Latent Epstein-Barr virus infection collaborates with Myc over-expression in normal human B cells to induce Burkitt-like Lymphomas in mice.

Epstein-Barr virus (EBV) is an important cause of human lymphomas, including Burkitt lymphoma (BL). EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-κB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (ΔEBNA2 EBV) to create the first in vivo model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both ΔEBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L/IL21 expressing feeder layer in vitro and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.

The Labyrinthine Journey: Unveiling Obstacles in addressing Mental Health Challenges in Prisons and its Confluence with Medico-Legal and Pharmacological Perspectives.

This paper delves into the intricate realm of mental health issues within prisons including other correctional facilities, the intersectionality with legal and medical aspects, and the potential of pharmacology as a viable treatment modality. The prevalence and diverse array of mental disorders among incarcerated individuals are thoroughly examined, underscoring the imperative for all-encompassing interventions. The legal structure, hurdles encountered in delivering mental healthcare, and the indispensability of interdisciplinary cooperation are scrutinized. Furthermore, the effectiveness and moral implications of pharmaceutical interventions in correctional environments are deliberated upon. Conclusive suggestions are put forth to enhance mental healthcare provisions in prisons. The research paper endeavors to penetrate the labyrinthine complexities of mental health predicaments within correctional institutions, with a specific emphasis on the convergence of medico-legal facets and the plausible impact of pharmacological interventions. The study strives to elucidate the intricate nature of mental health challenges among incarcerated populations, considering the intricate interplay of socio-cultural, environmental, and psychological factors that contribute to their pervasiveness. By delving into these interconnected dimensions, the research aims to unlock prospective remedies capable of efficaciously meeting the mental health requisites of incarcerated individuals.

Sight impairment registration in Trinidad: trend in causes and population coverage in comparison to the National Eye Survey of Trinidad and Tobago.

BACKGROUND: Little was known about the population coverage and causes of sight impairment (SI) registration within the Caribbean, or the extent to which register studies offer insights into population eye health. METHODS: We compared causes of SI registration in the Trinidad and Tobago Blind Welfare Association (TTBWA) register with findings from the 2014 National Eye Survey of Trinidad and Tobago (NESTT), and estimated registration coverage. Cross-sectional validation studies of registered clients included interviews, visual function and cause ascertainment in July 2013, and interviews and visual function in July 2016. RESULTS: The TTBWA register included 863 people (all ages, 48.1%(n = 415) male) registered between 1951 and 2015. The NESTT identified 1.1%(75/7158) people aged ≥5years eligible for partial or severe SI registration, of whom 49.3%(n = 37) were male. Registration coverage was approximately 7% of the eligible population of Trinidad. Nevertheless, there was close agreement in the causes of SI comparing the register and population-representative survey. Glaucoma was the leading cause in both the register (26.1%,n = 225) and population-based survey (26.1%, 18/69 adults), followed by cataract and diabetic retinopathy. In the validation studies combined, 62.6%(93/151) clients had severe SI, 28.5%(43/151) had partial SI and 9.9%(15/151) did not meet SI eligibility criteria. SI was potentially avoidable in at least 58%(n = 36/62) adults and 50%(n = 7/14) children. CONCLUSION: We report very low register coverage of the SI population, but close agreement in causes of SI to a contemporaneous national population-based eye survey, half of which resulted from preventable or treatable eye disease.

Common foods for boosting human immunity: A review.

We are frequently exposed to potentially harmful microbes of various types on a daily basis. Our immune system is an amazing collection of unique organs and cells that defends us from hazardous germs as well as certain diseases. It plays a crucial role in protecting the body against external invaders, including bacteria, viruses, and parasites. Maintaining a healthy immune system requires consuming a balanced diet that provides a variety of macro- and micronutrients. By consuming sufficient amounts of water, minerals such as zinc and magnesium, micronutrients, herbs, and foods rich in vitamins C, D, and E, and adopting a healthy lifestyle, one can enhance their health and immunity, and prevent infections. This article provides a comprehensive review of the scientific literature on common foods known for their potential to boost human immunity. The review begins by discussing the various components of the immune system and their functions. It then delves into the current understanding of how nutrition can influence immune response, highlighting the importance of a well-balanced diet in supporting optimal immune function. The article presents an extensive analysis of a range of common foods that have been studied for their immune-boosting properties. These foods include fruits, vegetables, whole grains, and animal-based foods. Each food category is explored in terms of its specific nutrients and bioactive compounds that contribute to immune support. Foods such as milk, eggs, fruits, leafy greens, and spices like onion, garlic, and turmeric contain beneficial compounds that can enhance the immune system's function, activate and inhibit immune cells, and interfere with multiple pathways that eventually lead to improved immune responses and defense. The available literature on the issue was accessed via online resources and evaluated thoroughly as a methodology for preparing this manuscript.

Epstein-Barr virus LMP1 protein promotes proliferation and inhibits differentiation of epithelial cells via activation of YAP and TAZ.

Latent Epstein-Barr virus (EBV) infection promotes undifferentiated nasopharyngeal carcinomas (NPCs) in humans, but the mechanism(s) for this effect has been difficult to study because EBV cannot transform normal epithelial cells in vitro and the EBV genome is often lost when NPC cells are grown in culture. Here we show that the latent EBV protein, LMP1 (Latent membrane protein 1), induces cellular proliferation and inhibits spontaneous differentiation of telomerase-immortalized normal oral keratinocytes (NOKs) in growth factor-deficient conditions by increasing the activity of the Hippo pathway effectors, YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif). We demonstrate that LMP1 enhances YAP and TAZ activity in NOKs both by decreasing Hippo pathway-mediated serine phosphorylation of YAP and TAZ and increasing Src kinase-mediated Y357 phosphorylation of YAP. Furthermore, knockdown of YAP and TAZ is sufficient to reduce proliferation and promote differentiation in EBV-infected NOKs. We find that YAP and TAZ are also required for LMP1-induced epithelial-to-mesenchymal transition. Importantly, we demonstrate that ibrutinib (an FDA-approved BTK inhibitor that blocks YAP and TAZ activity through an off-target effect) restores spontaneous differentiation and inhibits proliferation of EBV-infected NOKs at clinically relevant doses. These results suggest that LMP1-induced YAP and TAZ activity contributes to the development of NPC.

"Researchers' perceptions and awareness of predatory publishing: A survey".

The term "Predatory" alludes to the assumption that these organizations prey on academics for financial gain by charging article processing charges (APC) while failing to meet scholarly publishing standards.Predatory publishing is a growing threat to the academic society. Considering this,the University Grants Commission (UGC),India's statutory body for higher education,has responded by launching the University Grants Commission-Consortium for Academic Research and Ethics (UGC-CARE) list,which attempts to promote research quality,integration,and publication ethics.An online survey was undertaken to determine the perception and awareness of North Eastern Hill University's researchers concerning predatory journals.A total of 160 respondents were recorded.The survey reveals that while the majority of participants (58.75%) were aware of predatory publications, a significant portion (41.25%) were not.It was found that a journal's listing in UGC-CARE list is the most crucial factor in submitting an original manuscript for publication.Researchers,aware of the negative consequences of publishing in piracy-related publications,prefer not to submit their scientific work to such publishers as it risk tarnishing their reputation.As a result,research findings emphasize the necessity for awareness initiatives to educate researchers about predatory publications early in their academic careers.Research initiatives like the UGC-CARE list should be encouraged to minimize predatory publishing; promote quality and transparency in research.Abbreviation: NEHU- North Eastern Hill University, UGC- University Grants Commission, APC- Article Processing Charge, UGC-CARE- University Grants Commission - Consortium for Academic Research and Ethics, DOAJ- Directory of Open Access Journals, DOI - Digital Object Identifiers, API- Academic Performance Indicator.

Type 1 and Type 2 Epstein-Barr viruses induce proliferation, and inhibit differentiation, in infected telomerase-immortalized normal oral keratinocytes.

Differentiated epithelial cells are an important source of infectious EBV virions in human saliva, and latent Epstein-Barr virus (EBV) infection is strongly associated with the epithelial cell tumor, nasopharyngeal carcinoma (NPC). However, it has been difficult to model how EBV contributes to NPC, since EBV has not been shown to enhance proliferation of epithelial cells in monolayer culture in vitro and is not stably maintained in epithelial cells without antibiotic selection. In addition, although there are two major types of EBV (type 1 (T1) and type 2 (T2)), it is currently unknown whether T1 and T2 EBV behave differently in epithelial cells. Here we inserted a G418 resistance gene into the T2 EBV strain, AG876, allowing us to compare the phenotypes of T1 Akata virus versus T2 AG876 virus in a telomerase-immortalized normal oral keratinocyte cell line (NOKs) using a variety of different methods, including RNA-seq analysis, proliferation assays, immunoblot analyses, and air-liquid interface culture. We show that both T1 Akata virus infection and T2 AG876 virus infection of NOKs induce cellular proliferation, and inhibit spontaneous differentiation, in comparison to the uninfected cells when cells are grown without supplemental growth factors in monolayer culture. T1 EBV and T2 EBV also have a similar ability to induce epithelial-to-mesenchymal (EMT) transition and activate canonical and non-canonical NF-κB signaling in infected NOKs. In contrast to our recent results in EBV-infected lymphoblastoid cells (in which T2 EBV infection is much more lytic than T1 EBV infection), we find that NOKs infected with T1 and T2 EBV respond similarly to lytic inducing agents such as TPA treatment or differentiation. These results suggest that T1 and T2 EBV have similar phenotypes in infected epithelial cells, with both EBV types enhancing cellular proliferation and inhibiting differentiation when growth factors are limiting.

Glutamate binding triggers monomerization of unliganded mGluR2 dimers.

The Metabotropic glutamate receptor 2 (mGluR2) is involved in several neurological and psychiatric disorders and is an attractive drug target. It is believed to form a strict dimer and the dimeric assembly is necessary for glutamate induced activation. Although many studies have focused on glutamate induced conformational changes, the dimerization propensity of mGluR2 with and without glutamate has never been investigated. Also, the role of the unstructured loop in dimerization of mGluR2 is not clear. Here, using Forster Resonance Energy Transfer (FRET) based assay in live cells we show that mGluR2 does not form a "strict dimer" rather it exists in a dynamic monomer-dimer equilibrium. The unstructured loop moderately destabilizes the dimers. Furthermore, binding of glutamate to mGluR2 induces conformational change that promotes monomerization of mGluR2. In the absence of an unstructured loop, mGluR2 neither undergoes conformational change nor monomerizes upon binding to glutamate.

Defining the Homo- and Heterodimerization Propensities of Metabotropic Glutamate Receptors.

The eight metabotropic glutamate receptors (mGluRs) serve critical modulatory roles throughout the nervous system. The molecular diversity of mGluRs is thought to be further expanded by the formation of heterodimers, but the co-expression of mGluR subtypes at the cellular level and the relative propensities of heterodimer formation are not well known. Here, we analyze single-cell RNA sequencing data and find that cortical pyramidal cells express multiple mGluR subtypes with distinct profiles for different receptor combinations. We then develop quantitative, fluorescence-based assays to define the relative homo- and heterodimer propensities across group-I, -II, and -III mGluRs. We find a strong preference for heterodimerization in a number of cases, including mGluR2 with mGluR3, which we confirm in frontal cortex using in situ RNA hybridization and co-immunoprecipitation. Together, our findings support the biological relevance of mGluR heterodimerization and highlight the complex landscape of mGluR populations in the brain.

Revisiting a controversy: The effect of EGF on EGFR dimer stability.

EGFR is a receptor tyrosine kinase that plays a critical role in cell proliferation, differentiation, survival and migration. Its activating ligand, EGF, has long been believed to stabilize the EGFR dimer. Two research studies aimed at quantitative measurements of EGFR dimerization, however, have led to contradicting conclusions and have questioned this view. Given the controversy, here we sought to measure the dimerization of EGFR in the absence and in the presence of saturating EGF concentrations, and to tease out the effect of ligand on dimer stability, using a FRET-based quantitative method. Our measurements show that the dissociation constant is decreased ~150 times due to ligand binding, indicative of significant dimer stabilization. In addition, our measurements demonstrate that EGF binding induces a conformational change in the EGFR dimer.

Unstructured loop is essential for the activation of mGluR2.

Metabotropic Glutamate Receptors (mGluRs) are Class C G-protein coupled receptors (GPCRs) that are expressed throughout the central nervous system and are involved in several neurological and psychiatric disorders. Although, many studies focused on Glutamate induced activation of mGluR2, however, the role of unstructured loop (or "BC loop") in activation of metabotropic Glutamate receptors is currently unknown. Here, using Förster Resonance Energy Transfer (FRET) based assay in live cells we show that unstructured loop is required for Glutamate induced conformation and hence the activation of the receptor.

National Eye Survey of Trinidad and Tobago (NESTT): prevalence, causes and risk factors for presenting vision impairment in adults over 40 years.

AIM: To estimate the prevalence, causes and risk factors for presenting distance and near vision impairment (VI) in Trinidad and Tobago. METHODS: This is a national, population-based survey using multistage, cluster random sampling in 120 clusters with probability-proportionate-to-size methods. Stage 1 included standardised, community-based measurement of visual acuity. Stage 2 invited all 4263 people aged ≥40 years for comprehensive clinic-based assessment. The Moorfields Eye Hospital Reading Centre graded fundus photographs and optical coherence tomography images independently. RESULTS: The response rates were 84.2% (n=3589) (stage 1) and 65.4% (n=2790) (stage 2), including 97.1% with VI. The mean age was 57.2 (SD 11.9) years, 54.5% were female, 42.6% were of African descent and 39.0% were of South Asian descent. 11.88% (95% CI 10.88 to 12.97, n=468) had distance VI (logarithm of the minimum angle of resolution [logMAR] >0.30), including blindness (logMAR >1.30) in 0.73% (95% CI 0.48 to 0.97, n=31), after adjustment for study design, non-response, age, sex and municipality. The leading causes of blindness included glaucoma (31.7%, 95% CI 18.7 to 44.8), cataract (28.8%, 95% CI 12.6 to 45.1) and diabetic retinopathy (19.1%, 95% CI 4.2 to 34.0). The leading cause of distance VI was uncorrected refractive error (47.4%, 95% CI 43.4 to 51.3). Potentially avoidable VI accounted for 86.1% (95% CI 82.88 to 88.81), an estimated 176 323 cases in the national population aged ≥40 years. 22.3% (95% CI 20.7 to 23.8, n=695) had uncorrected near VI (logMAR >0.30 at 40 cm with distance acuity <0.30). Significant independent associations with distance VI included increasing age, diagnosed diabetes and unemployment. Significant independent associations with near VI included male sex, no health insurance and unemployment. CONCLUSIONS: Trinidad and Tobago's burden of avoidable VI exceeds that of other high-income countries. Population and health system priorities are identified to help close the gap.

Newly Discovered Micropeptide Regulators of SERCA Form Oligomers but Bind to the Pump as Monomers.

The recently-discovered single-span transmembrane proteins endoregulin (ELN), dwarf open reading frame (DWORF), myoregulin (MLN), and another-regulin (ALN) are reported to bind to the SERCA calcium pump in a manner similar to that of known regulators of SERCA activity, phospholamban (PLB) and sarcolipin (SLN). To determine how micropeptide assembly into oligomers affects the availability of the micropeptide to bind to SERCA in a regulatory complex, we used co-immunoprecipitation and fluorescence resonance energy transfer (FRET) to quantify micropeptide oligomerization and SERCA-binding. Micropeptides formed avid homo-oligomers with high-order stoichiometry (n > 2 protomers per homo-oligomer), but it was the monomeric form of all micropeptides that interacted with SERCA. In view of these two alternative binding interactions, we evaluated the possibility that oligomerization occurs at the expense of SERCA-binding. However, even the most avidly oligomeric micropeptide species still showed robust FRET with SERCA, and there was a surprising positive correlation between oligomerization affinity and SERCA-binding. This comparison of micropeptide family members suggests that the same structural determinants that support oligomerization are also important for binding to SERCA. Moreover, the unique oligomerization/SERCA-binding profile of DWORF is in harmony with its distinct role as a PLB-competing SERCA activator, in contrast to the inhibitory function of the other SERCA-binding micropeptides.

Erratum: Author Correction: The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures.

[This corrects the article DOI: 10.1038/s42003-018-0017-7.].

The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures.

The EphA2 receptor tyrosine kinase is capable of activating multiple diverse signaling pathways with roles in processes such as tissue homeostasis and cancer. EphA2 is known to form activated oligomers in the presence of ephrin-A ligands. Here, we characterize the lateral interactions between full-length EphA2 molecules in the plasma membrane in the presence of three types of ligands (dimeric ephrinA1-Fc, monomeric ephrinA1, and an engineered peptide ligand) as well as in the absence of ligand, using a quantitative FRET technique. The data show that EphA2 forms higher-order oligomers and two different types of dimers that all lead to increased EphA2 tyrosine phosphorylation, which is indicative of increased kinase-dependent signaling. We find that different ligands stabilize conformationally distinct oligomers that are assembled through two different interfaces. Our results suggest that these different oligomeric assemblies could have distinct signaling properties, contributing to the diverse activities of the EphA2 receptor.

Health system dynamics analysis of eyecare services in Trinidad and Tobago and progress towards Vision 2020 Goals.

Avoidable blindness is an important global public health concern. This study aimed to assess Trinidad and Tobago's progress towards achieving the Pan American Health Organization, 'Strategic Framework for Vision 2020: The Right to Sight-Caribbean Region,' indicators through comprehensive review of the eyecare system, in order to facilitate health system priority setting. We administered structured surveys to six stakeholder groups, including eyecare providers, patients and older adult participants in the National Eye Survey of Trinidad and Tobago. We reviewed reports, registers and policy documents, and used a health system dynamics framework to synthesize data. In 2014, the population of 1.3 million were served by a pluralistic eyecare system, which had achieved 14 out of 27 Strategic Framework indicators. The Government provided free primary, secondary and emergency eyecare services, through 108 health centres and 5 hospitals (0.26 ophthalmologists and 1.32 ophthalmologists-in-training per 50 000 population). Private sector optometrists (4.37 per 50 000 population), and ophthalmologists (0.93 per 50 000 population) provided 80% of all eyecare. Only 19.3% of the adult population had private health insurance, revealing significant out-of-pocket expenditure. We identified potential weaknesses in the eyecare system where investment might reduce avoidable blindness. These included a need for more ophthalmic equipment and maintenance in the public sector, national screening programmes for diabetic retinopathy, retinopathy of prematurity and neonatal eye defects, and pathways to ensure timely and equitable access to subspecialized surgery. Eyecare for older adults was responsible for an estimated 9.5% (US$22.6 million) of annual health expenditure. This study used the health system dynamics framework and new data to identify priorities for eyecare system strengthening. We recommend this approach for exploring potential health system barriers to addressing avoidable blindness, and other important public health problems.

Intracellular Domain Contacts Contribute to Ecadherin Constitutive Dimerization in the Plasma Membrane.

Epithelial cadherin (Ecadherin) is responsible for the intercellular cohesion of epithelial tissues. It forms lateral clusters within adherens cell-cell junctions, but its association state outside these clusters is unknown. Here, we use a quantitative Forster resonance energy transfer (FRET) approach to show that Ecadherin forms constitutive dimers and that these dimers exist independently of the actin cytoskeleton or cytoplasmic proteins. The dimers are stabilized by intermolecular contacts that occur along the entire length of Ecadherin, with the intracellular domains having a surprisingly strong favorable contribution. We further show that Ecadherin mutations and calcium depletion induce structural alterations that propagate from the N terminus all the way to the C terminus, without destabilizing the dimeric state. These findings provide context for the interpretation of Ecadherin adhesion experiments. They also suggest that early events of adherens junction assembly involve interactions between from preformed Ecadherin dimers.

The National Eye Survey of Trinidad and Tobago (NESTT): Rationale, Objectives and Methodology.

PURPOSE: This paper describes the rationale, study design and procedures of the National Eye Survey of Trinidad and Tobago (NESTT). The main objective of this survey is to obtain prevalence estimates of vision impairment and blindness for planning and policy development. METHODS: A population-based, cross-sectional survey was undertaken using random multistage cluster sampling, with probability-proportionate-to-size methods. Eligible participants aged 5 years and older were sampled from the non-institutional population in each of 120 cluster segments. Presenting distance and near visual acuity were screened in their communities. People aged 40 years and older, and selected younger people, were invited for comprehensive clinic assessment. The interview included information on potential risk factors for vision loss, associated costs and quality of life. The examination included measurement of anthropometrics, blood glucose, refraction, ocular biometry, corneal hysteresis, and detailed assessment of the anterior and posterior segments, with photography and optical coherence tomography imaging. Adult participants were invited to donate saliva samples for DNA extraction and storage. RESULTS: The fieldwork was conducted over 13 months in 2013-2014. A representative sample of 10,651 individuals in 3410 households within 120 cluster segments identified 9913 people who were eligible for recruitment. CONCLUSION: The study methodology was robust and adequate to provide the first population-based estimates of the prevalence and causes of visual impairment and blindness in Trinidad and Tobago. Information was also gathered on risk factors, costs and quality of life associated with vision loss, and on normal ocular parameters for the population aged 40 years and older.

The SAM domain inhibits EphA2 interactions in the plasma membrane.

All members of the Eph receptor family of tyrosine kinases contain a SAM domain near the C terminus, which has been proposed to play a role in receptor homotypic interactions and/or interactions with binding partners. The SAM domain of EphA2 is known to be important for receptor function, but its contribution to EphA2 lateral interactions in the plasma membrane has not been determined. Here we use a FRET-based approach to directly measure the effect of the SAM domain on the stability of EphA2 dimers on the cell surface in the absence of ligand binding. We also investigate the functional consequences of EphA2 SAM domain deletion. Surprisingly, we find that the EphA2 SAM domain inhibits receptor dimerization and decreases EphA2 tyrosine phosphorylation. This role is dramatically different from the role of the SAM domain of the related EphA3 receptor, which we previously found to stabilize EphA3 dimers and increase EphA3 tyrosine phosphorylation in cells in the absence of ligand. Thus, the EphA2 SAM domain likely contributes to a unique mode of EphA2 interaction that leads to distinct signaling outputs.