Rapid impact assessment of severe cyclone storm Michaung along coastal zones of Andhra and Tamil Nadu, India: A geospatial analysis.

The coastal regions of India, particularly the Bay of Bengal, are highly vulnerable to the severe weather conditions induced by tropical cyclones. This study presents a comprehensive analysis of the changes in vegetation cover, shoreline dynamics, and meteorological variations resulting from Cyclone Michaung and subsequent post-monsoon events along the coastal zones of Andhra Pradesh and Tamil Nadu, India. A suite of vegetation indices, including the Normalized Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI), Modified Vegetation Condition Index (mVCI), and Disaster Vegetation Damage Index (DVDI), were employed to assess changes in vegetation cover. The Digital Shoreline Assessment System (DSAS) was utilized to evaluate shoreline changes, and a range of meteorological variables were analyzed to assess the impacts of Cyclone Michaung and post-monsoon events. The findings reveal significant ecological impacts, with a notable decrease in Very Healthy Vegetation from 5.71% to 1.30%. The mean value of mVCI shifted from -0.2 to -0.16, indicating vegetation stress. DVDI analysis showed that 56.49% of the area experienced moderate damage, while 40.24% suffered severe vegetation damage. Additionally, erosion was observed along 79.46% of the shoreline transects in the study area. These insights are critical for assisting coastal managers in developing resilient coastal systems. Remarkably, a significant change in rainfall was recorded between the pre-cyclone period and the landfall day, with maximum rainfall intensifying from 13.93 mm/h on December 3rd to 164.26 mm/h on December 4th, and subsequently decreasing to 144.39 mm/h on December 5th.

Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities.

Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen-binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.

Cancer therapy with antibodies.

The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody-drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity.

Dynamic shoreline alterations and their impacts on Olive Ridley Turtle (Lepidochelys olivacea) nesting sites in Gahirmatha Marine Wildlife Sanctuary, Odisha (India).

Currently, sea turtle habitats are being altered by climate change and human activities, with habitat loss posing an urgent threat to Indian sea turtles. Thus, the objective of this study is to analyze the dynamic shoreline alterations and their impacts on Olive Ridley Sea Turtle (ORT) nesting sites in Gahirmatha Marine Wildlife Sanctuary from 1990 to 2022. Landsat satellite images served as input datasets to assess dynamic shoreline changes. This study assessed shoreline alterations and their rates across 929 transects divided into four zones using the Digital Shoreline Analysis System (DSAS) software. The results revealed a significant 14-km northward shift in the nesting site due to substantial coastal erosion, threatening the turtles' Arribada. This study underscores the need for conservation efforts to preserve nesting environments amidst changing coastal landscapes, offering novel insights into the interaction between coastal processes and marine turtle nesting behaviors.

TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers.

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor ß-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

A multi-temporal analysis of shoreline dynamics influenced by natural and anthropogenic factors: Erosion and accretion along the Digha Coast, West Bengal, India.

This investigation analyzed shoreline evolution along India's Digha Coast from 1992 to 2022, using multispectral Landsat satellite images and the Digital Shoreline Analysis System (DSAS). Methods included identifying zones and transects, shoreline extraction, and applying spatial statistical techniques. The study area, divided into five zones with 587 transects, enabled both short- and long-term analysis. Key findings indicate that the mean long-term rate of shoreline change is -0.54 m per year, with 70.70 % of transects experiencing erosion and 29.30 % accretion. Notably, Zone V had the highest accretion rate (8.55 m/year), while Zone III faced the most erosion (-7.47 m/year). Short-term analysis from 1997 to 2017 indicated significant erosion, contrasting with accretion during 1992-1997 and 2017-2022. Particularly, Zones II, III, and IV underwent major erosion, especially from 1997 to 2002. The study underscores the need for continuous shoreline management strategies and demonstrates geospatial technology's effectiveness in capturing coastal landscape changes.

NEDD4L intramolecular interactions regulate its auto and substrate NaV1.5 ubiquitination.

NEDD4L is a HECT-type E3 ligase that catalyzes the addition of ubiquitin to intracellular substrates such as the cardiac voltage-gated sodium channel, NaV1.5. The intramolecular interactions of NEDD4L regulate its enzymatic activity which is essential for proteostasis. For NaV1.5, this process is critical as alterations in Na+ current is involved in cardiac diseases including arrhythmias and heart failure. In this study, we perform extensive biochemical and functional analyses that implicate the C2 domain and the first WW-linker (1,2-linker) in the autoregulatory mechanism of NEDD4L. Through in vitro and electrophysiological experiments, the NEDD4L 1,2-linker was determined to be important in substrate ubiquitination of NaV1.5. We establish the preferred sites of ubiquitination of NEDD4L to be in the second WW-linker (2,3-linker). Interestingly, NEDD4L ubiquitinates the cytoplasmic linker between the first and second transmembrane domains of the channel (DI-DII) of NaV1.5. Moreover, we design a genetically encoded modulator of Nav1.5 that achieves Na+ current reduction using the NEDD4L HECT domain as cargo of a NaV1.5-binding nanobody. These investigations elucidate the mechanisms regulating the NEDD4 family and furnish a new molecular framework for understanding NaV1.5 ubiquitination.

Current patterns and trends of microplastic pollution in the marine environment: A bibliometric analysis.

Microplastics are pervasive in the natural environment and pose a growing concern for global health. Plastic waste in marine environments has emerged as a global issue, threatening not only marine biota but also human health due to its implications for the food chain. This study aims to discern the patterns and trends of research, specifically on Marine Microplastic Pollution (MMP), based on a bibliometric analysis of scientific publications from 2011 to 2022. The methodology utilized in this study comprises three stages: (a) creating a bibliographical dataset from Scopus by Elsevier and the Web of Science Core Collection by Clarivate Analytics, (b) analyzing current research (trends and patterns) using bibliometric analysis through Biblioshiny tool, and (c) examining themes and subthemes in MMP research (wastewater treatment, plastic ingestion, the Mediterranean Sea, microplastics pollution, microplastics in freshwater, microplastic ingestion, plastic pollution, and microplastic pollution in the marine environment). The findings reveal that during the studied period, the number of MMP publications amounted to 1377 articles, with an average citation per publication of 59.23 and a total citation count of 81,553. The most cited article was published in 2011, and since then, the number of publications on this topic has been increasing steadily. The author count stood at 5478, with 22 trending topics identified from the 1377 published titles. Between 2019 and 2022, the countries contributing most to the publication of MMP articles were China, the United States of America (USA), and the United Kingdom (UK). However, a noticeable shift in the origin of author countries was observed in the 2019-2022 timeframe, transitioning from a dominance by the USA and the UK to a predominance by China. In 2019, there was a substantial increase in the volume of publications addressing the topic of microplastics. The results show that the most prevalent themes and subthemes pertained to MMP in the Mediterranean Sea. The journals with the highest number of MMP articles published were the Marine Pollution Bulletin (253 articles) and Science of the Total Environment (190 articles). The analysis concludes that research on MMP remains prominent and appears to be increasing each year.

Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape.

Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD. This screen implicated disruption of kinase SMG1's phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from truncating mutations in vivo and in vitro . Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable HLA class I-associated peptides from NMD-downregulated proteins on the surface of cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases. One Sentence Summary: Disruption of the nonsense-mediated decay pathway with a newly developed SMG1 inhibitor with in-vivo activity increases the expression of T-cell targetable cancer neoantigens resulting from truncating mutations.

Geo-ecological, shoreline dynamic, and flooding impacts of Cyclonic Storm Mocha: A geospatial analysis.

This research comprehensively assesses the aftermath of Cyclonic Storm Mocha, focusing on the coastal zones of Rakhine State and the Chittagong Division, spanning Myanmar and Bangladesh. The investigation emphasizes the impacts on coastal ecology, shoreline dynamics, flooding patterns, and meteorological variations. Employed were multiple vegetation indices-Normalized Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI), Modified Vegetation Condition Index (mVCI), Disaster Vegetation Damage Index (DVDI), and Fractional Vegetation Cover (FVC)-to evaluate ecological consequences. The Digital Shoreline Assessment System (DSAS) aided in determining shoreline alterations pre- and post-cyclone. Soil exposure and flood extents were scrutinized using the Bare Soil Index (BSI) and Modified Normalized Difference Water Index (MNDWI), respectively. Additionally, the study encompassed an analysis of microclimatic variables, comparing meteorological data across pre- and post-cyclone periods. Findings indicate significant ecological impacts: an estimated 8985.46 km2 of dense vegetation (NDVI >0.6) was adversely affected. Post-cyclone, there was a discernible reduction in EVI values. The mean mVCI shifted negatively from -0.18 to -0.33, and the mean FVC decreased from 0.39 to 0.33. The DVDI underscored considerable vegetation damage in various areas, underscoring the cyclone's extensive impact. Meteorological analysis revealed a 245 % increase in rainfall (20.22 mm on May 14, 2023 compared to the May average of 5.86 mm), and significant increases in relative humidity (14 %) and wind speed (205 %). Erosion was observed along 74.60 % of the studied shoreline. These insights are pivotal for developing comprehensive strategies aimed at the rehabilitation and conservation of critical coastal ecosystems. They provide vital data for emergency response initiatives and offer resources for entities engaged in enhancing coastal resilience and protecting local community livelihoods.

Very low prevalence of bovine tuberculosis in cattle in Sylhet district of Bangladesh.

Bovine tuberculosis (bTB), a chronic zoonotic disease in cattle, has a substantial socio-economic and public health impact. This study was conducted to estimate the prevalence and geographical distribution of bTB in the Sylhet district of Bangladesh. A cross-sectional study was conducted at all 12 upazilas of Sylhet district, which included 512 randomly selected cattle from 48 farms. Selected animals were tested with the Caudal Fold Tuberculin (CFT) test to identify bTB-positive cattle. Out of 512 cattle, only one animal was identified as a reactor, providing an estimated prevalence of 0.19% (95% Confidence Interval; 0-0.58%). The only positive reactor was found in Zakiganj upazila. As the prevalence of bTB in cattle in Sylhet appears to be low, it indicates that most of the upazilas of Sylhet district are free of the bTB infection. This prevalence is lower than the reported prevalence in other parts of Bangladesh. Thus, attempts should be made to maintain the current situation of bTB infection in cattle of Sylhet district.

Evaluation of physical and mechanical characteristics of three-thread fleece knit fabric for their structural changes.

The aim of this research is to explore the variations that can arise when three-thread fleece (3- TFL) fabric is manufactured with the same yarn type, count, stitch length, knitting machine gauge, and diameter but in different structural configurations. The physical and mechanical properties of 3-TFL fabrics vary depending on their structural construction, which has a significant impact on their intended usage. For this study, four distinct types of three-thread fleece fabric structures were developed titled straight, three-butt diagonal, four-butt diagonal, and double tuck 3-TFL. Fabric weight, bursting strength, shrinkage percentage, spirality, pilling, stretch and recovery percentage tests were performed on the produced samples and the results were interpreted statistically. The ANOVA study revealed a strong association between the fabric design and its properties. Although all variants of fleece fabric showed better dimensional stability, the double tuck 3-TFL fabric demonstrated a relatively high dimensional change. In addition, double tuck 3-TFL fabric showed higher fabric weight, better pilling grade, and less spirality, whereas 4-butt diagonal 3-TFL fabric exhibited higher bursting strength. This research will assist commercial knit fabric producers in the textile industry to understand the effect of structural variations on fleece fabric qualities.

Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen.

Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics. Here, we describe the cryo-EM structure of an antibody-MANA pHLA complex. Specifically, we determine a TCR mimic (TCRm) antibody bound to its MANA target, the KRASG12V peptide presented by HLA-A*03:01. Hydrophobic residues appear to account for the specificity of the mutant G12V residue. We also determine the structure of the wild-type G12 peptide bound to HLA-A*03:01, using X-ray crystallography. Based on these structures, we perform screens to validate the key residues required for peptide specificity. These experiments led us to a model for discrimination between the mutant and the wild-type peptides presented on HLA-A*03:01 based exclusively on hydrophobic interactions.

13C- and 15N-labeling of amyloid-ß and inhibitory peptides to study their interaction via nanoscale infrared spectroscopy.

Interactions between molecules are fundamental in biology. They occur also between amyloidogenic peptides or proteins that are associated with different amyloid diseases, which makes it important to study the mutual influence of two polypeptides on each other's properties in mixed samples. However, addressing this research question with imaging techniques faces the challenge to distinguish different polypeptides without adding artificial probes for detection. Here, we show that nanoscale infrared spectroscopy in combination with 13C, 15N-labeling solves this problem. We studied aggregated amyloid-ß peptide (Aß) and its interaction with an inhibitory peptide (NCAM1-PrP) using scattering-type scanning near-field optical microscopy. Although having similar secondary structure, labeled and unlabeled peptides could be distinguished by comparing optical phase images taken at wavenumbers characteristic for either the labeled or the unlabeled peptide. NCAM1-PrP seems to be able to associate with or to dissolve existing Aß fibrils because pure Aß fibrils were not detected after mixing.

Quinoline Thiourea-Based Zinc Ionophores with Antibacterial Activity.

The increasing resistance of bacteria to commercially available antibiotics threatens patient safety in healthcare settings. Perturbation of ion homeostasis has emerged as a potential therapeutic strategy to fight against antibacterial resistance and other channelopathies. This study reports the development of 8-aminoquinoline (QN) derivatives and their transmembrane Zn2+ transport activities. Our findings showed that a potent QN-based Zn2+ transporter exhibits promising antibacterial properties against Gram-positive bacteria with reduced hemolytic activity and cytotoxicity to mammalian cells. Furthermore, this combination showed excellent in vivo efficacy against Staphylococcus aureus. Interestingly, this combination prevented bacterial resistance and restored susceptibility of gentamicin and methicillin-resistant S. aureus to commercially available ß-lactam and other antibiotics that had lost their activity against the drug-resistant bacterial strain. Our findings suggest that the transmembrane transport of Zn2+ by QN derivatives could be a promising strategy to combat bacterial infections and restore the activity of other antibiotics.

Characterization of Uranyl (UO22+) Ion Binding to Amyloid Beta (Aß) Peptides: Effects on Aß Structure and Aggregation.

Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions, including Alzheimer's disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the deposition of amyloid plaques, consisting mainly of amyloid-ß (Aß) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aß aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aß production, and these metals bind to Aß peptides and modulate their aggregation. The possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aß peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aß peptides with affinities in the micromolar range, induce structural changes in Aß monomers and oligomers, and inhibit Aß fibrillization. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation.

Sero-prevalence and risk factors associated with brucellosis in dairy cattle of Sylhet District, Bangladesh: A cross-sectional study.

BACKGROUND: Brucellosis is an emerging disease that causes a significant impact on productive and reproductive performance in dairy cattle. Though Brucella is a pivotal microorganism for dairy cattle, the scenario of brucellosis in Sylhet District is unknown. OBJECTIVES: A cross-sectional study was carried out to assess the prevalence and determinants associated with brucellosis in dairy cattle of Sylhet District. METHODS: A total of 386 sera and data on determinants from 63 dairy herds were collected from 12 sub-districts using simple random sampling. The sera were tested with Rose Bengal Brucella antigen test, Brucella abortus plate agglutination test and serum agglutination test to find out the sero-positivity. RESULTS: Overall, 17.09% (95% CI: 13.67-21.18) prevalence in cows were calculated. Relatively higher prevalence (56.08%; 95% CI: 42.23-70.32) was recorded in cows having parity ≥4 and were at higher risk (OR = 7.28) than the other cows with parity 0-3. Prevalence was significantly higher in cows with history of abortion 90.63% (95% CI: 75.79-96.76), repeat breeding 79.17% (95% CI: 65.74-88.27) and reproductive abnormalities 48.54% (95% CI: 39.12-58.07). Farm-level prevalence was high in farms with the previous history of abortion 95.45% (95% CI: 78.20-99.19) and repeat breeding 90.00% (95% CI: 74.38-96.54). CONCLUSIONS: The prevalence was high in Sylhet district, which might be a public health concern. Therefore, this study would represent the baseline information for guiding brucellosis control and prevention.

Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aß) peptides.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-ß (Aß) peptides, and Aß oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aß peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods-mainly spectroscopy and imaging techniques-to characterize Aß/Ni(II) interactions in vitro, for different Aß variants: Aß(1-40), Aß(1-40)(H6A, H13A, H14A), Aß(4-40), and Aß(1-42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aß monomers. Equimolar amounts of Ni(II) ions retard Aß aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aß binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aß dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aß monomers, while in a membrane-mimicking environment (SDS micelles) coil-coil helix interactions appear to be induced. For SDS-stabilized Aß oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aß aggregation processes that are involved in AD brain pathology.