FAK regulates tension transmission to the nucleus and endothelial transcriptome independent of kinase activity.

The mechanical environment generated through the adhesive interaction of endothelial cells (ECs) with the matrix controls nuclear tension, preventing aberrant gene synthesis and the transition from restrictive to leaky endothelium, a hallmark of acute lung injury (ALI). However, the mechanisms controlling tension transmission to the nucleus and EC-restrictive fate remain elusive. Here, we demonstrate that, in a kinase-independent manner, focal adhesion kinase (FAK) safeguards tension transmission to the nucleus to maintain EC-restrictive fate. In FAK-depleted ECs, robust activation of the RhoA-Rho-kinase pathway increased EC tension and phosphorylation of the nuclear envelope protein, emerin, activating DNMT3a. Activated DNMT3a methylates the KLF2 promoter, impairing the synthesis of KLF2 and its target S1PR1 to induce the leaky EC transcriptome. Repleting FAK (wild type or kinase dead) or inhibiting RhoA-emerin-DNMT3a activities in damaged lung ECs restored KLF2 transcription of the restrictive EC transcriptome. Thus, FAK sensing and control of tension transmission to the nucleus govern restrictive endothelium to maintain lung homeostasis.

Production of pharmaceutical grade [201Tl]Thallous chloride using 30 MeV cyclotron.

Multiple patient doses of [201Tl]TlCl has been produced using electrodeposited enriched 203Tl in 30 MeV cyclotron (Cyclone-30) with 28 MeV proton energy at 50 µA beam current for 8 h. Ion Exchange Column Chromatography (IECC) and liquid-liquid extraction has been employed for semi-automated radiochemical separation and purification of produced [201Tl]TlCl. The produced [201Tl]TlCl was used in coronary artery disease (CAD) patients.

Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice.

While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here, we report that the deletion of Ptpmt1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection - the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. Ptpmt1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, Ptpmt1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that Ptpmt1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.

Cells are powered by mitochondria, a group of organelles that produce chemical energy in the form of molecules called ATP. This energy is derived from the breakdown of carbohydrates, fats, and proteins. The number of mitochondria in a cell and the energy source they use to produce ATP varies depending on the type of cell. Mitochondria can also switch the molecules they use to produce energy when the cell is responding to stress or disease. The heart and the skeletal muscles ­ which allow movement ­ are two tissues that require large amounts of energy, but it remained unknown whether disrupting mitochondrial fuel selection affects how these tissues work. To answer these questions, Zheng, Li, Li et al. investigated the role of an enzyme found in mitochondria called Ptpmt1. Genetically deleting Ptpmt1 in the heart and skeletal muscle of mice showed that while the development of these organs was not affected, mitochondria in these cells switched from using carbohydrates to using fats as an energy source. Over time, this shift damaged both the mitochondria and the tissues, leading to muscle wasting, heart failure, and sudden death in the mice. This suggests that balanced use of carbohydrates and fats is essential for the muscles and heart. These findings imply that long-term use of medications that alter the fuel that mitochondria use may be detrimental to patients' health and could cause heart dysfunction. This may be important for future drug development, as well as informing decisions about medication taken in the clinic.

Pokkali: A Naturally Evolved Salt-Tolerant Rice Shows a Distinguished Set of lncRNAs Possibly Contributing to the Tolerant Phenotype.

Pokkali is a strong representation of how stress-tolerant genotypes have evolved due to natural selection pressure. Numerous omics-based investigations have indicated different categories of stress-related genes and proteins, possibly contributing to salinity tolerance in this wild rice. However, a comprehensive study towards understanding the role of long-noncoding RNAs (lncRNAs) in the salinity response of Pokkali has not been done to date. We have identified salt-responsive lncRNAs from contrasting rice genotypes IR64 and Pokkali. A total of 63 and 81 salinity-responsive lncRNAs were differentially expressed in IR64 and Pokkali, respectively. Molecular characterization of lncRNAs and lncRNA-miRNA-mRNA interaction networks helps to explore the role of lncRNAs in the stress response. Functional annotation revealed that identified lncRNAs modulate various cellular processes, including transcriptional regulation, ion homeostasis, and secondary metabolite production. Additionally, lncRNAs were predicted to bind stress-responsive transcription factors, namely ERF, DOF, and WRKY. In addition to salinity, expression profiling was also performed under other abiotic stresses and phytohormone treatments. A positive modulation in TCONS_00035411, TCONS_00059828, and TCONS_00096512 under both abiotic stress and phytohormone treatments could be considered as being of potential interest for the further functional characterization of IncRNA. Thus, extensive analysis of lncRNAs under various treatments helps to delineate stress tolerance mechanisms and possible cross-talk.

Spatially activated conserved auxin-transcription factor regulatory module controls de novo root organogenesis in rice.

MAIN CONCLUSION: This study reveals that the process of crown root development and auxin-induced de novo root organogenesis during in vitro plantlet regeneration share a common auxin-OsWOX10 regulatory module in rice. In the fibrous-type root system of rice, the crown roots (CR) are developed naturally from the shoot tissues. Generation of robust auxin response, followed by activation of downstream cell fate determinants and signaling pathways at the onset of crown root primordia (CRP) establishment is essential for new root initiation. During rice tissue culture, embryonic calli are induced to regenerate shoots in vitro which undergo de novo root organogenesis on an exogenous auxin-supplemented medium, but the mechanism underlying spatially restricted root organogenesis remains unknown. Here, we reveal the dynamics of progressive activation of genes involved in auxin homeostasis and signaling during initiation and outgrowth of rice crown root primordia. By comparative global dataset analysis, we identify the crown root primordia-expressed genes whose expression is also regulated by auxin signaling. In-depth spatio-temporal expression pattern analysis shows that the exogenous application of auxin induces a set of key transcription factors exclusively in the spatially positioned CRP. Further, functional analysis of rice WUSCHEL-RELATED HOMEOBOX 10 (OsWOX10) during in vitro plantlet regeneration from embryogenic calli shows that it promotes de novo root organogenesis from regenerated shoots. Expression of rice OsWOX10 also induces adventitious roots (AR) in Arabidopsis, independent of homologous endogenous Arabidopsis genes. Together, our findings reveal that a common auxin-transcription factor regulatory module is involved in root organogenesis under different conditions.

Integrated transcriptome, proteome and metabolome analyses revealed secondary metabolites and auxiliary carbohydrate metabolism augmenting drought tolerance in rice.

Drought is one of the major consequences of climate change and a serious threat to rice production. Drought stress activates interactions among genes, proteins and metabolites at the molecular level. A comparative multi-omics analysis of drought-tolerant and drought-sensitive rice cultivars can decipher the molecular mechanisms involved in drought tolerance/response. Here, we characterized the global-level transcriptome, proteome, and metabolome profiles, and performed integrated analyses thereof in a drought-sensitive (IR64) and a drought-tolerant (Nagina 22) rice cultivar under control and drought-stress conditions. The transcriptional dynamics and its integration with proteome analysis revealed the role of transporters in regulation of drought stress. The proteome response illustrated the contribution of translational machinery to drought tolerance in N22. The metabolite profiling revealed that aromatic amino acids and soluble sugars contribute majorly to drought tolerance in rice. The integrated transcriptome, proteome and metabolome analysis performed using statistical and knowledge-based methods revealed the preference for auxiliary carbohydrate metabolism through glycolysis and pentose phosphate pathway contributed to drought tolerance in N22. In addition, L-phenylalanine and the genes/proteins responsible for its biosynthesis were also found to contribute to drought tolerance in N22. In conclusion, our study provided mechanistic insights into the drought response/adaptation mechanism and is expected to facilitate engineering of drought tolerance in rice.

Medical Therapy for Large Idiopathic Full-Thickness Macular Holes.

PURPOSE: To describe the characteristics and outcomes of eyes with idiopathic full-thickness macular holes (FTMH) that underwent initial medical management. METHODS: This retrospective study included eyes with FTMH that were initially managed with one month of topical therapy. Eligible subjects were treated with dorzolamide 2% three times a day, nepafenac 0.1% twice a day, and prednisolone acetate 1% four times a day. The primary endpoints was hole closure at one month and secondary endpoint was change in best-corrected visual acuity (BCVA). RESULTS: Ten subjects (mean age: 62.80 years; female: 50%) with unilateral FTMH were studied. The mean basal diameter of the entire cohort at baseline was 824.1 µm (median 828 µm). Four (40%) of the smaller holes (mean 698 µm; median 698.50 µm) closed after one month of topical therapy, whereas larger holes (mean 908.17µm; median 889.50 µm) did not close. In one eye, the hole reopened 4 months after stopping the medication, but closed again at one month after re-starting the topical treatment. Median BCVA improved from 0.35 logMAR at baseline to 0.05 logMAR in eyes that closed but remained at 0.70 logMAR at one month in eyes that did not close. CONCLUSION: Topical corticosteroid, non-steroidal anti-inflammatory, and carbonic anhydrase inhibitor therapy may promote closure of small FTMHs, but large holes are less likely to respond. One month of topical therapy might avoid subjecting some patients to complex vitreo-retinal surgery without compromising visual outcomes. Macular hole may re-open after stopping the topical therapy.

Unravelling the molecular mechanism underlying drought stress response in chickpea via integrated multi-omics analysis.

Drought stress affects growth and productivity significantly in chickpea. An integrated multi-omics analysis can provide a better molecular-level understanding of drought stress tolerance. In the present study, comparative transcriptome, proteome and metabolome analyses of two chickpea genotypes with contrasting responses to drought stress, ICC 4958 (drought-tolerant, DT) and ICC 1882 (drought-sensitive, DS), was performed to gain insights into the molecular mechanisms underlying drought stress response/tolerance. Pathway enrichment analysis of differentially abundant transcripts and proteins suggested the involvement of glycolysis/gluconeogenesis, galactose metabolism, and starch and sucrose metabolism in the DT genotype. An integrated multi-omics analysis of transcriptome, proteome and metabolome data revealed co-expressed genes, proteins and metabolites involved in phosphatidylinositol signaling, glutathione metabolism and glycolysis/gluconeogenesis pathways, specifically in the DT genotype under drought. These stress-responsive pathways were coordinately regulated by the differentially abundant transcripts, proteins and metabolites to circumvent the drought stress response/tolerance in the DT genotype. The QTL-hotspot associated genes, proteins and transcription factors may further contribute to improved drought tolerance in the DT genotype. Altogether, the multi-omics approach provided an in-depth understanding of stress-responsive pathways and candidate genes involved in drought tolerance in chickpea.

Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies.

Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2'-pyrrolidin]-2-one/spiro[indoline-3,3'-pyrrolizin]-2-one 23a-f, 24a-f, and 25a-g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a-h, various substituted chalcones 21a-f, and 22a-c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC50 values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC50 = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies.

Post-vitrectomy secondary macular holes: Risk factors, clinical features, and multivariate analysis of outcome predictors.

Purpose: We report clinical characteristics, risk factors, treatment outcomes, and prognostic predictors of post-vitrectomy secondary macular holes (MHs). Methods: This was a retrospective observational case series from November 2014 to December 2020. Eyes that developed secondary MH, two weeks and beyond after primary vitrectomy for non-MH indications, were enrolled. Pre- and intraoperative records were screened to exclude pre-existence of MH. Eyes with multiple vitreoretinal surgeries prior to MH detection and tractional myopic maculopathy were excluded. Results: A total of 29 eyes of 29 patients with a mean age of 52 years developed secondary MH post-vitrectomy. The most common indications for primary vitrectomy were rhegmatogenous retinal detachment (RRD, 48.2%) and tractional retinal detachment (TRD, 24.1%). Time to MH detection after primary vitrectomy was 91.5 ± 117.6 days. The mean minimum hole diameter was 530 ± 298 microns. Epi-retinal membrane and cystoid degeneration was noted in 6 (20.7%) and 12 (41.3%) eyes, respectively (p = 0.088). The mean time from MH detection to MH repair was 34 ± 42 days. The surgical intervention included internal limiting membrane peeling with tamponade in 25 eyes. Overall, 80% showed anatomic hole closure, 90.9% versus 57.1% in the RRD and TRD (p = 0.092), respectively. The mean best-corrected visual acuity (BCVA) at the final visit was 0.71 logarithm of the minimum angle of resolution. Thirteen eyes (52%) had a BCVA of 20/100 or better. Minimal hole diameter (p = 0.029) only predicted final visual acuity. The interval between MH diagnosis and repair did not affect hole closure significantly (p = 0.064). Conclusion: Secondary MH post-vitrectomy closed successfully with limited visual improvement and trails behind idiopathic MH.

Retinal Pigment Epithelial Characteristics in Acute and Resolved Vogt-Koyanagi-Harada Disease.

Vogt-Koyanagi-Harada (VKH) disease is an auto-immune inflammatory disease of choroidal origin. During the acute stage, optical coherence tomography (OCT), however, may not be able to assess the entire choroid. The aims of the paper were to evaluate the role of retinal pigment epithelium (RPE) as a biomarker of inflammation in acute VKH. This was a retrospective observational study done in 55 eyes of 29 patients with acute VKH. RPE thickness, total choroidal thickness, and RPE reflectivity before and after resolution were analyzed using image J software. Correlations between several baseline and post-resolution parameters were performed, and factors affecting change in visual acuity were analyzed. A significant decrease in RPE thickness and a significant increase in RPE reflectivity were seen following resolution of the disease. Furthermore, there was a significant correlation between RPE and choroidal thickness during the acute stage of the disease. Baseline visual acuity and the presence of bacillary detachment at baseline were the only factors responsible for changes in visual acuity. We propose the utility of RPE layer as a surrogate biomarker of choroidal activity and inflammation in terms of RPE reflectivity and RPE thickness during the acute stage of VKH, especially when there is poor imaging of the choroid.

Krüppel-Like Factors Orchestrate Endothelial Gene Expression Through Redundant and Non-Redundant Enhancer Networks.

Background Proper function of endothelial cells is critical for vascular integrity and organismal survival. Studies over the past 2 decades have identified 2 members of the KLF (Krüppel-like factor) family of proteins, KLF2 and KLF4, as nodal regulators of endothelial function. Strikingly, inducible postnatal deletion of both KLF2 and KLF4 resulted in widespread vascular leak, coagulopathy, and rapid death. Importantly, while transcriptomic studies revealed profound alterations in gene expression, the molecular mechanisms underlying these changes remain poorly understood. Here, we seek to determine mechanisms of KLF2 and KLF4 transcriptional control in multiple vascular beds to further understand their roles as critical endothelial regulators. Methods and Results We integrate chromatin occupancy and transcription studies from multiple transgenic mouse models to demonstrate that KLF2 and KLF4 have overlapping yet distinct binding patterns and transcriptional targets in heart and lung endothelium. Mechanistically, KLFs use open chromatin regions in promoters and enhancers and bind in context-specific patterns that govern transcription in microvasculature. Importantly, this occurs during homeostasis in vivo without additional exogenous stimuli. Conclusions Together, this work provides mechanistic insight behind the well-described transcriptional and functional heterogeneity seen in vascular populations, while also establishing tools into exploring microvascular endothelial dynamics in vivo.

Genome-wide discovery of genetic variations between rice cultivars with contrasting drought stress response and their potential functional relevance.

Drought stress is a serious threat to rice productivity. Investigating genetic variations between drought-tolerant (DT) and drought-sensitive (DS) rice cultivars may decipher the candidate genes/regulatory regions involved in drought stress tolerance/response. In this study, whole-genome resequencing data of four DS and five DT rice cultivars were analyzed. We identified a total of approximately 4.8 million single nucleotide polymorphisms (SNPs) and 0.54 million insertions/deletions (InDels). The genetic variations (162,638 SNPs and 17,217 InDels) differentiating DS and DT rice cultivars were found to be unevenly distributed throughout the rice genome; however, they were more frequent near the transcription start and stop sites than in the genic regions. The cis-regulatory motifs representing the binding sites of stress-related transcription factors (MYB, HB, bZIP, ERF, ARR, and AREB) harboring the SNPs/InDels in the promoter regions of a few differentially expressed genes (DEGs) were identified. Importantly, many of these DEGs were located within the drought-associated quantitative trait loci. Overall, this study provides a valuable large-scale genotyping resource and facilitates the discovery of candidate genes associated with drought stress tolerance in rice.

KLF4 and CD55 expression and function depend on each other.

The transcription factor Kruppel-like factor 4 (KLF4) regulates the expression of immunosuppressive and anti-thrombotic proteins. Despite its importance in maintaining homeostasis, the signals that control its expression and the mechanism of its transactivation remain unclarified. CD55 [aka decay accelerating factor (DAF)], now known to be a regulator of T and B cell responses, biases between pro- and anti-inflammatory processes by controlling autocrine C3a and C5a receptor (C3ar1/C5ar1) signaling in cells. The similarity in CD55's and KLF4's regulatory effects prompted analyses of their functional relationship. In vascular endothelial cells (ECs), CD55 upregulation accompanied KLF4 expression via a p-CREB and CREB Binding Protein (CBP) mechanism. In both ECs and macrophages, CD55 expression was essential for KLF4's downregulation of pro-inflammatory/pro-coagulant proteins and upregulation of homeostatic proteins. Mechanistic studies showed that upregulation of KLF4 upregulated CD55. The upregulated CD55 in turn enabled the recruitment of p-CREB and CBP to KLF4 needed for its transcription. Activation of adenylyl cyclase resulting from repression of autocrine C3ar1/C5ar1 signaling by upregulated CD55 concurrently led to p-CREB and CBP recruitment to KLF4-regulated genes, thereby conferring KLF4's transactivation. Accordingly, silencing CD55 in statin-treated HUVEC disabled CBP transfer from the E-selectin to the eNOS promoter. Importantly, silencing CD55 downregulated KLF4's expression. It did the same in untreated HUVEC transitioning from KLF4low growth to KLF4hi contact inhibition. KLF4's and CD55's function in ECs and macrophages thus are linked via a novel mechanism of gene transactivation. Because the two proteins are co-expressed in many cell types, CD55's activity may be broadly tied to KLF4's immunosuppressive and antithrombotic activities.

Light-phase prednisone promotes glucose oxidation in heart through novel transactivation targets of cardiomyocyte-specific GR and KLF15.

Circadian time of intake determines the cardioprotective outcome of glucocorticoids in normal and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) is genetically required to preserve normal heart function in the long-term. The GR co-factor KLF15 is a pleiotropic regulator of cardiac metabolism. However, the cardiomyocyte-autonomous metabolic targets of the GR-KLF15 concerted epigenetic action remain undefined. Here we report that circadian time of intake determines the activation of a transcriptional and functional glucose oxidation program in heart by the glucocorticoid prednisone with comparable magnitude between sexes. We overlayed transcriptomics, epigenomics and cardiomyocyte-specific inducible ablation of either GR or KLF15. Downstream of a light-phase prednisone stimulation in mice, we found that both factors are non-redundantly required in heart to transactivate the adiponectin receptor expression (Adipor1) and promote insulin-stimulated glucose uptake, as well as transactivate the mitochondrial pyruvate complex expression (Mpc1/2) and promote pyruvate oxidation. We then challenged this time-specific drug effect in obese diabetic db/db mice, where the heart shows insulin resistance and defective glucose oxidation. Opposite to dark-phase dosing, light-phase prednisone rescued glucose oxidation in db/db cardiomyocytes and diastolic function in db/db hearts towards control-like levels with sex-independent magnitude of effect. In summary, our study identifies novel cardiomyocyte-autonomous metabolic targets of the GR-KLF15 concerted program mediating the time-specific cardioprotective effects of glucocorticoids on cardiomyocyte glucose utilization.

Internal limiting membrane detachment in acute Central Retinal Artery Occlusion: clinical features, multimodal imaging, outcomes & prognostic biomarker.

PURPOSE: To report the clinical features, multi-modal imaging characteristics and their corroboration, and prognostic value of internal limiting membrane detachment (ILMD), a novel OCT biomarker in acute CRAO. DESIGN: Retrospective observational case-control study at institutional tertiary eye care centers. METHODS: 60 eyes of 60 patients of acute CRAO with optical coherence tomography (OCT) at baseline were included. Eyes were grouped in (a) With ILMD; (b) With no-ILMD. Multimodal imaging correlation, BCVA change and binary logistic regression were studied. RESULTS: Eighteen eyes (30%) were noted to have ILMD. At presentation, ILMD on OCT corroborated with macular non-perfusion with enlarged foveal avascular zone both on OCT-angiography (OCTA) and fundus fluorescein angiography (FFA). On follow-up, ILMD had resolved in all cases with fragmentation, disruption and atrophy of the retinal layers. Logistic regression showed poor baseline visual acuity was significantly associated with the odds of ILMD [Odds Ratio (OR) 31.02, p = 0.0018, 95% confidence interval: 1.81-529] while controlling for potential confounders including age (p = 0.60), gender (p = 0.316) duration of symptoms (p = 0.114), follow-up duration (p = 0.450) and final BCVA (p = 0.357). Eyes with ILMD and no-ILMD had a baseline BCVA of 2.62 LogMAR (light perception) and 2.05 LogMAR (Snellen equivalent 20/2000), respectively. On follow up, none of the eyes with ILMD showed any improvement. In contrast, nine (21.4%) eyes in no-ILMD had a vision of 20/400 and above with a mean final visual acuity of 1.87 + 0.78 LogMAR (p = 0.000). CONCLUSION: ILMD correlated with macular non-perfusion and poor baseline visual acuity which showed no improvement on follow-up, suggesting it to be poor prognostic biomarker.

Genomic landscape of prominent XDR Acinetobacter clonal complexes from Dhaka, Bangladesh.

BACKGROUND: Acinetobacter calcoaceticus-A. baumannii (ACB) complex pathogens are known for their prevalence in nosocomial infections and extensive antimicrobial resistance (AMR) capabilities. While genomic studies worldwide have elucidated the genetic context of antibiotic resistance in major international clones (ICs) of clinical Acinetobacter spp., not much information is available from Bangladesh. In this study, we analysed the AMR profiles of 63 ACB complex strains collected from Dhaka, Bangladesh. Following this, we generated draft genomes of 15 of these strains to understand the prevalence and genomic environments of AMR, virulence and mobilization associated genes in different Acinetobacter clones. RESULTS: Around 84% (n = 53) of the strains were extensively drug resistant (XDR) with two showing pan-drug resistance. Draft genomes generated for 15 strains confirmed 14 to be A. baumannii while one was A. nosocomialis. Most A. baumannii genomes fell under three clonal complexes (CCs): the globally dominant CC1 and CC2, and CC10; one strain had a novel sequence type (ST). AMR phenotype-genotype agreement was observed and the genomes contained various beta-lactamase genes including blaOXA-23 (n = 12), blaOXA-66 (n = 6), and blaNDM-1 (n = 3). All genomes displayed roughly similar virulomes, however some virulence genes such as the Acinetobactin bauA and the type IV pilus gene pilA displayed high genetic variability. CC2 strains carried highest levels of plasmidic gene content and possessed conjugative elements carrying AMR genes, virulence factors and insertion sequences. CONCLUSION: This study presents the first comparative genomic analysis of XDR clinical Acinetobacter spp. from Bangladesh. It highlights the prevalence of different classes of beta-lactamases, mobilome-derived heterogeneity in genetic architecture and virulence gene variability in prominent Acinetobacter clonal complexes in the country. The findings of this study would be valuable in understanding the genomic epidemiology of A. baumannii clones and their association with closely related pathogenic species like A. nosocomialis in Bangladesh.

Atypical Presentation of Cystic Fibrosis in An Infant.

Dermatitis as an initial manifestation of cystic fibrosis (CF) is unusual. The eruption is usually first noted in the perineum anywhere from several days to few months after birth. It subsequently spreads to the extremities and trunk. We report a 2-month-old male baby who presented with failure to thrive, hypoproteinemia, anemia, and a cutaneous eruption resembling acrodermatitis enteropathica. Oral zinc supplementation resulted in temporary resolution of the dermatitis. A further workup revealed the diagnosis of CF. The rash was responsive to nutritional and pancreatic enzyme supplementation.

An integrated transcriptome mapping the regulatory network of coding and long non-coding RNAs provides a genomics resource in chickpea.

Large-scale transcriptome analysis can provide a systems-level understanding of biological processes. To accelerate functional genomic studies in chickpea, we perform a comprehensive transcriptome analysis to generate full-length transcriptome and expression atlas of protein-coding genes (PCGs) and long non-coding RNAs (lncRNAs) from 32 different tissues/organs via deep sequencing. The high-depth RNA-seq dataset reveal expression dynamics and tissue-specificity along with associated biological functions of PCGs and lncRNAs during development. The coexpression network analysis reveal modules associated with a particular tissue or a set of related tissues. The components of transcriptional regulatory networks (TRNs), including transcription factors, their cognate cis-regulatory motifs, and target PCGs/lncRNAs that determine developmental programs of different tissues/organs, are identified. Several candidate tissue-specific and abiotic stress-responsive transcripts associated with quantitative trait loci that determine important agronomic traits are also identified. These results provide an important resource to advance functional/translational genomic and genetic studies during chickpea development and environmental conditions.

KLF15 controls brown adipose tissue transcriptional flexibility and metabolism in response to various energetic demands.

Brown adipose tissue (BAT) is a specialized metabolic organ responsible for non-shivering thermogenesis. Recently, its activity has been shown to be critical in systemic metabolic health through its utilization and consumption of macronutrients. In the face of energetically demanding states, metabolic flexibility and systemic coordination of nutrient partitioning is requisite for health and survival. In this study, we elucidate BAT's differential transcriptional adaptations in response to multiple nutrient challenges and demonstrate its context-dependent prioritization of lipid, glucose, and amino acid metabolism. We show that the transcription factor Krüppel-like factor 15 (KLF15) plays a critical role in BAT metabolic flexibility. BAT-specific loss of KLF15 results in widespread changes in circulating metabolites and severely compromised thermogenesis in response to high energy demands, indicative of impaired nutrient utilization and metabolic flexibility. Together, our data demonstrate KLF15 in BAT plays an indispensable role in partitioning resources to maintain homeostasis and ensure survival.