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.

Home range, habitat use and capture-release of translocated leopards in Gir landscape, Gujarat, India.

Understanding the spatial ecology of translocated leopards (Panthera pardus fusca) is crucial for their conservation and the effective assessment of conflict management strategies. We investigated the home range and habitat preferences of five radio-collared leopards (n = 5; 2 males; 3 females) in the Gir landscape. Additionally, we examined the usefulness of the capture-release strategy for these animals. We assessed home range and habitat selection using kernel density estimation (at 95% and 50% levels) and compositional analysis. Our findings revealed that leopards exhibited distinct patterns of movement, often returning to their original capture site or nearby locations or exploring new areas within 3 to 25 days, covering distances ranging from 48 to 260 km. The average home range (95% FK) was estimated at 103.96±36.37 (SE) km2, with a core area usage (50% FK) of 21.38±5.95 km2. Seasonally, we observed the largest home ranges during summer and the smallest during winter. Males exhibited larger home ranges (95% FK, 151±64.28 km2) compared to females (56.18±14.22 km2). The habitat analysis indicated that agricultural areas were consistently preferred in the multi-use landscape at the 2nd order habitat selection level. Additionally, habitat around water bodies was highly favoured at the 3rd order, with distinct variations in habitat selection observed during day and night. This study highlights the significance of riverine and scrubland habitats, as leopards exhibited strong preferences for these habitats within their home ranges. We emphasize the importance of conserving natural habitat patches, particularly those surrounding water bodies. We also report on the characteristics of the capture-release strategy and provide our observations indicating no escalated aggression by leopards' post-release. In conclusion, this study evaluates widely employed approaches to conflict mitigation and suggests the continuous review and assessment of management strategies for mitigating human-leopard conflicts.

Conditioned medium-enriched umbilical cord mesenchymal stem cells: a potential therapeutic strategy for spinal cord injury, unveiling transcriptomic and secretomic insights.

INTRODUCTION: Spinal cord injury (SCI) leads to significant destruction of nerve tissue, causing the degeneration of axons and the formation of cystic cavities. This study aimed to examine the characteristics of human umbilical cord-derived mesenchymal stem cells (HUCMSCs) cultured in a serum-free conditioned medium (CM) and assess their effectiveness in a well-established hemitransection SCI model. MATERIALS AND METHODS: In this study, HUCMSCs cultured medium was collected and characterized by measuring IL-10 and identifying proteomics using mass spectroscopy. This collected serum-free CM was further used in the experiments to culture and characterize the HUMSCs. Later, neuronal cells derived from CM-enriched HUCMSC were tested sequentially using an injectable caffeic acid-bioconjugated gelatin (CBG), which was further transplanted in a hemitransection SCI model. In vitro, characterization of CM-enriched HUCMSCs and differentiated neuronal cells was performed using flow cytometry, immunofluorescence, electron microscopy, and post-transplant analysis using immunohistology analysis, qPCR, in vivo bioluminescence imaging, and behavioral analysis using an infrared actimeter. RESULTS: The cells that were cultured in the conditioned media produced a pro-inflammatory cytokine called IL-10. Upon examining the secretome of the conditioned media, the Kruppel-like family of KRAB and zinc-finger proteins (C2H2 and C4) were found to be activated. Transcriptome analysis also revealed an increased expression of ELK-1, HOXD8, OTX2, YY1, STAT1, ETV7, and PATZ1 in the conditioned media. Furthermore, the expression of Human Stem-101 confirmed proliferation during the first 3 weeks after transplantation, along with the migration of CBG-UCNSC cells within the transplanted area. The gene analysis showed increased expression of Nestin, NeuN, Calb-2, Msi1, and Msi2. The group that received CBG-UCNSC therapy showed a smooth recovery by the end of week 2, with most rats regaining their walking abilities similar to those before the spinal cord injury by week 5. CONCLUSIONS: In conclusion, the CBG-UCNSC method effectively preserved the integrity of the transplanted neuronal-like cells and improved locomotor function. Thus, CM-enriched cells can potentially reduce biosafety risks associated with animal content, making them a promising option for clinical applications in treating spinal cord injuries.

An Evaluation of Variations in the Carpal Tunnel Dimensions of Adult Subjects in a Hospital-Based Population: An Ultrasonographic Cross-Sectional Study.

Background The carpal tunnel is a groove that spans the palm as a 'U.' The ulnar and radial sides of the wrist are made up of the scaphoid tubercle and trapezium while the palmar aspect is made up of carpal bones. Our study aimed to see whether there were differences in carpal tunnel size between men and women. Material and methods The study was conducted on 65 healthy adults, 13 (20%) were males and 52 (80%) were females (both non-pregnant and pregnant). Inclusion criteria were healthy adults and bilaterally symmetrical limbs. Exclusion criteria were chronic disease, diabetes, hypertension, immunological disorders, any visible abnormalities, and a history of upper extremity pain on either side. A high-resolution ultrasound machine with a linear transducer was used to perform an ultrasound scan of the carpal tunnel. The anteroposterior dimension was measured at the midline, or along the axis of the middle finger, and the transverse diameter was measured at the midpoint of the flexor retinaculum. The cross-sectional area of the tunnel was measured at its largest diameter within the carpal tunnel. All the dimensions were measured in centimeters. Results The mean transverse diameter of the right side was 1.824 ± 0.223 cm (p-value 0.002) and of the left side was 1.742 ± 0.197 cm (p-value 0.004). The mean cross-sectional area of the carpal tunnel on the right side was 1.417 ± 0.379 cm2 (p-value 0.008) and on the left side was 1.306 ± 0.303 cm2 (p-value 0.004), respectively. Age, sex, weight, and BMI were discussed. The carpal tunnels of females were found to be comparatively squarer and smaller than those of males. Conclusion The transverse diameter and cross-sectional area of the carpal tunnel and their correlation with carpal tunnel syndrome are predicted by age, sex, weight, and BMI. Both sexes had the same wrist ratio.

Unravelling the secrets of lesser florican: a study of their home range and habitat use in Gujarat, India.

The home range of a species is determined by a complex interplay of extrinsic and intrinsic factors, which can have profound impacts on the species' resource use. Understanding these dynamics is especially important for conserving critically endangered species. In this study, we used satellite telemetry to investigate the home range of the critically endangered lesser florican (Sypheotides indicus) in Gujarat, India. We analysed GPS locations from 10 lesser floricans deployed with GPS/GSM transmitters between 2020 and 2022. The average home range size (95% KDE) was 10.73 ± 10.70 km2 (mean ± SD), while the average core area (50% KDE) was 1.95 ± 1.56 km2 (mean ± SD). The monthly and daily distances covered were 286.29 ± 599.42 km and 10.11 ± 19.78 km, respectively. Our analysis indicated that suitable habitats and movement patterns were the most important factors explaining the variation in home range size. Specifically, our results suggest that lesser floricans prefer multi-use agro-grassland habitat systems with heterogeneous structures to accommodate different life history requirements. This preference may reflect the depletion and degradation of grasslands across the species' range. Therefore, managing grassland habitats amidst croplands should be one of the key conservation strategies for the lesser florican.

The semi-arid ecosystem of Asiatic Lion Landscape in Saurashtra, Gujarat: Population density, biomass and conservation of nine wild prey species.

The present study aimed to assess the population density, structure, and population change of nine wild prey species in the semi-arid landscape of Saurashtra, Gujarat, India. A total of eight sites, representing a gradient from highly protected woodlands and grasslands to unreserved grasslands, were selected for sampling. We employed the road transect methodology under a distance sampling framework to achieve our objectives. We evaluated the realized growth rate of the Gir ungulate population through linear regression analysis. Our findings revealed that deer species exhibited higher density and biomass in woodlands compared to grasslands and coastal forests. On the other hand, antelopes showed higher density and biomass in grasslands and coastal forests compared to woodlands. The density gradient of wild prey species was influenced by various factors, including habitat structure, social organization, grouping tendencies, and topography. Over the last four decades, the population of wild prey species in Gir showed minimal changes. Our study provides a comprehensive understanding of wild prey species' density and biomass patterns at the landscape level. The inclusion of findings from ecologically significant and unique areas, such as coastal forests, further enhances the importance of this study. The implications of this study extend beyond the conservation of wild prey species alone; they also contribute to the conservation of the large carnivore guild in the Saurashtra landscape.

Hypoxia: syndicating triple negative breast cancer against various therapeutic regimens.

Triple-negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer (BC) for its high aggressiveness, heterogeneity, and hypoxic nature. Based on biological and clinical observations the TNBC related mortality is very high worldwide. Emerging studies have clearly demonstrated that hypoxia regulates the critical metabolic, developmental, and survival pathways in TNBC, which include glycolysis and angiogenesis. Alterations to these pathways accelerate the cancer stem cells (CSCs) enrichment and immune escape, which further lead to tumor invasion, migration, and metastasis. Beside this, hypoxia also manipulates the epigenetic plasticity and DNA damage response (DDR) to syndicate TNBC survival and its progression. Hypoxia fundamentally creates the low oxygen condition responsible for the alteration in Hypoxia-Inducible Factor-1alpha (HIF-1α) signaling within the tumor microenvironment, allowing tumors to survive and making them resistant to various therapies. Therefore, there is an urgent need for society to establish target-based therapies that overcome the resistance and limitations of the current treatment plan for TNBC. In this review article, we have thoroughly discussed the plausible significance of HIF-1α as a target in various therapeutic regimens such as chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapy, adjuvant therapy photodynamic therapy, adoptive cell therapy, combination therapies, antibody drug conjugates and cancer vaccines. Further, we also reviewed here the intrinsic mechanism and existing issues in targeting HIF-1α while improvising the current therapeutic strategies. This review highlights and discusses the future perspectives and the major alternatives to overcome TNBC resistance by targeting hypoxia-induced signaling.

Vaccination and Microbiota Manipulation Approaches for Colon Cancer Prevention in Rodent Models.

Colorectal cancer represents the third most common cancer type worldwide and is a leading cause of cancer-related mortality in the United States and Western countries. Rodent models have been invaluable to study the etiology of colorectal cancer and to test novel chemoprevention avenues. In the past, the laboratory mouse has become one of the best preclinical models for these studies due to the availability of genetic information for commonly used mouse strains with well-established and precise gene targeting and transgenic techniques. Well-established chemical mutagenesis technologies are also being used to develop mouse and rat models of colorectal cancer for prevention and treatment studies. In addition, xenotransplantation of cancer cell lines and patient-derived xenografts has been useful for preclinical prevention studies and drug development. This review focuses on the recent use of rodent models to evaluate the utility of novel strategies in the prevention of colon cancers including immune prevention approaches and the manipulation of the intestinal microbiota.

Morphometric Study of Sacral Hiatus in Dry Adult Human Sacra: Its Clinical Relevance in Caudal Epidural Block.

INTRODUCTION:  Correct localization of the sacral hiatus is essential for administering a successful caudal epidural block. The present study was undertaken to find out the anatomical variations of sacral hiatus by a metrical method so that it could help anaesthesiologists in the clinical field. MATERIALS AND METHODS: The study was performed on 140 (83 male and 57 female) adult human sacra. Various parameters of the sacrum studied were as follows: the shape of the hiatus, length of the sacral hiatus, transverse width at the base and anteroposterior diameter at the level of the apex. For each parameter, the mean value (calculated in mm), standard deviation, range and percentage of bones identified correctly were calculated. RESULTS: Various shapes of sacral hiatus were observed, including inverted "U" in 73 (52.14%), inverted "V" in 33 (23.57%), irregular in 10 (7.14%), elongated in 10 (7.14%) and dumbbell-shaped in 12 (8.57%). Absent sacral hiatus was observed in two (1.43%) specimens. The mean value for the length of sacral hiatus from the apex to the midpoint of the base was found to be 23.26 mm in males and 22.38 mm in females. However, the parameter was found to be statistically not significant. The mean value for transverse width at the base of hiatus was found to be 14.19 mm in males and 13.54 mm in females. The mean value for the anteroposterior diameter of the sacral canal at the apex was found to be 4.57 mm in males and 4.32 mm in females. Both the above parameters were found to be statistically not significant. SUMMARY AND CONCLUSION: The anatomical knowledge of sacral hiatus and its variations are important in caudal epidural anaesthesia, and it may improve the success rate of caudal epidural anaesthesia.

Conservation Management of the Endangered Asiatic Lions in Gujarat, India, Using GPS Satellite Telemetry.

Endangered Asiatic lions (Panthera leo persica) are found in the Asiatic Lion Landscape, Gujarat, which includes protected areas and a multi-use land matrix. Therefore, monitoring lions' space-use and spatio-temporal location is vital for managing various facets of human-lion interaction. Our study demonstrates how this was achieved by tracking lions using GPS radio-collars, triggering prompt action via an efficient communication network across political and forest administrative boundaries. We monitored the movement of 19 individual lions for 436.5 ± 32 days and also derived the mean daily activity from three-axis accelerometer-based activity-sensing feature of a radio-collar. We also monitored geofence breaches. We proposed that immobility and movement are two aspects that generate management action on the ground. While the movement is related to ranging and dispersal, immobility is a situation related to either the animal's feeding or its health status. From a management standpoint, we discussed the efficacy of the virtual geofence in preventing accidents when lions moved and also presented the advantages of being able to track dispersal through a case study of sub-adult lions. To strengthen our response to lion immobility, we developed a predictive model that specifically highlights an individual lion's health status and makes the alert response more precise. In conclusion, we critically reviewed the capabilities provided by GPS telemetry and provide protocols that help in the conservation management of lions and that will also have a wider application.

Noncanonical function of long myosin light chain kinase in increasing ER-PM junctions and augmentation of SOCE.

Increased endothelial permeability leads to excessive exudation of plasma proteins and leukocytes in the interstitium, which characterizes several vascular diseases including acute lung injury. The myosin light chain kinase long (MYLK-L) isoform is canonically known to regulate the endothelial permeability by phosphorylating myosin light chain (MLC-P). Compared to the short MYLK isoform, MYLK-L contains an additional stretch of ~919 amino acid at the N-terminus of unknown function. We show that thapsigargin and thrombin-induced SOCE was markedly reduced in Mylk-L-/- endothelial cells (EC) or MYLK-L-depleted human EC. These agonists also failed to increase endothelial permeability in MYLK-L-depleted EC and Mylk-L-/- lungs, thus demonstrating the novel role of MYLK-L-induced SOCE in increasing vascular permeability. MYLK-L augmented SOCE by increasing endoplasmic reticulum (ER)-plasma membrane (PM) junctions and STIM1 translocation to these junctions. Transduction of N-MYLK domain (amino acids 1-919 devoid of catalytic activity) into Mylk-L-/- EC rescued SOCE to the level seen in control EC in a STIM1-dependent manner. N-MYLK-induced SOCE augmented endothelial permeability without MLC-P via an actin-binding motif, DVRGLL. Liposomal-mediated delivery of N-MYLK mutant but not ∆DVRGLL-N-MYLK mutant in Mylk-L-/- mice rescued vascular permeability increase in response to endotoxin, indicating that targeting of DVRGLL motif within MYLK-L may limit SOCE-induced vascular hyperpermeability.