require direct get entry to via the floor layer of pores and skin (for this reason why the likes of laser remedy is used for Toenail fungus).
The factor is that if you're able to get right of entry to the infection (it is both at the surface of the skin or close), you can follow active ingredient immediately to it. In the case of the "cottage cheese" kind substance for most fungal infections, this means you can apply the likes of anti-dandruff shampoo, yoghurt or "Vicks Vapour Rub" to essentially kill off the fungal spores. This might be brief and painless.
If you have got an embedded contamination (heels / toenails / vagina), you need to be careful with what you come to be doing. Specifically, if the contamination is underneath the surface of the pores and skin, you have to cast off the top layer to be able to hit the fungus without delay. This is in which the likes of Tiger Balm comes in.
Tiger Balm is nothing unique. It's just a more powerful Vicks Vapour Rub without the Eucalyptus. The most crucial factor is that it's potent. Really strong. And it hurts.
The cream basically tricks the brain into "numbing" the ache receptors in your frame. It creates an "ice warmth" - GREAT for muscle injuries, however essentially means which you need to expect a few discomfort from the use of it (appearance up Tiger Balm on YouTube for greater data).
To this quit, if you want to get rid of a Toe nail infection with it, you first want in an effort to eliminate the surface layer of the nail. This is best done through submitting, or may be done by applying a cream to soften the nail earlier than looking to select off all the inflamed layers at the top.
Once you've got eliminated the "crusty" layer of the nail, you must then be using the likes of Tiger Balm to kill off the contamination at once. Again, this can hurt but you need to be definitely stoic in its application - put it all around the nail so it'll cast off it absolutely. If it works, the new nail that forms need to be completely "fungus loose".
Monday, June 17, 2019
Does Tiger Balm Cure Nail Fungus?
by Healthh on June 17, 2019
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. Volume XXII Number 17. . . .January 8, 2016
This evocative picture book about a friendship between a girl and her dog reads like a memoir with a surprising twist. The last page of text reveals that the narrator is a service animal whose relationship with Lola, a young blind girl, has promoted her independence. Flipping back through the pages, we can reread information about Lola's travels, knowing now that it is because of her canine companion that she is able to navigate the markets, spend days in the park, tobogganing, and enjoying a special trip to the seaside.
This title was originally published in Italy as Lola e io where it received the 2015 IBBY Outstanding Book for Young People with Disabilities.
Italian author Chiara Valentina both wrote and translated the story. Italian artist Paolo Domeniconi created the beautifully textured illustrations, painted entirely in digital media using Adobe Photoshop.
While this is very much a book about character rather than action, it will inspire personal responses in its readership, and it offers room for related talk as a response activity if used in elementary classrooms.
Although the target reading age involves younger elementary students, Lola and I is a book that will be appreciated by older readers in the way it takes action against stereotypes while offering a portrayal of an energetic young woman whose blindness is only one characteristic in a dynamic portrayal.
Highly Recommended.
Bev Brenna, a literacy professor at the University of Saskatchewan, has 10 published books for young people.
To comment
on this title or this review, send mail to firstname.lastname@example.com.
Copyright © the Manitoba Library Association. Reproduction for personal
use is permitted only if this copyright notice is maintained. Any
other reproduction is prohibited without permission.
Copyright © the Manitoba Library Association. Reproduction for personal use is permitted only if this copyright notice is maintained. Any other reproduction is prohibited without permission.
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Table of Contents for This Issue
- January 8, 2016.


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