Activity budget of Bengal Monitor Varanus bengalensis: Effect of daytime, season, age and temperature.

The Bengal Monitor (Varanus bengalensis) is a large, ecologically flexible species and commonly found in many ecological settings including human-modified habitats. We conducted a study on the activity budget of this species employing the focal sampling method in the Chandpur district of Bangladesh. The Bengal Monitor spent the highest proportion of time in resting (33.09%) and the least proportion (3.75%) of time in anti-predatory behavior. The proportion of time spent on each activity by Bengal Monitor varied significantly between age classes and seasons except anti-predatory behavior. The highest proportion of basking activity was recorded for adult and sub-adult individuals in the dry season. Meanwhile, resting and foraging behavior was higher during the wet season. Locomotion activities were higher in sub-adults than in adult individuals. The duration of the activities did not differ significantly for daytime and season. However, an increase of air temperature significantly impacted lowering basking and rising locomotion activities among all behaviors of adult Bengal Monitor. The present findings suggest that the activities of the Bengal Monitor varied according to temporal and seasonal changes in the habitat's temperature, and age may crucially affect the allocation time for different activities.

A protocol for harvesting biodiversity data from Facebook.

The expanding use of community science platforms has led to an exponential increase in biodiversity data in global repositories. Yet, understanding of species distributions remains patchy. Biodiversity data from social media can potentially reduce the global biodiversity knowledge gap. However, practical guidelines and standardized methods for harvesting such data are nonexistent. Following data privacy and protection safeguards, we devised a standardized method for extracting species distribution records from Facebook groups that allow access to their data. It involves 3 steps: group selection, data extraction, and georeferencing the record location. We present how to structure keywords, search for species photographs, and georeference localities for such records. We further highlight some challenges users might face when extracting species distribution data from Facebook and suggest solutions. Following our proposed framework, we present a case study on Bangladesh's biodiversity-a tropical megadiverse South Asian country. We scraped nearly 45,000 unique georeferenced records across 967 species and found a median of 27 records per species. About 12% of the distribution data were for threatened species, representing 27% of all species. We also obtained data for 56 DataDeficient species for Bangladesh. If carefully harvested, social media data can significantly reduce global biodiversity knowledge gaps. Consequently, developing an automated tool to extract and interpret social media biodiversity data is a research priority.

Un protocolo para recolectar datos sobre biodiversidad en Facebook Resumen El uso creciente de plataformas de ciencia comunitaria ha causado un incremento exponencial de los datos sobre biodiversidad en los repositorios mundiales. Sin embargo, el conocimiento sobre la distribución de las especies todavía está incompleto. Los datos sobre biodiversidad obtenidos de las redes sociales tienen el potencial para disminuir el vacío de conocimiento sobre la biodiversidad mundial. No obstante, no existe una guía práctica o un método estandarizado para recolectar dichos datos. Seguimos los protocolos de privacidad y protección de datos para diseñar un método estandarizado para extraer registros de la distribución de especies de grupos en Facebook que permiten el acceso a sus datos. El método consta de tres pasos: selección del grupo, extracción de datos y georreferenciación de la localidad registrada. También planteamos cómo estructurar las palabras clave, buscar fotografías de especies y georreferenciar las localidades de dichos registros. Además, resaltamos algunos retos que los usuarios pueden enfrentar al extraer los datos de distribución de Facebook y sugerimos algunas soluciones. Aplicamos nuestro marco de trabajo propuesto a un estudio de caso de la biodiversidad en Bangladesh, un país tropical megadiverso en el sureste de Asia. Reunimos casi 45,000 registros georreferenciados únicos para 967 especies y encontramos una media de 27 registros por especie. Casi el 12% de los datos de distribución correspondió a especies amenazadas, que representaban el 27% de todas las especies. También obtuvimos datos para 56 especies deficientes de datos en Bangladesh. Si los datos de las redes sociales se recolectan con cuidado, éstos pueden reducir de forma significativa el vacío de conocimiento para la biodiversidad mundial. Como consecuencia, es una prioridad para la investigación el desarrollo de una herramienta automatizada para extraer e interpretar los datos sobre biodiversidad de las redes sociales.

Using social media records to inform conservation planning.

Citizen science plays a crucial role in helping monitor biodiversity and inform conservation. With the widespread use of smartphones, many people share biodiversity information on social media, but this information is still not widely used in conservation. Focusing on Bangladesh, a tropical megadiverse and mega-populated country, we examined the importance of social media records in conservation decision-making. We collated species distribution records for birds and butterflies from Facebook and Global Biodiversity Information Facility (GBIF), grouped them into GBIF-only and combined GBIF and Facebook data, and investigated the differences in identifying critical conservation areas. Adding Facebook data to GBIF data improved the accuracy of systematic conservation planning assessments by identifying additional important conservation areas in the northwest, southeast, and central parts of Bangladesh, extending priority conservation areas by 4,000-10,000 km2 . Community efforts are needed to drive the implementation of the ambitious Kunming-Montreal Global Biodiversity Framework targets, especially in megadiverse tropical countries with a lack of reliable and up-to-date species distribution data. We highlight that conservation planning can be enhanced by including available data gathered from social media platforms.

Registros de las redes sociales para guiar la planeación de la conservación Resumen La ciencia ciudadana es importante para monitorear la biodiversidad e informar la conservación. Con el creciente uso de los teléfonos inteligentes, muchas personas comparten información de la biodiversidad en redes sociales, pero todavía no se usa ampliamente en la conservación. Analizamos la importancia de los registros de las redes sociales para las decisiones de conservación enfocados en Bangladesh, un país tropical megadiverso y mega poblado. Cotejamos los registros de distribución de especies de aves y mariposas en Facebook y Global Biodiversity Information Facility (GBIF), las agrupamos en datos sólo de GBIF o datos combinados de Facebook y GBIF e investigamos las diferencias en la identificación de las áreas de conservación críticas. La combinación de los datos de Facebook con los de GBIF mejoró la precisión de las evaluaciones de la planeación de la conservación sistemática al identificar otras áreas importantes de conservación en el noroeste, sureste y centro de Bangladesh, extendiendo así las áreas prioritarias de conservación en unos 4,000-10,000 km2 . Se requieren esfuerzos comunitarios para impulsar la implementación de los objetivos ambiciosos del Marco Global de Biodiversidad Kunming-Montreal, especialmente en países tropicales que carecen de datos confiables y actuales sobre la distribución de las especies. Destacamos que la planeación de la conservación puede mejorarse si se incluye información tomada de las redes sociales.

Biochemical characterization of the Drosophila insulin receptor kinase and longevity-associated mutants.

Drosophila melanogaster (fruit fly) insulin receptor (D-IR) is highly homologous to the human counterpart. Like the human pathway, D-IR responds to numerous insulin-like peptides to activate cellular signals that regulate growth, development, and lipid metabolism in fruit flies. Allelic mutations in the D-IR kinase domain elevate life expectancy in fruit flies. We developed a robust heterologous expression system to express and purify wild-type and longevity-associated mutant D-IR kinase domains to investigate enzyme kinetics and substrate specificities. D-IR exhibits remarkable similarities to the human insulin receptor kinase domain but diverges in substrate preferences. We show that longevity-associated mutations reduce D-IR catalytic activity. Deletion of the unique kinase insert domain portion or mutations proximal to activating tyrosines do not influence kinase activity, suggesting their potential role in substrate recruitment and downstream signaling. Through biochemical investigations, this study enhances our comprehension of D-IR's role in Drosophila physiology, complementing genetic studies and expanding our knowledge on the catalytic functions of this conserved signaling pathway.

Piezo1-mediated regulation of smooth muscle cell volume in response to enhanced extracellular matrix rigidity.

BACKGROUND AND PURPOSE: Decreased aortic compliance is a precursor to numerous cardiovascular diseases. Compliance is regulated by the rigidity of the aortic wall and the vascular smooth muscle cells (VSMCs). Extracellular matrix stiffening, observed during ageing, reduces compliance. In response to increased rigidity, VSMCs generate enhanced contractile forces that result in VSMC stiffening and a further reduction in compliance. Mechanisms driving VSMC response to matrix rigidity remain poorly defined. EXPERIMENTAL APPROACH: Human aortic-VSMCs were seeded onto polyacrylamide hydrogels whose rigidity mimicked either healthy (12 kPa) or aged/diseased (72 kPa) aortae. VSMCs were treated with pharmacological agents prior to agonist stimulation to identify regulators of VSMC volume regulation. KEY RESULTS: On pliable matrices, VSMCs contracted and decreased in cell area. Meanwhile, on rigid matrices VSMCs displayed a hypertrophic-like response, increasing in area and volume. Piezo1 activation stimulated increased VSMC volume by promoting calcium ion influx and subsequent activation of PKC and aquaporin-1. Pharmacological blockade of this pathway prevented the enhanced VSMC volume response on rigid matrices whilst maintaining contractility on pliable matrices. Importantly, both piezo1 and aquaporin-1 gene expression were up-regulated during VSMC phenotypic modulation in atherosclerosis and after carotid ligation. CONCLUSIONS AND IMPLICATIONS: In response to extracellular matrix rigidity, VSMC volume is increased by a piezo1/PKC/aquaporin-1 mediated pathway. Pharmacological targeting of this pathway specifically blocks the matrix rigidity enhanced VSMC volume response, leaving VSMC contractility on healthy mimicking matrices intact. Importantly, upregulation of both piezo1 and aquaporin-1 gene expression is observed in disease relevant VSMC phenotypes.

Colorectal cancer-associated mutations impair EphB1 kinase function.

Erythropoietin-producing hepatoma (Eph) receptor tyrosine kinases regulate the migration and adhesion of cells that are required for many developmental processes and adult tissue homeostasis. In the intestinal epithelium, Eph signaling controls the positioning of cell types along the crypt-villus axis. Eph activity can suppress the progression of colorectal cancer (CRC). The most frequently mutated Eph receptor in metastatic CRC is EphB1. However, the functional effects of EphB1 mutations are mostly unknown. We expressed and purified the kinase domains of WT and five cancer-associated mutant EphB1 and developed assays to assess the functional effects of the mutations. Using purified proteins, we determined that CRC-associated mutations reduce the activity and stability of the folded structure of EphB1. By mammalian cell expression, we determined that CRC-associated mutant EphB1 receptors inhibit signal transducer and activator of transcription 3 and extracellular signal-regulated kinases 1 and 2 signaling. In contrast to the WT, the mutant EphB1 receptors are unable to suppress the migration of human CRC cells. The CRC-associated mutations also impair cell compartmentalization in an assay in which EphB1-expressing cells are cocultured with ligand (ephrin B1)-expressing cells. These results suggest that somatic mutations impair the kinase-dependent tumor suppressor function of EphB1 in CRC.

Increasing biodiversity knowledge through social media: A case study from tropical Bangladesh.

Citizen science programs are becoming increasingly popular among naturalists but remain heavily biased taxonomically and geographically. However, with the explosive popularity of social media and the near-ubiquitous availability of smartphones, many post wildlife photographs on social media. Here, we illustrate the potential of harvesting these data to enhance our biodiversity understanding using Bangladesh, a tropical biodiverse country, as a case study. We compared biodiversity records extracted from Facebook with those from the Global Biodiversity Information Facility (GBIF), collating geospatial records for 1013 unique species, including 970 species from Facebook and 712 species from GBIF. Although most observation records were biased toward major cities, the Facebook records were more evenly spatially distributed. About 86% of the Threatened species records were from Facebook, whereas the GBIF records were almost entirely Of Least Concern species. To reduce the global biodiversity data shortfall, a key research priority now is the development of mechanisms for extracting and interpreting social media biodiversity data.

National Diagnostic Reference Levels for Nuclear Medicine in Qatar.

Nuclear medicine (NM) started in Qatar in the mid-1980s with a 1-head γ-camera in Hamad General Hospital. However, Qatar is expanding, and now Hamad Medical Corp. has 2 NM departments and 1 PET/CT Center for Diagnosis and Research, with several hybrid SPECT/CT and PET/CT cameras. Furthermore, 2 new NM departments will be established in Qatar in the coming 3 y. Therefore, there is a need to optimize radiation protection in NM imaging and establish diagnostic reference levels (DRLs) for the first time in Qatar. This need is not only for the NM part of the examination but also for the CT part, especially in hybrid SPECT/CT and PET/CT. Methods: Data for adult patients were collected from the 3 SPECT/CT machines in the 2 NM facilities and from the 2 PET/CT machines in the PET/CT center. The 75th percentile values (also known as the third quartile) were considered preliminary DRLs and were consistent with the most commonly administered activities. The results for various general NM protocols were described, especially 99mTc-based radiopharmaceuticals and PET/CT protocols including mainly oncologic applications. Results: The first DRLs for NM imaging in Qatar adults were established. The values agreed with other published DRLs, as was the case, for example, for PET oncology using 18F-FDG, with DRLs of 258, 230, 370, 400, and 461-710 MBq for Qatar, Kuwait, Korea, the United Kingdom, and the United States, respectively. Similarly, for cardiac stress or rest myocardial perfusion imaging using 99mTc-methoxyisobutylisonitrile, the DRLs were 926, 976, 1,110, 800, and 945-1,402 MBq for Qatar, Kuwait, Korea, the United Kingdom, and the United States, respectively. Conclusion: The optimization of administered activity that this study will enable for NM procedures in Qatar will be of great value, especially for new departments that adhere to these DRLs.

The noncatalytic regions of the tyrosine kinase Tnk1 are important for activity and substrate specificity.

Human Tnk1 (thirty-eight negative kinase 1) is a member of the Ack family of nonreceptor tyrosine kinases. Tnk1 contains a sterile alpha motif, a tyrosine kinase catalytic domain, an SH3 (Src homology 3) domain, and a large C-terminal region that contains a ubiquitin association domain. However, specific physiological roles for Tnk1 have not been characterized in depth. Here, we expressed and purified Tnk1 from Sf9 insect cells and established an in vitro assay system using a peptide substrate derived from the Wiskott-Aldrich Syndrome Protein (WASP). By Tnk1 expression in mammalian cells, we found that the N-terminal SAM domain is important for self-association and kinase activity. We also studied a fusion protein, originally discovered in a Hodgkin's Lymphoma cell line, that contains an unrelated sequence from the C17ORF61 gene fused to the C-terminus of Tnk1. Cells expressing the fusion protein showed increased tyrosine phosphorylation of cellular substrates relative to cells expressing WT Tnk1. A truncated Tnk1 construct (residues 1-465) also showed enhanced phosphorylation, indicating that the C17ORF61 sequence was dispensable for the effect. Additionally, in vitro kinase assays with the WASP peptide substrate showed no increase in intrinsic Tnk1 activity in C-terminally truncated constructs, suggesting that the truncations did not simply remove an autoinhibitory element. Fluorescence microscopy experiments demonstrated that the C-terminus of Tnk1 plays an important role in the subcellular localization of the kinase. Taken together, our data suggest that the noncatalytic regions of Tnk1 play important roles in governing activity and substrate phosphorylation.

Antimicrobial Resistance Profile of Common Foodborne Pathogens Recovered from Livestock and Poultry in Bangladesh.

Multidrug-resistant (MDR) foodborne pathogens have created a great challenge to the supply and consumption of safe & healthy animal-source foods. The study was conducted to identify the common foodborne pathogens from animal-source foods & by-products with their antimicrobial drug susceptibility and resistance gene profile. The common foodborne pathogens Escherichia coli (E. coli), Salmonella, Streptococcus, Staphylococcus, and Campylobacter species were identified in livestock and poultry food products. The prevalence of foodborne pathogens was found higher in poultry food & by-product compared with livestock (p < 0.05). The antimicrobial drug susceptibility results revealed decreased susceptibility to penicillin, ampicillin, amoxicillin, levofloxacin, ciprofloxacin, tetracycline, neomycin, streptomycin, and sulfamethoxazole-trimethoprim whilst gentamicin was found comparatively more sensitive. Regardless of sources, the overall MDR pattern of E. coli, Salmonella, Staphylococcus, and Streptococcus were found to be 88.33%, 75%, 95%, and 100%, respectively. The genotypic resistance showed a prevalence of blaTEM, blaSHV, blaCMY, tetA, tetB, sul1, aadA1, aac(3)-IV, and ereA resistance genes. The phenotype and genotype resistance patterns of isolated pathogens from livestock and poultry had harmony and good concordance, and sul1 & tetA resistance genes had a higher prevalence. Good agricultural practices along with proper biosecurity may reduce the rampant use of antimicrobial drugs. In addition, proper handling, processing, storage, and transportation of foods may decline the spread of MDR foodborne pathogens in the food chain.

Generic learning mechanisms can drive social inferences: The role of type frequency.

How do we form opinions about typical and morally acceptable behavior in other social groups despite variability in behavior? Similar learning problems arise during language acquisition, where learners need to infer grammatical rules (e.g., the walk/walk-ed past-tense) despite frequent exceptions (e.g., the go/went alternation). Such rules need to occur with many different words to be learned (i.e., they need a high type frequency). In contrast, frequent individual words do not lead to learning. Here, we ask whether similar principles govern social learning. Participants read a travel journal where a traveler observed behaviors in different imaginary cities. The behaviors were performed once by many distinct actors (high type frequency) or frequently by a single actor (low type frequency), and could be good, neutral or bad. We then asked participants how morally acceptable the behavior was (in general or for the visited city), and how widespread it was in that city. We show that an ideal observer model estimating the prevalence of behaviors is only sensitive to the behaviors' type frequency, but not to how often they are performed. Empirically, participants rated high type frequency behaviors as more morally acceptable more prevalent than low type frequency behaviors. They also rated good behaviors as more acceptable and prevalent than neutral or bad behaviors. These results suggest that generic learning mechanisms and epistemic biases constrain social learning, and that type frequency can drive inferences about groups. To combat stereotypes, high type frequency behaviors might thus be more effective than frequently appearing individual role models.

Trigeminal Neuralgia As the Principal Manifestation of Anaplasmosis: A Case Report.

Unlike the tick-borne diseases ehrlichiosis and Lyme disease, human granulocytic anaplasmosis is rarely associated with neurological complications. In this case report, we present a patient who developed a severe, lancinating headache shortly after known tick exposure. A tick-borne PCR panel was positive for Anaplasmosis phagocytophilum and neurology evaluation yielded a concomitant diagnosis of new-onset trigeminal neuralgia. Our case explores the relationship between anaplasmosis infection and trigeminal neuralgia.

Using Polyacrylamide Hydrogels to Model Physiological Aortic Stiffness Reveals that Microtubules Are Critical Regulators of Isolated Smooth Muscle Cell Morphology and Contractility.

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aortic wall and normally exist in a quiescent, contractile phenotype where actomyosin-derived contractile forces maintain vascular tone. However, VSMCs are not terminally differentiated and can dedifferentiate into a proliferative, synthetic phenotype. Actomyosin force generation is essential for the function of both phenotypes. Whilst much is already known about the mechanisms of VSMC actomyosin force generation, existing assays are either low throughput and time consuming, or qualitative and inconsistent. In this study, we use polyacrylamide hydrogels, tuned to mimic the physiological stiffness of the aortic wall, in a VSMC contractility assay. Isolated VSMC area decreases following stimulation with the contractile agonists angiotensin II or carbachol. Importantly, the angiotensin II induced reduction in cell area correlated with increased traction stress generation. Inhibition of actomyosin activity using blebbistatin or Y-27632 prevented angiotensin II mediated changes in VSMC morphology, suggesting that changes in VSMC morphology and actomyosin activity are core components of the contractile response. Furthermore, we show that microtubule stability is an essential regulator of isolated VSMC contractility. Treatment with either colchicine or paclitaxel uncoupled the morphological and/or traction stress responses of angiotensin II stimulated VSMCs. Our findings support the tensegrity model of cellular mechanics and we demonstrate that microtubules act to balance actomyosin-derived traction stress generation and regulate the morphological responses of VSMCs.

Covid-19 Pandemic and its Effect on Residents' Mental Well-Being

Concerns about COVID-19s long-term consequences on the mental health of frontline health professionals are mounting as the entire world strives anew to contain it. The primary objective of this research is to describe the impact of working during the COVID-19 pandemic on junior doctors mental health and to investigate the effect of the COVID-19 pandemic on junior doctors training and professional performance. A cross-sectional online survey using the Google Forms platform was conducted from May 1st to May 30th, 2021, in 311 healthcare workers who were currently enrolled in a residency program at the Kuwait Institutional of Medical Specialization (KIMS). Socio-demographic details of each health worker were collected and the scores related to depression, anxiety, and stress were measured using the previously validated depression anxiety stress scale-21 (DASS-21). Higher stress scores were seen in those who were devoid of the option to work with COVID-19 patients (adjusted {beta} 5.1 (95%CI:1.2-9);p=0.01), who reported that working during the pandemic affected their study schedule (adjusted {beta} 4.8 (95%CI:1.6-8.1);p= 0.004), and who lost off service training time (adjusted {beta} 2.7 (95%CI:0.13-5.2); p=0.034). Further, the anxiety scores were significantly higher in females. The impact of the ongoing pandemic on residents mental health is grave, necessitating psychological treatment and support. The study discovered various factors linked to depression, anxiety, and stress. As a result, these aspects must be regarded to protect the residents mental health.

Flexible Antifreeze Zn-Ion Hybrid Supercapacitor Based on Gel Electrolyte with Graphene Electrodes.

Zn-ion energy storage devices employing hydrogel electrolytes are considered as promising candidates for flexible and wearable electronics applications. This is because of their safe nature, low cost, and good mechanical characteristics. However, conventional hydrogel electrolytes face limitation at subzero temperatures. Herein, we report an antifreezing, safe, and nontoxic gel electrolyte based on the poly(vinyl alcohol) (PVA)/Zn/ethylene glycol system. The optimal gel electrolyte membrane exhibits a high ionic conductivity (15.03 mS cm-1 at room temperature) and promising antifreezing performance (9.05 mS cm-1 at -20 °C and 3.53 mS cm-1 at -40 °C). Moreover, the antifreezing gel electrolyte can suppress the growth of Zn dendrites to display a uniform Zn plating/stripping behavior. Also, a flexible antifreezing Zn-ion hybrid supercapacitor fabricated with the optimum antifreezing gel electrolyte membrane exhibits excellent electrochemical properties. The supercapacitor possesses a high specific capacity of 247.7 F g-1 at room temperature under a high working voltage of 2 V. It also displays an outstanding cyclic stability at room temperature. Moreover, the supercapacitor shows an extraordinary electrochemical behavior and cyclic stability over up to 30 000 cycles at -20 °C under a current load of 5 A g-1, demonstrating its outstanding low-temperature electrochemical performance. Besides, the antifreezing supercapacitor device also offers high flexibility under different deformation conditions. Therefore, it is believed that this work provides a simplistic method of realizing the application of flexible antifreezing Zn-ion energy storage devices in a subzero-temperature environment.

A longitudinal study of rural Bangladeshi children with long-term arsenic and cadmium exposures and biomarkers of cardiometabolic diseases.

There is growing interest in understanding the contribution of environmental toxicant exposure in early life to development of cardiometabolic diseases (CMD) in adulthood. We aimed to assess associations of early life exposure to arsenic and cadmium with biomarkers of CMD in children in rural Bangladesh. From a longitudinal mother-child cohort in Matlab, Bangladesh, we followed up 540 pairs. Exposure to arsenic (U-As) and cadmium (U-Cd) was assessed by concentrations in urine from mothers at gestational week 8 (GW8) and children at ages 4.5 and 9 years. Blood pressure and anthropometric indices were measured at 4.5 and 9 years. Metabolic markers (lipids, glucose, hemoglobin A1c, adipokines, estimated glomerular filtration rate (eGFR) were determined in plasma/blood of 9 years old children. In linear regression models, adjusted for child sex, age, height-for-age z score (HAZ), BMI-for-age z score (BAZ), socioeconomic status (SES) and maternal education, each doubling of maternal and early childhood U-Cd was associated with 0.73 and 0.82 mmHg increase in systolic blood pressure (SBP) respectively. Both early and concurrent childhood U-Cd was associated with diastolic (D)BP (ß = 0.80 at 4.5 years; ß = 0.75 at 9 years). Each doubling of U-Cd at 9 years was associated with decrements of 4.98 mg/dL of total cholesterol (TC), 1.75 mg/dL high-density lipoprotein (HDL), 3.85 mg/dL low-density lipoprotein (LDL), 0.43 mg/dL glucose and 4.29 units eGFR. Each doubling of maternal U-Cd was associated with a decrement of 1.23 mg/dL HDL. Both maternal and childhood U-As were associated with decrement in TC and HDL. Multiple comparisons were checked with family-wise error rate Bonferroni-type-approach. The negative associations of arsenic and cadmium with biomarkers of CMD in preadolescent children indicated influence of both metal(loid)s on fat and carbohydrate metabolism, while cadmium additionally influenced kidney function and BP. Thus, fewer outcomes were associated with U-As compared to U-Cd at preadolescence.

Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity.

BACKGROUND: Multidrug-resistant (MDR) tuberculosis has low treatment success rates, and new treatment strategies are needed. We explored whether treatment with active vitamin D3 (vitD) and phenylbutyrate (PBA) could improve conventional chemotherapy by enhancing immune-mediated eradication of Mycobacterium tuberculosis. METHODS: A clinically relevant model was used consisting of human macrophages infected with M. tuberculosis isolates (n = 15) with different antibiotic resistance profiles. The antimicrobial effect of vitD+PBA, was tested together with rifampicin or isoniazid. Methods included colony-forming units (intracellular bacterial growth), messenger RNA expression analyses (LL-37, ß-defensin, nitric oxide synthase, and dual oxidase 2), RNA interference (LL-37-silencing in primary macrophages), and Western blot analysis and confocal microscopy (LL-37 and LC3 protein expression). RESULTS: VitD+PBA inhibited growth of clinical MDR tuberculosis strains in human macrophages and strengthened intracellular growth inhibition of rifampicin and isoniazid via induction of the antimicrobial peptide LL-37 and LC3-dependent autophagy. Gene silencing of LL-37 expression enhanced MDR tuberculosis growth in vitD+PBA-treated macrophages. The combination of vitD+PBA and isoniazid were as effective in reducing intracellular MDR tuberculosis growth as a >125-fold higher dose of isoniazid alone, suggesting potent additive effects of vitD+PBA with isoniazid. CONCLUSIONS: Immunomodulatory agents that trigger multiple immune pathways can strengthen standard MDR tuberculosis treatment and contribute to next-generation individualized treatment options for patients with difficult-to-treat pulmonary tuberculosis.

Early childhood malnutrition trajectory and lung function at preadolescence.

OBJECTIVE: Chronic undernutrition is a common phenomenon in Bangladesh. However, information is grossly lacking to report the correlation between chronic undernutrition trajectory and lung function in children. The aim of the current study was to understand the association between early-childhood chronic undernutrition trajectory and lung function at preadolescence. DESIGN: The current study is a part of the 9-year follow-up of a large-scale cohort study called the Maternal and Infant Nutrition Interventions in Matlab. SETTINGS: The current study was conducted in Matlab, a sub-district area of Bangladesh that is located 53 km south of the capital, Dhaka. PARTICIPANTS: A total of 517 children participated in lung function measured with a spirometer at the age of 9 years. Weight and height were measured at five intervals from birth till the age of 9 years. RESULTS: Over half of the cohort have experienced a stunting undernutrition phenomenon up to 9 years of age. Children who were persistently or intermittently stunted showed lower forced expiratory volume (ml/s) than normal-stature children (P < 0·05). Children who exhibited catch-up growth throughout 4·5 years from the stunted group showed similar lung function with normal counterparts, and a better lung function than in children with the same growth velocity or who had faltering growth. In the multivariable models, similar associations were observed in children who experienced catch-up growth than their counterparts after adjusting for covariates. CONCLUSION: Our data suggest that catch-up growth in height during early childhood is associated with a better lung function at preadolescence.

The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity.

The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D3 analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E2, IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients' tumour immune surveillance. Thus, vitamin D3 analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications.

Mannose receptor-derived peptides neutralize pore-forming toxins and reduce inflammation and development of pneumococcal disease.

Cholesterol-dependent cytolysins (CDCs) are essential virulence factors for many human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes (streptolysin O, SLO), and Listeria monocytogenes (Listeriolysin, LLO) and induce cytolysis and inflammation. Recently, we identified that pneumococcal PLY interacts with the mannose receptor (MRC-1) on specific immune cells thereby evoking an anti-inflammatory response at sublytic doses. Here, we identified the interaction sites between MRC-1 and CDCs using computational docking. We designed peptides from the CTLD4 domain of MRC-1 that binds to PLY, SLO, and LLO, respectively. In vitro, the peptides blocked CDC-induced cytolysis and inflammatory cytokine production by human macrophages. Also, they reduced PLY-induced damage of the epithelial barrier integrity as well as blocked bacterial invasion into the epithelium in a 3D lung tissue model. Pre-treatment of human DCs with peptides blocked bacterial uptake via MRC-1 and reduced intracellular bacterial survival by targeting bacteria to autophagosomes. In order to use the peptides for treatment in vivo, we developed calcium phosphate nanoparticles (CaP NPs) as peptide nanocarriers for intranasal delivery of peptides and enhanced bioactivity. Co-administration of peptide-loaded CaP NPs during infection improved survival and bacterial clearance in both zebrafish and mice models of pneumococcal infection. We suggest that MRC-1 peptides can be employed as adjunctive therapeutics with antibiotics to treat bacterial infections by countering the action of CDCs.