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Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from patients with PAH. Endothelial haploinsufficiency of RAB7 caused spontaneous pulmonary hypertension (PH) in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA-Seq, and RAB7-silenced ECs showed impaired angiogenesis and expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, suggesting inhibition of autophagy at the predegradation level. Furthermore, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in rats with chronic hypoxia/SU5416. In conclusion, we demonstrate for the first time to our knowledge the fundamental impairment of EC function by loss of RAB7, causing PH, and show RAB7 activation to be a potential therapeutic strategy in a preclinical model of PH.

We evaluated immune cell subsets in patients with chronic lymphocytic leukemia (CLL) who received first-line therapy with 3 cycles of ibrutinib then 13 cycles of ibrutinib plus venetoclax in the minimal residual disease (MRD) cohort of the CAPTIVATE study (NCT02910583). Patients with Confirmed undetectable MRD (uMRD) were randomly assigned to placebo or ibrutinib groups; patients without Confirmed uMRD were randomly assigned to ibrutinib or ibrutinib plus venetoclax groups. We compared immune cell subsets in samples collected at 7 time points with age-matched healthy donors. CLL cells decreased within 3 cycles after venetoclax initiation; from cycle 16 onward, levels were similar to healthy donor levels (HDL; ≤0.8 cells per μL) in patients with Confirmed uMRD and slightly above HDL in patients without Confirmed uMRD. By 4 months after cycle 16, normal B cells had recovered to HDL in patients randomly assigned to placebo. Regardless of randomized treatment, abnormal counts of T cells, classical monocytes, and conventional dendritic cells recovered to HDL within 6 months (median change from baseline -49%, +101%, and +91%, respectively); plasmacytoid dendritic cells recovered by cycle 20 (+598%). Infections generally decreased over time regardless of randomized treatment and were numerically lowest in patients randomly assigned to placebo within 12 months after cycle 16. Sustained elimination of CLL cells and recovery of normal B cells were confirmed in samples from patients treated with fixed-duration ibrutinib plus venetoclax in the GLOW study (NCT03462719). These results demonstrate promising evidence of restoration of normal blood immune composition with ibrutinib plus venetoclax.

Pulmonary arterial hypertension (PAH) features pathogenic and abnormal endothelial cells (ECs), and one potential origin is clonal selection. We studied the role of p53 and toll-like receptor 3 (TLR3) in clonal expansion and pulmonary hypertension (PH) via regulation of bone morphogenetic protein (BMPR2) signaling. ECs of PAH patients had reduced p53 expression. EC-specific p53 knockout exaggerated PH, and clonal expansion reduced p53 and TLR3 expression in rat lung CD117+ ECs. Reduced p53 degradation (Nutlin 3a) abolished clonal EC expansion, induced TLR3 and BMPR2, and ameliorated PH. Polyinosinic/polycytidylic acid [Poly(I:C)] increased BMPR2 signaling in ECs via enhanced binding of interferon regulatory factor-3 (IRF3) to the BMPR2 promoter and reduced PH in p53-/- mice but not in mice with impaired TLR3 downstream signaling. Our data show that a p53/TLR3/IRF3 axis regulates BMPR2 expression and signaling in ECs. This link can be exploited for therapy of PH.

Abstract The advancement of RNAseq and isoform-specific expression platforms has led to the understanding that isoform changes can alter molecular signaling to promote tumorigenesis. An active area in cancer research is uncovering the roles of ubiquitination on spliceosome assembly contributing to transcript diversity and expression of alternative isoforms. However, the effects of isoform changes on functionality of ubiquitination machineries (E1, E2, E3, E4, and deubiquitinating (DUB) enzymes) influencing onco- and tumor suppressor protein stabilities is currently understudied. Characterizing these changes could be instrumental in improving cancer outcomes via the identification of novel biomarkers and targetable signaling pathways. In this review, we focus on highlighting reported examples of direct, protein-coded isoform variation of ubiquitination enzymes influencing cancer development and progression in gastrointestinal (GI) malignancies. We have used a semi-automated system for identifying relevant literature and applied established systems for isoform categorization and functional classification to help structure literature findings. The results are a comprehensive snapshot of known isoform changes that are significant to GI cancers, and a framework for readers to use to address isoform variation in their own research. One of the key findings is the potential influence that isoforms of the ubiquitination machinery have on oncoprotein stability.

The present research examined patulin's presence across the whole supply chain of selected fruits. A comprehensive analysis was conducted on 442 samples of fruits (oranges, apples, apricots, lemons, and guava) to determine the presence of patulin contamination. This analysis used Liquid Chromatography (HPLC) with a UV detector. The findings indicate that 17, 23, and 28 % of selected fruit samples tested positive for patulin levels in farm, transportation, and market samples. However, the sample collected during the transportation step showed that 56 % (percentage of positive samples) of fruits have patulin levels greater than 50 μg/kg, and 41 % (percentage of positive samples) have greater levels than 50 μg/kg in market samples. The findings of the one-way analysis of variance indicated that no statistically significant variation existed between the amounts of patulin across the various stages of the food supply chain system (p > 0.05). Nevertheless, the analysis of the correlation study, namely Kendall's tau_b and Spearman's rho, denote a robust association between the levels of patulin and the food supply system. The apple samples exhibited the most significant average dietary intake of patulin, with an average value of 0.11 μg/kg bw/day. The maximum mean hazard quotient (HQ) of 0.28 was also recorded. The prevalence and incidence of patulin in specific fruits were found to be relatively high, and it was observed that market samples had elevated levels of patulin in the selected fruits.

The higher education system of India is one of the largest systems on the globe, where there is a huge young population. The central government aims to increase the higher education gross enrolment ratio, which will improve the living and economic standards of youth. However, enrolment in higher education is lower for many reasons, including the accessibility of institutions in the rural region and the affordability of learning. The institutional capacity cannot be expanded in an accelerated manner with more than three times the existing capacity in a short period of time. As an alternative, the regulation to award degrees and diplomas through online education is formulated with the assurance of recognition on par with regular degrees and diplomas. The regulatory norms, recognition process, human resources, infrastructure requirements, and quality mechanisms of online programs are reviewed in this paper.

BackgroundInadequate or excessive intake of micronutrients in pregnancy has potential to negatively impact maternal/offspring health outcomes.ObjectiveThe aim was to compare risks of inadequate or excessive micronutrient intake in diverse females with singleton pregnancies by strata of maternal age, race/ethnicity, education, and prepregnancy BMI.MethodsFifteen observational cohorts in the US Environmental influences on Child Health Outcomes (ECHO) Consortium assessed participant dietary intake with 24-h dietary recalls (n = 1910) or food-frequency questionnaires (n = 7891) from 1999-2019. We compared the distributions of usual intake of 19 micronutrients from food alone (15 cohorts; n = 9801) and food plus dietary supplements (10 cohorts with supplement data; n = 7082) to estimate the proportion with usual daily intakes below their age-specific daily Estimated Average Requirement (EAR), above their Adequate Intake (AI), and above their Tolerable Upper Intake Level (UL), overall and within sociodemographic and anthropometric subgroups.ResultsRisk of inadequate intake from food alone ranged from 0% to 87%, depending on the micronutrient and assessment methodology. When dietary supplements were included, some women were below the EAR for vitamin D (20-38%), vitamin E (17-22%), and magnesium (39-41%); some women were above the AI for vitamin K (63-75%), choline (7%), and potassium (37-53%); and some were above the UL for folic acid (32-51%), iron (39-40%), and zinc (19-20%). Highest risks for inadequate intakes were observed among participants with age 14-18 y (6 nutrients), non-White race or Hispanic ethnicity (10 nutrients), less than a high school education (9 nutrients), or obesity (9 nutrients).ConclusionsImproved diet quality is needed for most pregnant females. Even with dietary supplement use, >20% of participants were at risk of inadequate intake of ≥1 micronutrients, especially in some population subgroups. Pregnancy may be a window of opportunity to address disparities in micronutrient intake that could contribute to intergenerational health inequalities.

Objective: Emerging evidence suggests that essential trace elements, including iodine, play a vital role in depressive disorders. This study investigated whether prenatal dietary iodine intake alone and in combination with supplemental iodine intake during pregnancy were associated with antepartum and postpartum depressive and anhedonia symptoms. Methods: The study population included 837 mothers in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study. The modified BLOCK food frequency questionnaire was used to estimate prenatal dietary and supplemental iodine intake, while the 10-item Edinburg Postpartum Depression Scale (EPDS) ascertained depressive symptoms. Analyses considered the global EPDS score and the anhedonia and depressive symptom subscale scores using dichotomized cutoffs. Logistic regression estimating odds ratios and 95% confidence intervals (CIs) assessed associations of iodine intake in the second trimester of pregnancy and 6-month postpartum depressive and anhedonia symptoms considering dietary intake alone and combined dietary and supplementary intake in separate models. Results: Most women were Black/Hispanic Black (43%) and non-Black Hispanics (35%), with 39% reporting a high school education or less. The median (interquartile range, IQR) dietary and supplemental iodine intake among Black/Hispanic Black (198 (115, 337) µg/day) and non-Black Hispanic women (195 (126, 323) µg/day) was higher than the overall median intake level of 187 (116, 315) µg/day. Relative to the Institute of Medicine recommended iodine intake level of 160–220 µg/day, women with intake levels < 100 µg/day, 100–220–Conclusions: Prenatal iodine intake, whether below or above the recommended levels for pregnant women, was most strongly associated with greater anhedonia symptoms, particularly in the 6-month postpartum period. Further studies are warranted to corroborate these findings, as dietary and supplemental iodine intake are amenable to intervention.

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange–mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment.

Background: High burden of morbidity and mortality due to respiratory illnesses was witnessed during the COVID-19 pandemic. We developed a portable automated mechanical respiratory assist device (RespirAID R20) that delivers Intermittent Positive Pressure Ventilation by mechanically compressing a Bag Valve Mask. The objective of the study is to evaluate the safety and efficacy of the RespirAID R20, a mechanical ventilation device in post-operative care patients. Method: This pilot study enrolled five subjects at Yenepoya Medical College Hospital, India. Post-operative subjects were transferred from the Mindray Synovent E3 (standard ventilator) to the RespirAID R20 for 3 hours. Ventilator and physiologic parameters were recorded and compared. Result: All patients maintained normal blood pressure, heart rate, and heart rhythm. The delivered mean tidal volume (VT) and peak inspiratory pressure (PIP) was 419.64 +/- 11 ml and 20 +/- 2 cmH2O, which remained within the initial set range of 428 +/- 12 ml and 24 +/- 2 cmH2O throughout the study duration. Arterial blood gas (ABG) parameters during RespirAID R20, except PaO2, were within the normal range. PaO2 levels were greater than 300 mm Hg during the first four hours (323 +/- 163 mmHg and 344 +/- 97 mmHg). Conclusion: The findings of this study suggests that RespirAID R20 may be an alternative device in providing respiratory assistance to sedated and intubated adult patients in the postoperative period. Additional studies are required to evaluate other possible applications of the RespirAID R20.

Abstract Background Many children would benefit from a diet richer in vegetables and fruit. ‘Flavour School’ is a programme of ‘sensory food education’, which aims to increase children’s confidence and curiosity in exploring foods and flavours, especially vegetables and fruit. This study will conduct a cluster-randomised controlled trial to assess the outcomes of the Flavour School programme in primary school children aged 4–7 years. Methods Four hundred plus children from 4+ schools will either complete the Flavour School programme (experimental group) or have no intervention with normal school teaching (control group), cluster-randomised within-schools, by school class. Baseline data collection will consist of video recorded behavioural observation during a tasting activity, and post-intervention data collection will repeat this activity after the experimental group have completed the intervention. Process measures will be assessed using a teacher engagement feedback questionnaire. Discussion This study will provide causal data on the efficacy of a sensory food education intervention for increasing children’s confidence and curiosity in exploring foods and flavours, especially vegetables and fruit. This new knowledge will help educators and policy makers to make evidence based decisions on uptake of sensory food education. Trial registration ISRCTN: 40249947 Date assigned 17 March 2020 Last edited 22 September 2021 Version 1.2 Trial Acronym OASES (Outcomes Assessment of Sensory Education in Schools)

Background and aim: Hertwig’s Εpithelial Root Sheath (HΕRS) has a major function in the developing tooth roots. Earlier research revealed that it undergoes epithelial–mesenchymal transition, a vital process for the morphogenesis and complete development of the tooth and its surrounding periodontium. Few studies have demonstrated the role of HERS in cementogenesis through ΕMΤ. The background of this in-silico system biology approach is to find a hub protein and gene involved in the EMT of HERS that may uncover novel insights in periodontal regenerative drug targets. Materials and methods: The protein and gene list involved in epithelial–mesenchymal transition were obtained from literature sources. The protein interaction was constructed using STRING software and the protein interaction network was analyzed. Molecular docking simulation checks the binding energy and stability of protein-ligand complex. Results: Results revealed the hub gene to be DYRK1A(Hepcidin), and the ligand was identified as isoetharine. SΤRIΝG results showed a confidence cutoff of 0.9 in sensitivity analysis with a condensed protein interaction network. Overall, 98 nodes from 163 nodes of expected edges were found with an average node degree of 11.9. Docking results show binding energy of −4.70, and simulation results show an RMSD value of 5.6 Å at 50 ns. Conclusion: Isoetharine could be a potential drug for periodontal regeneration.

Summary: Pulmonary arterial hypertension (PAH) features pathogenic and abnormal endothelial cells (ECs), and one potential origin is clonal selection. We studied the role of p53 and toll-like receptor 3 (TLR3) in clonal expansion and pulmonary hypertension (PH) via regulation of bone morphogenetic protein (BMPR2) signaling. ECs of PAH patients had reduced p53 expression. EC-specific p53 knockout exaggerated PH, and clonal expansion reduced p53 and TLR3 expression in rat lung CD117+ ECs. Reduced p53 degradation (Nutlin 3a) abolished clonal EC expansion, induced TLR3 and BMPR2, and ameliorated PH. Polyinosinic/polycytidylic acid [Poly(I:C)] increased BMPR2 signaling in ECs via enhanced binding of interferon regulatory factor-3 (IRF3) to the BMPR2 promoter and reduced PH in p53−/− mice but not in mice with impaired TLR3 downstream signaling. Our data show that a p53/TLR3/IRF3 axis regulates BMPR2 expression and signaling in ECs. This link can be exploited for therapy of PH.

When Pierre Robin sequence is associated with many congenital abnormalities, prompt diagnosis and treatment are essential. As Pierre robin sequence can cause significant upper respiratory tract obstruction and aspiration pneumonia it needs detailed evaluation and early correction. Here we report a two years-old girl child with patent ductus arteriosus associated with cleft palate and tongue tie (Pierre Robbin sequence) who was promptly treated. This type of presentation is rare and important. A girl child with a Pierre robin sequence, associated with PDA was under follow-up since birth. The baby was mildly tachypnoeic & was started on diuretics at one month of age. Early closure of PDA with a device was done at 11 months of age. At the age of two years, corrective surgery was done for cleft palate, and tongue tie (Pierre Robin sequence). Pierre Robin sequence may be associated with congenital heart disease, like ventricular septal defect, patent ductus arteriosus, and atrial septal defect in 20 percent of patients. If not treated, the airway obstruction can produce cardiac or respiratory failure, pulmonary hypertension, etc. Early diagnosis and timely intervention helps to alleviate the difficulties. Antenatal screening in high-risk mothers and early identification of the congenital anomaly are the only methods to detect and treat such congenital anomalies.

Convolutional Neural Networks (CNN) are playing a vital role nowadays in every aspect of computer vision applications. In this paper we have used the state of the art CNN in recognizing handwritten Tamil characters in offline mode. CNNs differ from traditional approach of Handwritten Tamil Character Recognition (HTCR) in extracting the features automatically. We have used an isolated handwritten Tamil character dataset developed by HP Labs India. We have developed a CNN model from scratch by training the model with the Tamil characters in offline mode and have achieved good recognition results on both the training and testing datasets. This work is an attempt to set a benchmark for offline HTCR using deep learning techniques. This work have produced a training accuracy of 95.16% which is far better compared to the traditional approaches.

Objective: To describe the personal and professional behavior and assess the perceptions of protection and fear of contracting coronavirus disease 2019 (COVID‐19) among faculty, staff, and students from all 10 Canadian dental schools during the second year of the pandemic. Method: Participants from a Pan‐Canadian prospective study answered monthly questionnaires about their activities between April 2021 and March 2022. In May 2022, additional questions were asked about their perception of protection, fear of infection, and instances of COVID‐19 testing. Results: Six hundred participants were initially recruited. Over time, the participants spent less time at home and increased their participation in indoor social activities, a trend influenced by the fluctuations in COVID‐19 cases (β = ‒0.02). Over 90% of the participants were fully vaccinated, which decreased their fear of contracting the virus (χ2[4, 241‒243] = 196.07, p < 0.0001). Yet, their attitude toward protective measures did not change, and they followed them within school. Conclusions: This work shows a paradoxical behavior among dental students, staff, and faculty members in Canadian dental schools. While factors such as the vaccine's limited efficacy and a desire to protect others may contribute to stringent protective behaviors within dental schools, the mandatory nature of these measures was likely the primary motivator for the compliance. Despite potential efforts to minimize exposure to the virus during risk periods and the frequent COVID‐19 testing, this paradoxical behavior raises questions about professional responsibilities extending beyond the workplace. Thus, dental schools should incorporate education about the rationale behind following different protocols and the potential consequences of outside school behaviors. [ABSTRACT FROM AUTHOR]

BackgroundDisclosure of tuberculosis (TB) status by patients is a critical step in their treatment cascade of care. There is a lack of systematic assessment of TB disclosure patterns and its positive outcomes which happens dynamically over the disease period of individual patients with their family and wider social network relations.MethodsThis prospective observational study was conducted in Chennai Corporation treatment units during 2019-2021. TB patients were recruited and followed-up from treatment initiation to completion. Information on disease disclosures made to different social members at different time points, and outcomes were collected and compared. Bivariate and multi variate analysis were used to identify the patients and contact characteristics predictive of TB disclosure status.ResultsA total of 466 TB patients were followed-up, who listed a total of 4039 family, extra familial and social network contacts of them. Maximum disclosures were made with family members (93%) and half of the relatives, occupational contacts and friendship contacts (44-58%) were disclosed within 15 days of treatment initiation. Incremental disclosures made during the 150-180 days of treatment were highest among neighbourhood contacts (12%), and was significantly different between treatment initiation and completion period. Middle aged TB patients (31 years and 46-55 years) were found less likely to disclose (AOR 0.56 and 0.46 respectively; p71%).ConclusionFindings explain that family level disclosures were predominant and disclosures made to extra familial network contacts significantly increased during the latter part of treatment. Emotional support was predominantly received by TB patients from all their contacts post disclosure. Findings could inform in developing interventions to facilitate disclosure of disease status in a beneficial way for TB patients.

Melanins are ubiquitous pigments which are naturally produced and distributed throughout the biological kingdom. Pseudomonas mosselii strain STSGRDS1 producing melanin was used in the study. STSGRDS1 melanin reported to have metal chelating potential of increasing effect with increase in the concentration of melanin. The anti-proliferative activity of the purified melanin by MTT assay had IC50 value 87.15µg/ml towards A431skin cancer cell line for standard 5-flurouracil and also showed substantial apoptotic activity. The minimal inhibitory concentration (MIC) against bacteria and fungi were also evaluated. Hence, the purified melanin having anti-proliferative properties can be exploited in therapeutic applications.

Abstract Pulmonary arterial hypertension (PAH) is a progressive, devastating disease, and its main histological manifestation is an occlusive pulmonary arteriopathy. One important functional component of PAH is aberrant endothelial cell (EC) function including apoptosis‐resistance, unchecked proliferation, and impaired migration. The mechanisms leading to and maintaining physiologic and aberrant EC function are not fully understood. Here, we tested the hypothesis that in PAH, ECs have increased expression of the transmembrane protein integrin‐β5, which contributes to migration and survival under physiologic and pathological conditions, but also to endothelial‐to‐mesenchymal transition (EnMT). We found that elevated integrin‐β5 expression in pulmonary artery lesions and lung tissue from PAH patients and rats with PH induced by chronic hypoxia and injection of CD117+ rat lung EC clones. These EC clones exhibited elevated expression of integrin‐β5 and its heterodimerization partner integrin‐αν and showed accelerated barrier formation. Inhibition of integrin‐ανβ5 in vitro partially blocked transforming growth factor (TGF)‐β1‐induced EnMT gene expression in rat lung control ECs and less in rat lung EC clones and human lung microvascular ECs. Inhibition of integrin‐ανβ5 promoted endothelial dysfunction as shown by reduced migration in a scratch assay and increased apoptosis in synergism with TGF‐β1. In vivo, blocking of integrin‐ανβ5 exaggerated PH induced by chronic hypoxia and CD117+ EC clones in rats. In summary, we found a role for integrin‐ανβ5 in lung endothelial survival and migration, but also a partial contribution to TGF‐β1‐induced EnMT gene expression. Our results suggest that integrin‐ανβ5 is required for physiologic function of ECs and lung vascular homeostasis.