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Cetylpyridinium chloride (CPC) is a quaternary ammonium antimicrobial used in numerous personal care products, human food, cosmetic products, and cleaning solutions. Yet, there is minimal published data on CPC effects on eukaryotes, immune signaling, and human health. Previously, it was shown that low-micromolar CPC inhibits rat mast cell function by inhibiting antigen (Ag)-stimulated Ca2+ mobilization, microtubule polymerization, and degranulation. In the current study, these findings are extended to human mast cells (LAD2); this paper presents data indicating that a mechanism of action for CPC might center on its positively-charged quaternary nitrogen in its pyridinium headgroup. The inhibitory effect of CPC was independent of signaling platform receptor architecture. Tyrosine phosphorylation events are a trigger of Ca2+ mobilization necessary for degranulation. CPC inhibits global tyrosine phosphorylation in Ag-stimulated mast cells. Specifically, CPC inhibits tyrosine phosphorylation of specific key players Syk kinase and LAT, a substrate of Syk. In contrast, CPC did not affect Lyn kinase phosphorylation. Thus, a root mechanism for CPC effect might be electrostatic disruption of particular tyrosine phosphorylation events essential for signaling. This work presented here outlines biochemical mechanisms underlying the effects of CPC on immune signaling. [ABSTRACT FROM AUTHOR]

Post-translational ubiquitination is an essential mechanism for the regulation of protein stability and function, which contributes to the regulation of the immune system. Cbl, an E3 ubiquitin ligase, is particularly well-characterized in the context of T and NK cell signaling, where it serves as a key regulator of receptor downstream signaling events and as a modulator of cell activation. Cbl promotes the proteasomal degradation of TCR/CD3 subunits as well as the protein kinases Fyn and Lck in T cells. Additionally, the scaffold protein linker for activation of T cells (LAT) is a universal target for Cbl-mediated ubiquitination and degradation in both T and NK cells. Recent findings suggest that CrkII-mediated ubiquitination and degradation of C3G by Cbl during early T cell activation may also be relevant to NK cell signaling. Given its role in modulating immune responses and its manageable impact on autoimmunity, Cbl is being investigated as a target for cancer immunotherapy. This review explores the ubiquitin ligase activity of Cbl and its implications for CAR T and NK cell immunotherapies. [ABSTRACT FROM AUTHOR]

The delimitation of maritime boundaries plays a significant role in preserving the country's sovereignty and jurisdiction. The maritime baseline was established based on the combination of maritime basepoints, which represents the Lowest Astronomical Tide (LAT) along the coast. However, the current approach still relies on the limited and sparsely distributed tide gauge stations for the determination of LAT. Therefore, this study aims to develop the Peninsular Malaysia Near-Seamless Tidal Datum (PMNSTD) by integrating tide gauge, satellite altimetry, and Tide Model Driver (TMD) data. PMNSTD was further integrated with Digital Elevation Models (DEM) for the delimitation of maritime boundaries. This study methodology includes data acquisitions of 12 tide gauge stations along the coast of Peninsular Malaysia, satellite altimetry data for TOPEX, Jason-1, Jason-2, and GEOSAT Follow-On (GFO) from Radar Altimeter Database System (RADS), TMD, and TerraSAR-X add on for Digital Elevation Measurement 30 m (TanDEM-X) data. The tide gauge, satellite altimetry, and TMD data encompass 23 years of tidal observation data from 1993 to 2015. For the derivation of the tidal datum, the tide gauge and satellite altimetry data were analysed using harmonic analysis in UTide, whereas, for the TMD data, the tidal datum was determined based on tidal prediction. For compatibility in data integration, the derived Lowest and Highest Astronomical Tide (LAT and HAT) from tide gauge, satellite altimetry, and TMD data were referenced to the Mean Sea Level (MSL), denoted as ${\rm{LA}}{{\rm{T}}_{{\rm{msl}}}}{\rm{ }}$ LA T msl and ${\rm{HA}}{{\rm{T}}_{{\rm{msl}}}}$ HA T msl respectively. Next, the ${\rm{LA}}{{\rm{T}}_{{\rm{msl}}}}{\rm{ }}$ LA T msl and ${\rm{HA}}{{\rm{T}}_{{\rm{msl}}}}$ HA T msl was interpolated using Inverse Distance Weighting (IDW) to develop the PMNSTD (${\rm{LA}}{{\rm{T}}_{{\rm{msl}}}}{\rm{ }}$ LA T msl and ${\rm{HA}}{{\rm{T}}_{{\rm{msl}}}}$ HA T msl ) using ArcGIS. The statistical assessment indicates that the PMNSTD (${\rm{LA}}{{\rm{T}}_{{\rm{msl}}}}{\rm{ }}$ LA T msl and ${\rm{HA}}{{\rm{T}}_{{\rm{msl}}}}$ HA T msl ) established from the integration of tide gauge, satellite altimetry, and TMD has a better agreement with the Department of Survey and Mapping Malaysia (DSMM) tide gauges with a Root Mean Square Error (RMSE) and Standard Deviation (STD) of 0.228 m and 0.175 m for ${\rm{LA}}{{\rm{T}}_{{\rm{msl}}}}$ LA T msl , as well as 0.159 m and 0.079 m for ${\rm{HA}}{{\rm{T}}_{{\rm{msl}}}}$ HA T msl . Next, the PMNSTD (${\rm{LA}}{{\rm{T}}_{{\rm{msl}}}}$ LA T msl ) was integrated with TanDEM-X using ArcGIS and SURFER for the delimitation of maritime boundaries. The reliability assessment illustrated a significant improvement in the continuation of 201 maritime basepoints in comparison to the 95 maritime basepoints by the DSMM. In conclusion, the proposed approach has shown a continuous, consistent, and wider establishment of the country's maritime baseline for the Peninsular Malaysia region. [ABSTRACT FROM AUTHOR]

Background: Despite the short- and long-term acknowledged benefits of breastfeeding for mothers and their infants, worldwide rates trail behind international goals. Prior research confirms that breastfeeding is a nurse sensitive indicator and that problems with latching the baby and painful breastfeeding rank high among the reasons given for not continuing to breastfeed. The Lactation Assessment Tool (LATTM) was previously evaluated in a study conducted in Latvia by nurse midwives. Use of the LAT to assess breastfeeding and suggesting corrective interventions were shown to decrease pain and promote healing in traumatized nipples. The inter-rater reliability for that study was by test/re-test amongst participating researcher midwives. The aim of the current study is to expand the understanding of LAT inter-rater reliability to include novice and expert assessors. Methods: A convenience sample of twenty participants, including both novices (nine nursing students) and 11 self-identified experts, assessed four videos of breastfeeding dyads using the assessment tool, the LAT. Novice participants received a 2 h training session before final tool assessment. Each video was viewed three times, with a 3 min pause between viewings. All elements of the LAT that could be visually evaluated were included, with each element appearing in at least two of the videos. Results: Acceptable internal consistency of the LAT tool was found, with Cronbach's alpha measuring 0.799, 0.740, 0.756 and 0.735 for each video, respectively. The reliability of the novice assessors improved over the course of the four videos, from 0.484 and 0.610 to 0.714 and 0.711. All of the experts had Cronbach's alpha numbers that were acceptable, ranging from 0.769 to 1.00. Conclusions: Results indicate that experts perform much better using the tool than trained novices. However, the subsequent use of the tool resulted in the last two video assessments having an acceptable measure for the trained novice group. The LAT is a reliable tool for trained novices and experts to assess breastfeeding positioning and latch. [ABSTRACT FROM AUTHOR]

Precise and timely diagnosis is essential to prevent severe outcomes of leptospirosis in humans and animals. Existing diagnostic methods face challenges and limitations, underscoring the need for novel, field-applicable screening, and diagnostic tests/assays. This study evaluates the diagnostic utility of a recombinant ErpY-like lipoprotein (rErpY-LIC11966) in a latex agglutination test (LAT) for diagnosis of animal leptospirosis. The ErpY gene sequence from Leptospira interrogans serovar Pomona, excluding the signal peptide, was amplified, cloned into the pETite vector, and expressed in Escherichia coli. The expressed rErpY (∼16 kDa) was characterized by Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis and Western blot using Leptospira -specific standard sera. To assess the diagnostic potential of rErpY, Ni-NTA affinity-purified protein was used to sensitize latex-coated beads (0.8 µm colour beads), which were then employed in the LAT for standardization and optimization with standard positive and negative sera. For evaluation, the rErpY-LAT was tested on serum samples from 177 suspected animal cases and compared to the microscopic agglutination test. It showed a relative diagnostic sensitivity of 90.6%, a specificity of 89.1%, and an overall accuracy of 90%. This study proposes rErpY-LAT as a field testing/screening diagnostic tool for preliminary serodiagnosis of leptospirosis, highlighting the potential of recombinant protein-based assays to address current diagnostic challenges. [ABSTRACT FROM AUTHOR]

Background: Despite the short- and long-term acknowledged benefits of breastfeeding for mothers and their infants, worldwide rates trail behind international goals. Prior research confirms that breastfeeding is a nurse sensitive indicator and that problems with latching the baby and painful breastfeeding rank high among the reasons given for not continuing to breastfeed. The Lactation Assessment Tool (LATTM) was previously evaluated in a study conducted in Latvia by nurse midwives. Use of the LAT to assess breastfeeding and suggesting corrective interventions were shown to decrease pain and promote healing in traumatized nipples. The inter-rater reliability for that study was by test/re-test amongst participating researcher midwives. The aim of the current study is to expand the understanding of LAT inter-rater reliability to include novice and expert assessors. Methods: A convenience sample of twenty participants, including both novices (nine nursing students) and 11 self-identified experts, assessed four videos of breastfeeding dyads using the assessment tool, the LAT. Novice participants received a 2 h training session before final tool assessment. Each video was viewed three times, with a 3 min pause between viewings. All elements of the LAT that could be visually evaluated were included, with each element appearing in at least two of the videos. Results: Acceptable internal consistency of the LAT tool was found, with Cronbach’s alpha measuring 0.799, 0.740, 0.756 and 0.735 for each video, respectively. The reliability of the novice assessors improved over the course of the four videos, from 0.484 and 0.610 to 0.714 and 0.711. All of the experts had Cronbach’s alpha numbers that were acceptable, ranging from 0.769 to 1.00. Conclusions: Results indicate that experts perform much better using the tool than trained novices. However, the subsequent use of the tool resulted in the last two video assessments having an acceptable measure for the trained novice group. The LAT is a reliable tool for trained novices and experts to assess breastfeeding positioning and latch.

Latex agglutination test (LAT) assay was carried out for the diagnosis of Dirofilaria repens infection in dogs by using adult worm somatic antigen. A total of 250 blood and serum samples of dogs were screened for the detection of microfilaria by quantitative buffy coat method (QBC) and D. repens circulatory antibodies by LAT. During the study, QBC detected microfilaria in 93 samples with a prevalence rate of 37.2%. Among 250 serum samples screened by LAT, 142 (56.8%) showed positive reaction with an agglutination ranging from +1 to +4 and the remaining 108 samples were negative with uniform turbidity and no agglutination. Among 142 positive samples, 78 (54.92%) serum samples of dogs showed agglutination of +3 to +4 and the remaining 64 (45.08%) showed +1 to +2 agglutination. The sensitivity and specificity of LAT was found to be 100 and 76.21 per cent, respectively. The morphology and micrometry of microfilaria was studied by modified Knott’s method. The species was identified as D. repens based on the morphology and micrometry of adult worm and microfilaria. [ABSTRACT FROM AUTHOR]

Human alphaherpesvirus 1 (HSV-1) establishes life-long latency in sensory neurons in trigeminal ganglia (TG), brainstem neurons, and other CNS neurons. Two important segments of the brainstem were examined in this study: principal sensory nucleus of the spinal trigeminal tract (Pr5) because it receives direct afferent inputs from TG, and locus coeruleus (LC) because it is indirectly connected to Pr5 and LC sends axonal projections to cortical structures, which may facilitate viral spread from brainstem to the brain. The only viral gene abundantly expressed during latency is the latency associated transcript (LAT). Previous studies revealed 8-week old female C57Bl/6 mice infected with a LAT null mutant (dLAT2903) versus wild-type (wt) HSV-1 exhibit higher levels of senescence markers and inflammation in LC of females. New studies revealed 1-year old mice latently infected with wt HSV-1 or dLAT2903 contained differences in neuroinflammation and senescence in Pr5 and LC versus young mice. In summary, these studies confirm HSV-1 promotes neuro-inflammation in the brainstem, which may accelerate neurodegenerative disease.

Introduction: Patients with oligometastatic NSCLC benefit from locally ablative therapies (LAT); the role of adjuvant systemic therapies, however, remains less clear. In a single-arm, phase II clinical trial, we found that patients with oligometastatic NSCLC treated with a year of pembrolizumab after LAT had superior progression-free survival (PFS) compared with a historical control cohort. Herein, we present long-term follow-up on PFS and overall survival (OS). Methods: From February 1, 2015, to September 30, 2017, 45 patients with synchronous or metachronous oligometastatic (≤4 metastatic sites) NSCLC treated with LAT to all sites received adjuvant pembrolizumab every 21 days for up to 16 cycles. The primary efficacy end point was PFS from the start of pembrolizumab. Secondary end points included OS and safety. Median duration of follow-up was 66 months, and data cutoff was December 1, 2022. Results: A total of 45 patients were enrolled and treated with pembrolizumab after LAT (median age, 64 y [range, 46–82]; 21 women [47%]; 31 with a solitary oligometastatic site [69%]). At the data cutoff, 32 patients had progressive disease, 19 patients had died, and 13 patients had no evidence of relapse. Median PFS was 19.7 months (95% confidence interval: 7.6–31.7 mo); median OS was not reached (95% confidence interval: 37.7 mo–not reached). OS at 5 years was 60.0% (SE, 7.4%). Metachronous oligometastatic disease was associated with improved OS and PFS through Cox proportional hazard models. Conclusions: Pembrolizumab after LAT for oligometastatic NSCLC results in promising PFS and OS with a tolerable safety profile.

The determination of the maritime boundary is related to the selection of the tidal datum used in relation to the zero-depth reference. This research was conducted to determine the impact of the zero-depth reference that has been used, the Mean Low Water Spring (MLWS), against the zero-depth recommended by the International Hydrographic Organization (IHO), the Lowest Astronomical Tide (LAT). Tidal data is obtained from BIG's tidal station processing, while the MLWS value data is obtained from a combination of analysis from the Hydrographic Office of Indonesia (Pushidros). Based on these data, it is found that 25 out of 37 tidal stations indicate that the LAT value is below the MLWS in its vertical position. This shows that sea boundary claims can potentially be shifted by changing the zero-depth reference from the original by switching from MLWS to LAT. Lastly, this study presents the benefits of implementing the vertical system reference recommended by the IHO, the LAT, as an international chart datum.

Herpes simplex virus 1 (HSV-1) produces a long noncoding RNA, the latency-associated transcript (LAT), that mediates silencing of the virus in neurons through unknown mechanisms. Here, we show that the LAT binds both the cellular transmembrane protein 43 (TMEM43) and HSV-1 genomes in human neurons. Additionally, loss of TMEM43 prior to infection results in a decreased ability of the virus to establish latency, mirroring phenotypes of LAT promoter mutant viruses which are also defective in establishing latency. These data support a unique mechanism whereby the LAT binds TMEM43 and the HSV genome to localize HSV-1 genomes to the nuclear periphery to repress lytic viral transcription and establish viral latency and suggests that TMEM43 may play a similar role in regulating cellular genes. [ABSTRACT FROM AUTHOR]

The determination of the maritime boundary is related to the selection of the tidal datum used in relation to the zero-depth reference. This research was conducted to determine the impact of the zero-depth reference that has been used, the Mean Low Water Spring (MLWS), against the zero-depth recommended by the International Hydrographic Organization (IHO), the Lowest Astronomical Tide (LAT). Tidal data is obtained from BIG's tidal station processing, while the MLWS value data is obtained from a combination of analysis from the Hydrographic Office of Indonesia (Pushidros). Based on these data, it is found that 25 out of 37 tidal stations indicate that the LAT value is below the MLWS in its vertical position. This shows that sea boundary claims can potentially be shifted by changing the zero-depth reference from the original by switching from MLWS to LAT. Lastly, this study presents the benefits of implementing the vertical system reference recommended by the IHO, the LAT, as an international chart datum. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii is a globally found intracellular parasite that infected a large proportion of the world population, it remained asymptomatic in immunocompetent patients but the acquisition of the infection during pregnancy can lead to abortions and other congenital defects. The present study aimed to find the seroprevalence of T. gondii among suspected women who visited local hospitals in Khyber Pakhtunkhwa (KP), Pakistan. Sera of 425 suspected women were screened by latex agglutination test (LAT) and enzyme-linked immunosorbent assay (ELISA) was performed to measure the IgG and IgM antibodies level. Univariate analysis and odds ratios were calculated to determine the strength of association. The overall T. gondii infection was 60% with LAT, 52% IgG, and 56.26% with IgM ELISA. The seroprevalence was 7.2%-15% among the five study districts of KP province. The toxoplasmosis was found significantly (p<0.001) higher in 34.7% to 44.2% of pregnant women as compared to non-pregnant. The high prevalence of infection was recorded among women belonging to the 20-30 years and 31-40 years age group (16.78%-36.45), 1st and 3rd trimesters (33.2%-40.3%), and housewives (28.8%-37.4%). The mean of IgG and IgM antibodies titer was observed higher than >1.3 in pregnant women and in the 2nd and 3rd trimesters. The present study concluded a higher prevalence of T. gondii infection in women of childbearing age in KP, Pakistan, and requires preventive measures to reduce the abortion risks and congenital abnormalities in fetus. [ABSTRACT FROM AUTHOR]

Simple Summary: Tyrosine phosphorylation is the first biochemical event that occurs after TCR engagement, which is crucial for T-cell development, activation and differentiation. Early TCR signals include phosphorylation events in which the tyrosine kinases Lck and ZAP70 are involved. The sequential activation of these kinases leads to the phosphorylation of the transmembrane adaptor LAT, which constitutes a signaling hub for the generation of a signalosome, finally resulting in T-cell activation. The negative regulation of these early signals is key to avoid aberrant processes that could generate inappropriate cellular responses and disease. In this review, we examine and discuss the roles of the tyrosine kinases Lck and ZAP70 and the membrane adaptor LAT in the TCR-signaling cassette, both of their functions in activation signal transduction and the negative-feedback loops in which they participate. A better knowledge of these negative regulatory mechanisms may be critical not only for understanding T-cell activation, but also for a more efficient design of therapeutic approaches and a better understanding of some immune-based pathologies. Specific antigen recognition is one of the immune system's features that allows it to mount intense yet controlled responses to an infinity of potential threats. T cells play a relevant role in the host defense and the clearance of pathogens by means of the specific recognition of peptide antigens presented by antigen-presenting cells (APCs), and, to do so, they are equipped with a clonally distributed antigen receptor called the T-cell receptor (TCR). Upon the specific engagement of the TCR, multiple intracellular signals are triggered, which lead to the activation, proliferation and differentiation of T lymphocytes into effector cells. In addition, this signaling cascade also operates during T-cell development, allowing for the generation of cells that can be helpful in the defense against threats, as well as preventing the generation of autoreactive cells. Early TCR signals include phosphorylation events in which the tyrosine kinases Lck and ZAP70 are involved. The sequential activation of these kinases leads to the phosphorylation of the transmembrane adaptor LAT, which constitutes a signaling hub for the generation of a signalosome, finally resulting in T-cell activation. These early signals play a relevant role in triggering the development, activation, proliferation and apoptosis of T cells, and the negative regulation of these signals is key to avoid aberrant processes that could generate inappropriate cellular responses and disease. In this review, we will examine and discuss the roles of the tyrosine kinases Lck and ZAP70 and the membrane adaptor LAT in these cellular processes. [ABSTRACT FROM AUTHOR]

Thirteen benzylethoxyaryl ureas have been synthesized and biologically evaluated as multitarget inhibitors of VEGFR-2 and PD-L1 proteins to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on several tumor cell lines (HT-29 and A549), on the endothelial cell line HMEC-1, on immune cells (Jurkat T) and on the non-tumor cell line HEK-293 has been determined. Selective indexes (SI) have been also determined and compounds bearing p-substituted phenyl urea unit together with a diaryl carbamate exhibited high SI values. Further studies on these selected compounds to determine their potential as small molecule immune potentiators (SMIPs) and as antitumor agents have been performed. From these studies, we have concluded that the designed ureas have good tumor antiangiogenic properties, exhibit good inhibition of CD11b expression, and regulate pathways involved in CD8 T-cell activity. These properties suggest that these compounds could be potentially useful in the development of new cancer immune treatments. [ABSTRACT FROM AUTHOR]

Abstract Background Toxoplasma is an obligate intracellular protozoan that causes an important zoonotic disease with a worldwide distribution. Felids are the definitive hosts of this parasite, while virtually all warm-blooded animals, including birds, serve as intermediate hosts. Four ring-tailed lemurs (Lemur catta) in the Taipei Zoo died of acute Toxoplasma infection in June 2019. Since then, Toxoplasma has occasionally been identified in this Zoo during necropsy of dead animals and PCR of animal blood samples. Therefore, a general survey of Toxoplasma infection in animals in the Zoo seems to be needed. Methods and results An indirect multispecies ELISA was used for the first time to screen for Toxoplasma infection in 326 serum samples collected from 75 species of animals. The infection rate of Toxoplasma was 27% (88/326). A commercial latex agglutination (LAT) assay was used to re-examine the samples with doubtful and uncertain ELISA results (151 samples from 42 species). The infection rate increased to 36.2% (118/326), and the indirect multispecies ELISA appeared to be applicable to 31 of 75 species animals included in this study. Nested PCR assays targeting the dense granule protein 7 (GRA7) gene and B1 gene were also used to detect Toxoplasma in DNA samples extracted from 10 liver or blood specimens from 8 animals. GRA7 gene fragments were amplified from 8 samples from 7 animals, while B1 gene fragments were amplified from only 4 samples from 4 animals. From the B1 nested PCR and the sequence data of GRA7 fragments amplified from infectious specimens, the animals in the Zoo were speculated to have been infected by at least three different Toxoplasma variants. Conclusions According to the serological investigation, we speculated that over one-third (36.2%) of animals in Taipei Zoo presented the infection of Toxoplasma, and the indirect multispecies ELISA we used can be applied to detect Toxoplasma infection in 31 animal species included in this study. Sequence analysis revealed that at least three Toxoplasma variants were infecting the animals of Taipei Zoo.

The aim of this work is to verify the possibility of transport of 26 biologically active ultrashort peptides (USPs) into cells via LAT and PEPT family transporters. Molecular modeling and computer-assisted docking of peptide ligands revealed that the size and structure of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analysis of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters has been carried out. The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides, for which no biological activity has been established. This indicates an important possible role which LAT and PEPT family transporters may play in a variety of biological activities of the 26 biologically active peptides under investigation in this study. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp− or Glu− amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide are found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters. The data obtained lead to new prospects for further study of the mechanisms of transport of USP-based drugs into the cell and design of new antitumor drugs. [ABSTRACT FROM AUTHOR]

The steady‐state laminar nonisothermal, incompressible viscoelastic fluid flows with the Jeffrey model between two counterrotating (same direction) rolls are studied analytically. The Jeffrey model is reduced to the Newtonian model after some appropriate modifications. The new dimensionless governing equations are acquired through suitable nondimensional values. The lubrication approximation theory is employed for the simplification of emerging equations. The exact expressions for pressure gradient, velocity, temperature, and flow rate are accomplished whereas some quantities of interest such as pressure, coating thickness, power transmitted by rolls to the fluid, and roll separation force are computed numerically by using a numerical method. The influence of emerging parameters such as the ratio of relaxation time to the retardation time λ1 ${\lambda }_{1}$, magnetohydrodynamic (MHD) parameter M $M$ and Brinkman number Br $Br$ on velocity profile, temperature profile, pressure gradient, pressure distribution, coating thickness, power input, and force of roll separation are presented numerically in a tabular way and specific outcomes are demonstrated graphically. The MHD acts as a regulatory parameter for various quantities of important interest, such as velocity, coating thickness, and temperature. It is worth noting that the coating thickness decreases as modified capillaries number is increased. [ABSTRACT FROM AUTHOR]

Background: While immunotherapy has shown potent efficacy in clinical practices, patient selection to receive checkpoint blockade is still challenging in prostate cancer (PCa). LAT and ZAP70 functions in lymphocyte activation and plays a critical role in T cell receptor (TCR) signal transduction. However, PCa genomic and clinical data regarding the role of LAT and ZAP70 are limited. We aim to identify and characterize LAT/ZAP70 defined subtypes of PCa. Methods: We elaborated the TCGA PCa data and metastatic castration-resistant prostate cancer (mCRPC) RNA-seq data bioinformatic analysis and systematically elucidated the role of intra-tumoral expressed LAT and ZAP70 in the progression-free survival and immunotherapeutic-related signals. LAT/ZAP70-associated immune infiltration was evaluated using bioinformatic tools. Immunohistochemical staining of serial sections was used to confirm the expression and distribution of LAT, ZAP70 and androgen receptor (AR) in PCa tissues. Results: Specifically, LAT and ZAP70 revealed increased expressions in PCa when compared to normal tissues and positively associated with intra-tumoral immune cells infiltration. LAT/ZAP70 defined immune-high early-stage PCa revealed higher TP53 mutation frequency and poor prognosis. Transcriptome analysis indicated immune-related signals and CTLA4 expression were highly enhanced in immune-high PCa parallel with higher protein level of MYC and lower AR expression. In mCRPC, LAT/ZAP70 defined immune-high patients also revealed upregulated immune related signals, higher CTLA4 expression and DNA repair deficiency. Conclusion: LAT/ZAP70 defined immune-high PCa linked to immune infiltration and predicts poor prognosis. Immune-high PCa may receive effective response from immune checkpoint inhibitor parallel with systemic treatment. [ABSTRACT FROM AUTHOR]

This document is a comment letter published in the Journal of Virology. It discusses the presence of HSV-1 LAT (latency-associated transcript) in non-neuronal ganglionic cells of mice and humans. The authors respond to a reanalysis of their data that claimed no LAT in non-neuronal cells, highlighting concerns about the reanalysis methodology. They argue that their study and a repeated scRNA-seq experiment provide ample evidence for the presence of LAT in non-neuronal cells. The authors recommend readers review both papers and draw their own conclusions. [Extracted from the article]

Background: Toxoplasma is an obligate intracellular protozoan that causes an important zoonotic disease with a worldwide distribution. Felids are the definitive hosts of this parasite, while virtually all warm-blooded animals, including birds, serve as intermediate hosts. Four ring-tailed lemurs (Lemur catta) in the Taipei Zoo died of acute Toxoplasma infection in June 2019. Since then, Toxoplasma has occasionally been identified in this Zoo during necropsy of dead animals and PCR of animal blood samples. Therefore, a general survey of Toxoplasma infection in animals in the Zoo seems to be needed. Methods and results: An indirect multispecies ELISA was used for the first time to screen for Toxoplasma infection in 326 serum samples collected from 75 species of animals. The infection rate of Toxoplasma was 27% (88/326). A commercial latex agglutination (LAT) assay was used to re-examine the samples with doubtful and uncertain ELISA results (151 samples from 42 species). The infection rate increased to 36.2% (118/326), and the indirect multispecies ELISA appeared to be applicable to 31 of 75 species animals included in this study. Nested PCR assays targeting the dense granule protein 7 (GRA7) gene and B1 gene were also used to detect Toxoplasma in DNA samples extracted from 10 liver or blood specimens from 8 animals. GRA7 gene fragments were amplified from 8 samples from 7 animals, while B1 gene fragments were amplified from only 4 samples from 4 animals. From the B1 nested PCR and the sequence data of GRA7 fragments amplified from infectious specimens, the animals in the Zoo were speculated to have been infected by at least three different Toxoplasma variants. Conclusions: According to the serological investigation, we speculated that over one-third (36.2%) of animals in Taipei Zoo presented the infection of Toxoplasma, and the indirect multispecies ELISA we used can be applied to detect Toxoplasma infection in 31 animal species included in this study. Sequence analysis revealed that at least three Toxoplasma variants were infecting the animals of Taipei Zoo. [ABSTRACT FROM AUTHOR]

Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. The latency associated transcript (LAT) is the only viral gene abundantly expressed during latency. Wild-type (WT) HSV-1 reactivates more efficiently than LAT mutants because LAT promotes establishment and maintenance of latency. While sensory neurons in trigeminal ganglia (TG) are important sites for latency, brainstem is also a site for latency and reactivation from latency. The principal sensory nucleus of the spinal trigeminal tract (Pr5) likely harbors latent HSV-1 because it receives afferent inputs from TG. The locus coeruleus (LC), an adjacent brainstem region, sends axonal projections to cortical structures and is indirectly linked to Pr5. Senescent cells accumulate in the nervous system during aging and accelerate neurodegenerative processes. Generally senescent cells undergo irreversible cell cycle arrest and produce inflammatory cytokines and chemokines. Based on these observations, we hypothesized HSV-1 influences senescence and inflammation in Pr5 and LC of latently infected mice. This hypothesis was tested using a mouse model of infection. Strikingly, female but not age-matched male mice latently infected with a LAT null mutant (dLAT2903) exhibited significantly higher levels of senescence markers and inflammation in LC, including cell cycle inhibitor p16, NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), IL-1α, and IL-β. Conversely, Pr5 in female but not male mice latently infected with WT HSV-1 or dLAT2903 exhibited enhanced expression of important inflammatory markers. The predilection of HSV-1 to induce senescence and inflammation in key brainstem regions of female mice infers that enhanced neurodegeneration occurs. [ABSTRACT FROM AUTHOR]

Simple Summary: Toxoplasmosis is a zoonotic disease caused by T. gondii infection. The main aims of this study were to assess the seropositivity to toxoplasmosis of an exotic breed of cattle (n = 400) from different farms using the Latex Agglutination Test, validate the Cattle Toxo IgG ELISA kit with the help of the commercially available ELISA kit and compare the efficacy of the LAT and Cattle Toxo IgG ELISA kit for assessing seropositivity of cattle to toxoplasmosis. Four hundred cattle sera were collected from an exotic breed of cattle in Pakistan. These sera were evaluated through an LAT and Cattle Toxo IgG ELISA kit. Of 400 samples, 90 were elected and screened through a commercially available ELISA kit. The sensitivity and specificity of the Cattle Toxo IgG ELISA kit came out to be 100% and 96.15%, and in LAT, it was found as 26.31% and 61.53%, respectively. The Cattle Toxo IgG ELISA kit revealed 29.75% (119/400) seropositivity, 6% less than that found through LAT. The results of this study show that Cattle Toxo IgG ELISA kit is a highly accurate and reliable serodiagnostic tool to diagnose bovine toxoplasmosis. Toxoplasma gondii is a protozoan parasite that causes toxoplasmosis in warm-blooded vertebrates, globally. The main aims of this study were to assess the seropositivity to toxoplasmosis of an exotic breed of cattle (n = 400) from different farms using the Latex Agglutination Test and validate Cattle Toxo IgG ELISA kit. Of a total of 400 cattle sera that were evaluated by LAT, 143 (35.75%) were found positive. Based on these data, 90 samples (n = 60 seronegative by LAT; n = 30 seropositive by LAT) were elected for screening through a commercially available ELISA kit. The same 90 samples were screened through a Cattle Toxo IgG ELISA kit for validation purposes. Of 90 samples, 40 were seropositive in the Cattle Toxo IgG ELISA kit (100% sensitivity), and 38 were seropositive in a commercially available ELISA kit. All 50 samples in the Cattle Toxo IgG ELISA kit (96.15% specificity) were also seronegative in the commercially available ELISA kit. Hence, the sensitivity and specificity of the Cattle Toxo IgG ELISA kit came out to be 100% and 96.15%, and in LAT, it was found as 26.31% and 61.53%, respectively. Therefore, the Cattle Toxo IgG ELISA kit is a highly reliable serodiagnostic tool to diagnose bovine toxoplasmosis. [ABSTRACT FROM AUTHOR]

Living-apart-together (LAT) partnerships are gaining prominence in many high-income societies, prompting ongoing discussions about their significance and their role in the family formation process. This study provides a contemporary update on LAT relationships in Spain, with a specific emphasis on variations across different life stages. The study focuses on several key aspects: (1) recent trends in the prevalence of LAT relationships, (2) socio-demographic factors associated with being in a LAT relationship, (3) joint influence of both partners' characteristics, and (4) short-term intentions to co-reside. Using data from the 2018 Spanish Fertility Survey, we employ logistic regression models to analyze the factors influencing individuals' likelihood of being in a LAT relationship as opposed to a co-residential partnership. Our findings reveal a noticeable rise in LAT partnerships in Spain over the past two decades, except among the youngest age group. Personal motivations and socially attributed meanings of LAT relationships, however, differ depending on an individual's life stage. Among young adults, LAT partnerships largely serve as a transitional phase in the family formation process, preceding co-residence with a partner. In this early adulthood stage, unemployment and temporary work contracts – affecting any of the partners – often hinder household formation, but intentions to co-reside in the near future remain strong. In contrast, LAT partnerships in the mid-life stage often stem from a desire to maintain personal independence and are frequently linked to prior partnership and reproductive biographies. ● The prevalence of LAT relationships has risen in Spain over the last two decades. ● Among young adults, LAT serves as a transitional phase preceding co-residence. ● Young couples in which any of the partners lacks stable work are more likely to LAT. ● Middle-aged adults with children from prior partnerships are more likely to LAT. ● The desire for autonomy is a relatively common reason to LAT in the mid-life stage. [ABSTRACT FROM AUTHOR]

Establishing both central and peripheral tolerance requires the appropriate TCR signaling strength to discriminate self‐ from agonist‐peptide bound to self MHC molecules. ZAP70, a cytoplasmic tyrosine kinase, directly interacts with the TCR complex and plays a central and requisite role in TCR signaling in both thymocytes and peripheral T cells. By studying ZAP70 hypomorphic mutations in mice and humans with a spectrum of hypoactive or hyperactive activities, we have gained insights into mechanisms of central and peripheral tolerance. Interestingly, both hypoactive and hyperactive ZAP70 can lead to the development of autoimmune diseases, albeit through distinct mechanisms. Immature thymocytes and mature T cells rely on normal ZAP70 function to complete their development in the thymus and to modulate T cell responses in the periphery. Hypoactive ZAP70 function compromises key developmental checkpoints required to establish central tolerance, allowing thymocytes with potentially self‐reactive TCRs a greater chance to escape negative selection. Such 'forbidden clones' may escape into the periphery and may pose a greater risk for autoimmune disease development since they may not engage negative regulatory mechanisms as effectively. Hyperactive ZAP70 enhances thymic negative selection but some thymocytes will, nonetheless, escape negative selection and have greater sensitivity to weak and self‐ligands. Such cells must be controlled by mechanisms involved in anergy, expansion of Tregs, and upregulation of inhibitory receptors or signaling molecules. However, such potentially autoreactive cells may still be able to escape control by peripheral negative regulatory constraints. Consistent with findings in Zap70 mutants, the signaling defects in at least one ZAP70 substrate, LAT, can also lead to autoimmune disease. By dissecting the similarities and differences among mouse models of patient disease or mutations in ZAP70 that affect TCR signaling strength, we have gained insights into how perturbed ZAP70 function can lead to autoimmunity. Because of our work and that of others on ZAP70, it is likely that perturbations in other molecules affecting TCR signaling strength will be identified that also overcome tolerance mechanisms and cause autoimmunity. Delineating these molecular pathways could lead to the development of much needed new therapeutic targets in these complex diseases. [ABSTRACT FROM AUTHOR]

Toxoplasmosis is an important worldwide foodborne zoonotic disease. Infected cattle meats is considered a serous cause of human toxoplasmosis. Here, this study assesses the infection with Toxoplasma gonddi (T. gondii) in cattle using meat juice samples from diaphragmatic muscles collected at the slaughter. An in house indirect enzyme linked immunosorbent assay (ELISA), and commercial latex agglutination test (LAT) followed by immunoblotting were developed on the meat juice (fluids) using tachyzoites of locally isolated T. gondii strain. The comparative analysis of the results of the tested juice samples showed an excellent agreement between the in-house indirect ELISA and LAT test in the positive and negative of meat juice. Relative sensitivity was higher for ELISA on diaphragms fluids random samples 80.39%, for the LAT test was 68.6%. Immune-reactive bands of T. gondii local strain Ag with naturally infected meat juice were 116, 83, 65, 30 and 23 KDa. The obtained results concluded that the development of an effective ELISA test to be used in for detection of toxoplasmosis infection of slaughtered cattle in large-scale would be exactly valuable, since the important role that beef plays in epidemiology of T. gondii, in particular the hazard of transmission to human and food safety.

Neurotrophic herpes simplex virus type 1 (HSV-1) establishes lifelong latent infection in humans. Accumulating studies indicate that HSV-1, a risk factor of neurodegenerative diseases, exacerbates the sporadic Alzheimer's disease (AD). The analysis of viral genetic materials via genomic sequencing and quantitative PCR (qPCR) is the current approach used for the detection of HSV-1; however, this approach is limited because of its difficulty in detecting both latent and lytic phases of the HSV-1 life cycle in infected hosts. RNAscope, a novel in situ RNA hybridization assay, enables visualized detection of multiple RNA targets on tissue sections. Here, we developed a fluorescent multiplex RNAscope assay in combination with immunofluorescence to detect neuronal HSV-1 transcripts in various types of mouse brain samples and human brain tissues. Specifically, the RNA probes were designed to separately recognize two transcripts in the same brain section: (1) the HSV-1 latency-associated transcript (LAT) and (2) the lytic-associated transcript, the tegument protein gene of the unique long region 37 (UL37). As a result, both LAT and UL37 signals were detectable in neurons in the hippocampus and trigeminal ganglia (TG). The quantifications of HSV-1 transcripts in the TG and CNS neurons are correlated with the viral loads during lytic and latent infection. Collectively, the development of combinational detection of neuronal HSV-1 transcripts in mouse brains can serve as a valuable tool to visualize HSV-1 infection phases in various types of samples from AD patients and facilitate our understanding of the infectious origin of neurodegeneration and dementia. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii is a protozoan parasite prevalent in humans and other animals worldwide having medical and veterinary importance on account of reproductive failure causing significant socioeconomic losses. The aims of this study were to estimate the seroprevalence of T. gondii infection in goats, determined the possible risk factors associated, and evaluate the performances of the latex agglutination test (LAT) to anti-T. gondii antibodies screening using the indirect Enzyme-linked immunosorbent assay as a reference test (iELISA). A total of 184 serum samples from goats reared on 25 farms in Mila district from North-Eastern Algeria were collected and tested for anti-T. gondii IgG antibodies using two commercial serological tests (ELISA and LAT). A seroprevalence rate of 71.73 % and 63.58 % was obtained by both ELISA and LAT tests, respectively. The analysis of some factors thought to be related to the onset of this infection such as age, sex, management system, locality and presence of cats showed no significant relationship (P > 0.05); these factors did not seem to affect the frequency of the infection. The seropositivity level of T. gondii was significantly higher in aborted goats (P = 0.007), which suggested that they may play a significant role in pregnancy failure. In the concordance evaluation between the two serological tests (ELISA and LAT), the Cohen’s Kappa value was calculated and the results showed a K of 0.519 (p = 0.000) belonging to the range of 0.41—0.60 indicating just average agreement. The results of the Mc Nemar test showed that both tests gave significantly different results and seropositivity values (P < 0.05). The high prevalence observed in this study indicated a widespread exposure to T. gondii from goats and the potential risk of T. gondii infection for humans in North-Eastern Algeria. These results elucidate the challenges of applying serology to estimate goat exposure to T. gondii. The choice between the two serological tests will depend on their performances, as well as the availability of the equipment, laboratory conditions and the number of samples to be tested.

Background: Reverse shoulder arthroplasty (RSA) with concurrent latissimus dorsi transfer (LDT) is a potential treatment option for restoration of external rotation (ER). Biomechanical studies have emphasized the importance of the insertion site location for achieving optimal outcomes. In this systematic review and meta-analysis, we aimed to describe what insertion sites for LDT are utilized during concomitant RSA and their associated clinical outcomes., Methods: A systematic review and meta-analysis were performed per PRISMA guidelines. We queried PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases to identify articles reporting on patients who received RSA with LDT to restore ER and specified the site of tendon transfer insertion on the humerus. We first describe reported insertion sites in the literature. Secondarily, we present preoperative and postoperative range of motion and Constant score for different insertion sites as well as reported complications., Results: Sixteen studies, analyzed as 19 separate cohorts (by insertion site and tendon-transfer), reporting on 264 RSAs with LDT (weighted mean age 66 years, follow-up 39 months, 61% female) were evaluated. Of these, 143 (54%) included a concomitant teres major transfer (LDT/TMT) and 121 (46%) were LDT-only. Fourteen cohorts (14/19, 74%) reported insertion at the posterolateral aspect of the greater tuberosity, four cohorts (4/19, 21%) reported insertion site at the lateral bicipital groove, and one cohort (1/19, 5%) reported separate LDT and TMT with insertion of the TMT to the posterolateral aspect of the greater tuberosity and LDT to the lateral bicipital groove. Meta-analysis revealed no differences in range of motion or Constant score based on humeral insertion site or whether the LDT was transferred alone or with TMT. Leading complications included dislocation, followed by infection and neuropraxia. No discernible correlation was observed between postoperative outcomes and the strategies employed for tendon transfer, prosthesis design, or subscapularis management., Conclusion: The posterolateral aspect of the greater tuberosity was the most-utilized insertion site for LDT performed with RSA. However, in the current clinical literature, LDT with or without concomitant TMT result in similar postoperative ROM and Constant score regardless of insertion site. Analysis of various proposed transfer sites reinforce the ability of LDT with RSA to restore both FE and ER in patients with preoperative active elevation and external rotation loss. Meta-analysis revealed significant improvements in range of motion and Constant score regardless of humeral insertion site or whether the LDT was transferred alone or with TMT, although future studies are needed to determine whether an ideal tendon transfer technique exists., Level of Evidence: IV., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Neurotrophic herpes simplex virus type 1 (HSV-1) establishes lifelong latent infection in humans. Accumulating studies indicate that HSV-1, a risk factor of neurodegenerative diseases, exacerbates the sporadic Alzheimer's disease (AD). The analysis of viral genetic materials via genomic sequencing and quantitative PCR (qPCR) is the current approach used for the detection of HSV-1; however, this approach is limited because of its difficulty in detecting both latent and lytic phases of the HSV-1 life cycle in infected hosts. RNAscope, a novel in situ RNA hybridization assay, enables visualized detection of multiple RNA targets on tissue sections. Here, we developed a fluorescent multiplex RNAscope assay in combination with immunofluorescence to detect neuronal HSV-1 transcripts in various types of mouse brain samples and human brain tissues. Specifically, the RNA probes were designed to separately recognize two transcripts in the same brain section: (1) the HSV-1 latency-associated transcript (LAT) and (2) the lytic-associated transcript, the tegument protein gene of the unique long region 37 (UL37). As a result, both LATand UL37 signals were detectable in neurons in the hippocampus and trigeminal ganglia (TG). The quantifications of HSV-1 transcripts in the TG and CNS neurons are correlated with the viral loads during lytic and latent infection. Collectively, the development of combinational detection of neuronal HSV-1 transcripts in mouse brains can serve as a valuable tool to visualize HSV-1 infection phases in various types of samples from AD patients and facilitate our understanding of the infectious origin of neurodegeneration and dementia. [ABSTRACT FROM AUTHOR]

Livestock meat is considered a potential source of human infection, therefore evaluation of the infection rate with Toxoplasma gondii (T. gondii) in these animals’ meat is needed for public health protection. Serum and meat samples were collected from slaughtered animals (n=106) (27 sheep, 42 cattle and 37 camels) from slaughterhouses in Aswan Governorate, located in southern Egypt. T. gondii infection status was detected by Latex agglutination test (LAT), microscopic examination and PCR. Our results revealed that the overall prevalence of anti-T. gondii antibodies among serum samples was 48.1 % using LAT. Male sheep, cattle, and camels had a higher positive percentage (42.9 %, 69.4% and 33.3 %, respectively) than females (40 %, 50 % and 30.8 %, respectively). The infection rate of T. gondii was higher in adult sheep and camels, while it was lower in adult cattle (64.5 %) than in young (72.7 %). There was a high statistically significant difference (P ≤ 0.01) between the animal species using LAT. T. gondii trophozoites were detected microscopically in 47.1 % of meat samples, while T. gondii DNA was detected in 56.9 % by using conventional Polymerase Chain Reaction (cPCR) based B1 gene. There was no significant difference between the results of both microscopy and PCR methods. In conclusion, PCR outperforms LAT in the detection of T. gondii infection and can thus be applied to routine diagnosis of toxoplasmosis in red meat producing animals.

Adaptor molecules lack enzymatic and transcriptional activities. Instead, they exert their function by linking multiple proteins into intricate complexes, allowing for transmitting and fine-tuning of signals. Many adaptor molecules play a crucial role in T-cell signaling, following engagement of the T-cell receptor (TCR). In this review, we focus on Linker of Activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 KDa (SLP-76). Monogenic defects in these adaptor proteins, with known roles in T-cell signaling, have been described as the cause of human inborn errors of immunity (IEI). We describe the current knowledge based on defects in cell lines, murine models and human patients. Germline mutations in Adhesion and degranulation adaptor protein (ADAP), have not resulted in a T-cell defect.

Adaptor molecules lack enzymatic and transcriptional activities. Instead, they exert their function by linking multiple proteins into intricate complexes, allowing for transmitting and fine-tuning of signals. Many adaptor molecules play a crucial role in T-cell signaling, following engagement of the T-cell receptor (TCR). In this review, we focus on Linker of Activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 KDa (SLP-76). Monogenic defects in these adaptor proteins, with known roles in T-cell signaling, have been described as the cause of human inborn errors of immunity (IEI). We describe the current knowledge based on defects in cell lines, murine models and human patients. Germline mutations in Adhesion and degranulation adaptor protein (ADAP), have not resulted in a T-cell defect. [ABSTRACT FROM AUTHOR]

Linker for activation in T cells (LAT) is a critical regulator of T‐cell development and function. It organises signalling events at the plasma membrane. However, the mechanism, which controls LAT localisation at the plasma membrane, is not fully understood. Here, we studied the impact of helix‐breaking amino acids, two prolines and one glycine, in the transmembrane segment on localisation and function of LAT. Using in silico analysis, confocal and super‐resolution imaging and flow cytometry, we demonstrate that central proline residue destabilises transmembrane helix by inducing a kink. The helical structure and dynamics are further regulated by glycine and another proline residue in the luminal part of LAT transmembrane domain. Replacement of these residues with aliphatic amino acids reduces LAT dependence on palmitoylation for sorting to the plasma membrane. However, surface expression of these mutants is not sufficient to recover function of nonpalmitoylated LAT in stimulated T cells. These data indicate that geometry and dynamics of LAT transmembrane segment regulate its localisation and function in immune cells. [ABSTRACT FROM AUTHOR]

Self- and non-self ligand discrimination is a core principle underlying T cell-mediated immunity. Mature αβ T cells can respond to a foreign peptide ligand presented by major histocompatibility complex molecules (pMHCs) on antigen presenting cells, on a background of continuously sensed self–pMHCs. How αβ T cells can properly balance high sensitivity and high specificity to foreign pMHCs, while surrounded by a sea of self-peptide ligands is not well understood. Such discrimination cannot be explained solely by the affinity parameters of T cell antigen receptor (TCR) and pMHC interaction. In this review, we will discuss how T cell ligand discrimination may be molecularly defined by events downstream of the TCR–pMHC interaction. We will discuss new evidence in support of the kinetic proofreading model of TCR ligand discrimination, and in particular how the kinetics of specific phosphorylation sites within the adaptor protein linker for activation of T cells (LAT) determine the outcome of TCR signaling. In addition, we will discuss emerging data regarding how some kinases, including ZAP-70 and LCK, may possess scaffolding functions to more efficiently direct their kinase activities.

Self- and non-self ligand discrimination is a core principle underlying T cell-mediated immunity. Mature αβ T cells can respond to a foreign peptide ligand presented by major histocompatibility complex molecules (pMHCs) on antigen presenting cells, on a background of continuously sensed self–pMHCs. How αβ T cells can properly balance high sensitivity and high specificity to foreign pMHCs, while surrounded by a sea of self-peptide ligands is not well understood. Such discrimination cannot be explained solely by the affinity parameters of T cell antigen receptor (TCR) and pMHC interaction. In this review, we will discuss how T cell ligand discrimination may be molecularly defined by events downstream of the TCR–pMHC interaction. We will discuss new evidence in support of the kinetic proofreading model of TCR ligand discrimination, and in particular how the kinetics of specific phosphorylation sites within the adaptor protein linker for activation of T cells (LAT) determine the outcome of TCR signaling. In addition, we will discuss emerging data regarding how some kinases, including ZAP-70 and LCK, may possess scaffolding functions to more efficiently direct their kinase activities. [ABSTRACT FROM AUTHOR]

Clustering is a prominent feature of receptors at the plasma membrane (PM). It plays an important role in signaling. Liquid–liquid phase separation (LLPS) of proteins is emerging as a novel mechanism underlying the observed clustering. Receptors/transmembrane signaling proteins can be core components essential for LLPS (such as LAT or nephrin) or clients enriched at the phase-separated condensates (for example, at the postsynaptic density or at tight junctions). Condensate formation has been shown to regulate signaling in multiple ways, including by increasing protein binding avidity and by modulating the local biochemical environment. In moving forward, it is important to study protein LLPS at the PM of living cells, its interplay with other factors underlying receptor clustering, and its signaling and functional consequences. [Display omitted] • Protein phase separation is a mechanism for plasma membrane receptor clustering. • Membrane proteins can be core phase separating components or enriched clients. • Increased binding avidity at condensates promotes signaling molecule activation. • Phase separation regulates actin nucleation, enzyme activity and RNA processing. • Signaling complexes and pathways may consist of multiple phase separating modules. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify the seroprevalence of Toxoplasma gondii (T. gondii) and hematological alterations in captive pheasant species of Bahawalpur Zoo, Bahawalpur, Pakistan. The blood samples of 100 birds belonging to three different species viz. ring-necked pheasant (Phasianus colchicus) (n=46), green pheasant (Phasianus versicolor) (n=40), and silver pheasant (Lophura nycthemera) (n=14) were analyzed through Latex Agglutination Test (LAT) and Enzyme Linked Immunosorbent Assay (ELISA). Seroprevalance through LAT in ring-necked, silver and green pheasants was 10.86%, 7.14% and 7.5%, and through ELISA was 32.60%, 22.5% and 14.28%, respectively. Adults and males had higher prevalence as compared to their counterparts, though, statistically nn-significant (P=0.05). In all the studied species, hematological results revealed that mean values of Hb and TEC were higher (P=0.05) in noninfected birds as compared to infected ones. This is a preliminary study of a kind and needs further research with large number of sample and population across the country. [ABSTRACT FROM AUTHOR]

The main purpose of this narrative review is to educate general practitioners about a crucial pleural procedure, namely local anesthetic thoracoscopy (LAT), and to provide established respiratory physicians with an expert opinion-based summary of the literature. This narrative review focuses on the indications, technical aspects and complications of LAT, highlighting its safety and high degree of diagnostic sensitivity for patients who present with an unexplained pleural effusion and have a high pre-test probability of cancer., (Copyright © 2024 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

The adaptor LAT plays a crucial role in the transduction of signals coming from the TCR/CD3 complex. Phosphorylation of some of its tyrosines generates recruitment sites for other cytosolic signaling molecules. Tyrosine 132 in human LAT is essential for PLC-γ activation and calcium influx generation. It has been recently reported that a conserved glycine residue preceding tyrosine 132 decreases its phosphorylation kinetics, which constitutes a mechanism for ligand discrimination. Here we confirm that a LAT mutant in which glycine 131 has been substituted by an aspartate (LATG131D) increases phosphorylation of Tyr132, PLC-γ activation and calcium influx generation. Interestingly, the LATG131D mutant has a slower protein turnover while being equally sensitive to Fas-mediated protein cleavage by caspases. Moreover, J.CaM2 cells expressing LATG131D secrete greater amounts of interleukin-2 (IL-2) in response to CD3/CD28 engagement. However, despite this increased IL-2 secretion, J.CaM2 cells expressing the LATG131D mutant are more sensitive to inhibition of IL-2 production by pre-treatment with anti-CD3, which points to a possible role of this residue in the generation of anergy. Our results suggest that the increased kinetics of LAT Tyr132 phosphorylation could contribute to the establishment of T cell anergy, and thus constitutes an earliest known intracellular event responsible for the induction of peripheral tolerance.

Global navigation satellite systems (GNSS) is widely utilized in marine applications for high accuracy vertical positioning. The errors introduced to charts by the present use of traditional shore-based discrete point chart datum (CD) can become a significant part of the total vertical error and deteriorates the vertical positioning accuracy estimated by GNSS technique. Therefore, a need for developing a CD in a continuous form is essential to replace the traditional CD so that it can be transformed from/to another continuous datum such as the reference ellipsoid (WGS84). The importance of the development of CD-to-WGS84 separation model is that it can be utilized by the hydrographers to develop an accurate vertical control for hydrographic surveys applications and can be utilized by the mariners to produce an accurate dynamic electronic navigation charts (ENC). In this paper, a Saudi continuous chart datum in the Arabian Gulf area is developed to provide CD-to-WGS84 separation model. It is shown that the Saudi continuous chart datum ranges from –14.96 m to –34.64 m and can be achieved with uncertainty ranges from 0.11 m to 0.16 m. The developed CD-to-WGS84 separation model in this paper can meet many maritime applications.

A traditional shore-based discrete point chart datum (CD) that represents the lowest astronomical tide (LAT) in Saudi Arabia using tide gauge data is utilized to reduce the observed depth collected from hydrographic surveying test to CD-referenced depth for producing navigation charts for maritime navigation applications. A need for developing CD in a continuous form is essential to replace the traditional discrete CD using tide gauge data. The importance of the development of CD-to-ellipsoid (WGS84) separation model is that it can be utilized by the hydrographers to develop an accurate vertical control for hydrographic surveys applications and can be utilized by the mariners to produce accurate dynamic electronic navigation charts (ENCs). In this paper, a continuous CD to WGS84 ellipsoid separation model for the Sharm Obhur area is developed using a multibeam hydrographic surveying test. It is shown that the continuous chart datum ranges from −4.920 m to −4.766 m and can be achieved with standard deviation ranges from 0.1 cm to 2.3 cm. To validate the separation model, a comparison was made with the gravimetric/oceanographic method based on the separation height developed from geoid height, the sea surface topography and LAT value (chart datum to mean sea level) at the tide gauge located in the study area. The comparison showed that the average value of the developed continuous CD to WGS84 separation model heights using multibeam hydrographic surveying agrees with the separation height estimated from gravimetric/oceanographic method.

The human heart is an organ of high complexity and hence, very challenging to simulate. To calculate the force developed by the human heart and therefore the tension of the muscle fibers, accurate models are necessary. The force generated by the cardiac muscle has physiologically imposed limits and depends on various characteristics such as the length, strain and the contraction velocity of the cardiomyocytes. Another characteristic is the activation time of each cardiomyocyte, which is a wave and not a static value for all cardiomyocytes. To simulate a physiologically correct excitation, the functionality of the cardiac simulation framework CardioMechanics was extended to incorporate inhomogeneous activation times. The functionality was then used to evaluate the effects of local activation times with two different tension models. The active stress generated by the cardiomyocytes was calculated by (i) an explicit function and (ii) an ode-based model. The results of the simulations showed that the maximum pressure in the left ventricle dropped by 2.3% for the DoubleHill model and by 5.3% for the Lumens model. In the right ventricle the simulations showed similar results. The maximum pressure in both the left and the right atrium increased using both models. Given that the simulation of the inhomogeneously activated cardiomyocytes increases the simulation time when used with the more precise Lumens model, the small drop in maximum pressure seems to be negligible in favor of a simpler simulation model