High prevalence of CD44 and its ligand low molecular weight hyaluronan in plasma of HNSCC patients: clinical significance.

BACKGROUND: This study aims to evaluate the role of cancer stem cell marker, CD44, and its ligand HA as potential molecular biomarker for early detection of HNSCC. METHODS AND RESULTS: The expression profile (mRNA/Protein) of CD44 variants were analysed in primary HNSCC lesions and plasma of the patients. Then, prevalence of HA variants was analysed in plasma of the patients. The mRNA expression of CD44 variants, CD44S and CD44v3, were significantly high in both early (stage I/II) and late (stage III/IV) invasive lesions, with predominant expression of CD44v3 in the late-stage lesions. In plasma of HNSCC patients, increased levels of SolCD44, CD44-ICD and unique 62 KD CD44 variants with respect to standard CD44S were seen, in comparison to their prevalence in plasma of normal individuals. The abundance of CD44-ICD and 62 KD variants were significantly high in plasma of late stage HNSCC patients. Interestingly, significantly high level of low molecular weight HA(LMW HA) with respect to high molecular weight HA(HMW HA) was seen in plasma of HNSCC patients irrespective of clinical stages. On the contrary, high HMW HA level in plasma of normal individuals was seen. The high level of LMW HA in plasma of HNSCC patients might be due to combinatorial effect of increased mRNA expression of HA synthesizing enzyme HAS1/2/3 and HA degrading enzyme HYAL1/2, as seen in the primary HNSCC samples. CONCLUSION: Thus, our data revealed the importance of specific CD44 and HA variants in plasma of HNSCC patients during its development as potential non-invasive molecular biomarker of the disease.

Modelling of soil erosion susceptibility incorporating sediment connectivity and export at landscape scale using integrated machine learning, InVEST-SDR and Fragstats.

Evaluating the linkage between soil erosion and sediment connectivity for export assessment in different landscape patterns at catchment scale is valuable for optimization of soil and water conservation (SWC) practices. Present research attempts to identify the soil erosion susceptible (SES) sites in Kangsabati River Basin (KRB) using machine learning algorithm (decision trees, decision trees cross validation, CV, Extreme Gradient Boosting, XGB CV and bagging CV) taken thirty five variables, for investigating the linkage between erosion rates and sediment connectivity to assess the sediment export at sub-basin level employing connectivity index (IC) and Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) sediment delivery ratio (SDR) model. Based on AUC of receiving operating curve in validation test, excellent capacity of extreme Gradient Boosting, XGB CV and bagging CV (0.95, 0.90) than decision tree and decision tree CV (0.78, 0.82), exhibits about 18.58 % of basin areas facing susceptible to very high erosion. Conversely, considering universal soil loss equation (RUSLE) parameters, InVEST-SDR model estimated about 64.24 % of soil loss rate occurred from high SES in where sediment export rate become very high (136.995 t/ha-1/y-1). The IC result show that high sediment connectivity (<-4.4) measured in high SES of laterite and bare land in upper catchment, and double crop agricultural areas in lower catchment, while least connectivity (>-7.1) observed in low SES of dense forest, vegetation cover and settlement built-up areas. Pearson correlation matrix revealed that four landscape indices category i.e. edge metrics (p < 0.01), aggregation metrics (p < 0.001), shape metrics (p < 0.01-0.001) and diversity metrics (p < 0.01) signified the influence of landscape patterns on IC and SES. Accordingly, RUSLE, SDR and landscape matrices reveals that maximum sediment export rate associated with high connective delivery outlet and high SES in laterite, double crop and bare land due to simple landscape and greater homogeneity, whilst minimum export rate related with low connectivity and low SES in dense forest, vegetation cover and settlement built up area causes of fragmented landscape and spatial heterogeneity. Finally, findings could immense useful for formulating the optimizing measures of SWC in the watershed.

Prevalence of novel gamma HPV types 223 and 225 in oral cavity and skin of Indian normal and neoplastic participants.

Gamma-papillomaviruses, though traditionally classified as cutaneotropic, actual tissue tropism is largely unexplored. This study aimed to evaluate the tissue-specific prevalence of two novel-HPV 223 and 225 in samples of oral mucosa and keratinized epithelium of varied skin parts from 226 female and male subjects, with or without neoplastic/dysplastic lesions in oral cavity or cervix. The gamma-human papillomavirus (gamma-HPV) 223 and 225 DNA presences were determined by polymerase chain reaction (PCR) ursing the HPV type-specific primers and confirmed by Sanger sequencing. Viral load in the HPV 223 and HPV 225 positive samples were determined by absolute real-time quantification method. Alpha-HPV DNA prevalence was also checked in oral mucosa to ascertain coinfection status. Novel HPV 223 was present in 4.4% (10/226) oral mucosal samples of the study population; interestingly all were females with no prevalence in their corresponding skin swab samples. Whereas, the prevalence of HPV 225 was found both in the skin and oral mucosa of 28.2% (N = 37/131) female and 17.9% (N = 17/95) male participants. Alongside, HPV 223 viral load was found to be significantly higher (p = 0.02 < 0.05) in the oral mucosa of diseased participants, whereas, HPV 225 viral load was higher in the oral mucosa of normal participants. Our results suggest that gamma-HPV 223 has its prevalence only in the oral mucosal epithelium, whereas, HPV 225 has its prevalence on both mucosal and keratinized skin epithelium, indicating its dual tropism nature.

Multifunctional resilience of river health to human service demand in an alluvial quarried reach: a comparison amongst fuzzy logic, entropy, and AHP-based MCDM models.

Riverine ecosystem services to human beings are dynamically evaluated by harmonic relationships; however, over growing human service demands (HSDs) are leading to deteriorate the river health resilience. In this study, an assessment index system of river health involving pressure-state-response (PSR) based on twenty indicators of riparian, channel geomorphic, hydroecological, and social attributes was developed to detect the multifunctional reliability and resilience of river system integrity for HSDs at upper (US), middle (MS), and lower segments (LS) of Kangsabati River using fuzzy logic, analytical hierarchical process (AHP), and entropy weight-based multi-criteria decision matrix (MCDM) methods. Borda integrating MCDM results revealed that overall indicator performance is high health score in US (77), medium score in MS (69), but mostly unhealthy score in LS (34); thus, entropy-MCDM models give highest rank to US, medium rank to MS, and least rank to LS, while AHP and fuzzy MCDM models assigned as high priority rank to MS, medium rank to US, and least rank to LS, respectively. According to model validation performances, entropy-MCDM models (RMSE < 2.48) are rationalized to the harmonic relationship of riverine system, whereas fuzzy and AHP-MCDM models (RMSE < 2.79) are signified to HSDs, and these results are closer to real problems. With the acceptability of AHP-MCDM models through the percentage change (73.89%) and intensity change (17.16) assessment, it points that over HSDs are crucial factors for river health degradation. Moreover, final outcome of the present research helps to find out the sick river health sites for ecological restoration.

Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.

Brahma safeguards canalization of cardiac mesoderm differentiation.

Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1,2. Canalization is essential for stabilizing cell fate, but the mechanisms that underlie robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite the establishment of a well-differentiated precardiac mesoderm, Brm-/- cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed a sudden acquisition of a non-mesodermal identity in Brm-/- cells. Mechanistically, the loss of Brm prevented de novo accessibility of primed cardiac enhancers while increasing the expression of neurogenic factor POU3F1, preventing the binding of the neural suppressor REST and shifting the composition of BRG1 complexes. The identity switch caused by the Brm mutation was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modelling supports these observations and demonstrates that Brm deletion affects cell fate trajectory by modifying saddle-node bifurcations2. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1-mutant phenotypes, severely compromising cardiogenesis, and reveals an in vivo role for Brm. Our results show that Brm is a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.

Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling.

Native Human Antibody to Shr Promotes Mice Survival After Intraperitoneal Challenge With Invasive Group A Streptococcus.

BACKGROUND: A vaccine against group A Streptococcus (GAS) has been actively pursued for decades. The surface receptor Shr is vital in GAS heme uptake and provides an effective target for active and passive immunization. Here, we isolated human monoclonal antibodies (mAbs) against Shr and evaluated their efficacy and mechanism. METHODS: We used a single B-lymphocyte screen to discover the mAbs TRL186 and TRL96. Interactions of the mAbs with whole cells, proteins, and peptides were investigated. Growth assays and cultured phagocytes were used to study the mAbs' impact on heme uptake and bacterial killing. Efficacy was tested in prophylactic and therapeutic vaccination using intraperitoneal mAb administration and GAS challenge. RESULTS: Both TRL186 and TRL96 interact with whole GAS cells, recognizing the NTR and NEAT1 domains of Shr, respectively. Both mAbs promoted killing by phagocytes in vitro, but prophylactic administration of only TRL186 increased mice survival. TRL186 improved survival also in a therapeutic mode. TRL186 but not TRL96 also impeded Shr binding to hemoglobin and GAS growth on hemoglobin iron. CONCLUSIONS: Interference with iron acquisition is central for TRL186 efficacy against GAS. This study supports the concept of antibody-based immunotherapy targeting the heme uptake proteins to combat streptococcal infections.

Sub-basin prioritization for assessment of soil erosion susceptibility in Kangsabati, a plateau basin: A comparison between MCDM and SWAT models.

Kangsabati basin located in tropical plateau region faces multiple problems of soil erosion susceptibility (SES), soil fertility deterioration, and sedimentation in reservoirs. Hence, identification of SES zones in thirty-eight sub-basins (SB) for basin prioritization is necessary. The present research addressed the issue by using four multi-criteria decision-making (MCDM) models: VlseKriterijumska optimizacija I Kompromisno Resenje (VIKOR), technique for order preference by similarity to ideal solution (TOPSIS), simple additive weighing (SAW), compound factor (CF). To determine the best fitted method from MCDM for erosion susceptibility (ES), a comparison has been made with Soil and Water Assessment Tool (SWAT), where fifteen morphometric parameters were considered for MCDM, and meteorological data, soil, slope and land use land cover (LULC) were considered for SWAT model. Two validation indices of percentage change and intensity change were used for evaluation and comparison of MCDM results. With SWAT model performance, SWAT calibration and uncertainty analysis programs (CUP) was used for sensitive analysis of SWAT parameters on flow discharge and sediment load simulation. The results showed that 23, 16, 18 SB have high ES; therefore they were given 1 to 3 ranks, whereas 31, 37, 21SB have low ES, hence given 38 to 36 rank as predicted by MCDM methods and SWAT. MCDM validation results depict that VIKOR and CF methods are more acceptable than TOPSIS and SAW. Calibration (flow discharge R2 0.86, NSE 0.75; sediment load R2 0.87, NSE 0.69) and validation (flow discharge R2 0.79, NSE 0.55; sediment load R2 0.79, NSE 0.76) of SWAT model indicated that simulated results are well fitted with observed data. Therefore, VIKOR reflects the significant role of morphometric parameters on ES, whereas SWAT reflects the significant role of LULC, slope, and soil on ES. However, it could be concluded that VIKOR is more effective MCDM method in comparison to SWAT prediction.

A Novel Heme Transporter from the Energy Coupling Factor Family Is Vital for Group A Streptococcus Colonization and Infections.

Group A streptococcus (GAS) produces millions of infections worldwide, including mild mucosal infections, postinfection sequelae, and life-threatening invasive diseases. During infection, GAS readily acquires nutritional iron from host heme and hemoproteins. Here, we identified a new heme importer, named SiaFGH, and investigated its role in GAS pathophysiology. The SiaFGH proteins belong to a group of transporters with an unknown ligand from the recently described family of energy coupling factors (ECFs). A siaFGH deletion mutant exhibited high streptonigrin resistance compared to the parental strain, suggesting that iron ions or an iron complex is the likely ligand. Iron uptake and inductively coupled plasma mass spectrometry (ICP-MS) studies showed that the loss of siaFGH did not impact GAS import of ferric or ferrous iron, but the mutant was impaired in using hemoglobin iron for growth. Analysis of cells growing on hemoglobin iron revealed a substantial decrease in the cellular heme content in the mutant compared to the complemented strain. The induction of the siaFGH genes in trans resulted in the induction of heme uptake. The siaFGH mutant exhibited a significant impairment in murine models of mucosal colonization and systemic infection. Together, the data show that SiaFGH is a new type of heme importer that is key for GAS use of host hemoproteins and that this system is imperative for bacterial colonization and invasive infection.IMPORTANCE ECF systems are new transporters that take up various vitamins, cobalt, or nickel with a high affinity. Here, we establish the GAS SiaFGH proteins as a new ECF module that imports heme and demonstrate its importance in virulence. SiaFGH is the first heme ECF system described in bacteria. We identified homologous systems in the genomes of related pathogens from the Firmicutes phylum. Notably, GAS and other pathogens that use a SiaFGH-type importer rely on host hemoproteins for a source of iron during infection. Hence, recognizing the function of this noncanonical ABC transporter in heme acquisition and the critical role that it plays in disease has broad implications.

Sub-basin prioritization for assessment of soil erosion susceptibility in Kangsabati, a plateau basin: A comparison between MCDM and SWAT models.

Kangsabati basin located in tropical plateau region faces multiple problems of soil erosion susceptibility (SES), soil fertility deterioration, and sedimentation in reservoirs. Hence, identification of SES zones in thirty-eight sub-basins (SB) for basin prioritization is necessary. The present research addressed the issue by using four multi-criteria decision-making (MCDM) models: VlseKriterijumska optimizacija I Kompromisno Resenje (VIKOR), technique for order preference by similarity to ideal solution (TOPSIS), simple additive weighing (SAW), compound factor (CF). To determine the best fitted method from MCDM for erosion susceptibility (ES), a comparison has been made with Soil and Water Assessment Tool (SWAT), where fifteen morphometric parameters were considered for MCDM, and meteorological data, soil, slope and land use land cover (LULC) were considered for SWAT model. Two validation indices of percentage change and intensity change were used for evaluation and comparison of MCDM results. With SWAT model performance, SWAT calibration and uncertainty analysis programs (CUP) was used for sensitive analysis of SWAT parameters on flow discharge and sediment load simulation. The results showed that 23, 16, 18 SB have high ES; therefore they were given 1 to 3 ranks, whereas 31, 37, 21SB have low ES, hence given 38 to 36 rank as predicted by MCDM methods and SWAT. MCDM validation results depict that VIKOR and CF methods are more acceptable than TOPSIS and SAW. Calibration (flow discharge R2 0.86, NSE 0.75; sediment load R2 0.87, NSE 0.69) and validation (flow discharge R2 0.79, NSE 0.55; sediment load R2 0.79, NSE 0.76) of SWAT model indicated that simulated results are well fitted with observed data. Therefore, VIKOR reflects the significant role of morphometric parameters on ES, whereas SWAT reflects the significant role of LULC, slope, and soil on ES. However, it could be concluded that VIKOR is more effective MCDM method in comparison to SWAT prediction.

Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.

Transcriptomic Analysis of Streptococcus pyogenes Colonizing the Vaginal Mucosa Identifies hupY, an MtsR-Regulated Adhesin Involved in Heme Utilization.

Streptococcus pyogenes (group A streptococcus [GAS]) is a serious human pathogen with the ability to colonize mucosal surfaces such as the nasopharynx and vaginal tract, often leading to infections such as pharyngitis and vulvovaginitis. We present genome-wide transcriptome sequencing (RNASeq) data showing the transcriptomic changes GAS undergoes during vaginal colonization. These data reveal that the regulon controlled by MtsR, a master metal regulator, is activated during vaginal colonization. This regulon includes two genes highly expressed during vaginal colonization, hupYZ Here we show that HupY binds heme in vitro, affects intracellular concentrations of iron, and is essential for proper growth of GAS using hemoglobin or serum as the sole iron source. HupY is also important for murine vaginal colonization of both GAS and the related vaginal colonizer and pathogen Streptococcus agalactiae (group B streptococcus [GBS]). These data provide essential information on the link between metal regulation and mucosal colonization in both GAS and GBS.IMPORTANCE Colonization of the host requires the ability to adapt to an environment that is often low in essential nutrients such as iron. Here we present data showing that the transcriptome of the important human pathogen Streptococcus pyogenes shows extensive remodeling during in vivo growth, resulting in, among many other differentially expressed genes and pathways, a significant increase in genes involved in acquiring iron from host heme. Data show that HupY, previously characterized as an adhesin in both S. pyogenes and the related pathogen Streptococcus agalactiae, binds heme and affects intracellular iron concentrations. HupY, a protein with no known heme binding domains, represents a novel heme binding protein playing an important role in bacterial iron homeostasis as well as vaginal colonization.

Polytherapy and Targeted Cancer Drug Resistance.

A current challenge in cancer treatment is drug resistance. Even the most effective therapies often fail to produce a complete and durable tumor response and ultimately give rise to therapy resistance and tumor relapse. However, how resistance arises in cancer remains incompletely understood. While drug resistance in cancer is thought to be driven by irreversible genetic mutations, emerging evidence also implicates reversible proteomic and epigenetic mechanisms in the development of drug resistance. Tumor microenvironment-mediated mechanisms and tumor heterogeneity can significantly contribute to cancer treatment resistance. Here, we discuss the diverse and dynamic strategies that cancers use to evade drug response, the promise of upfront combination and intermittent therapies and therapy switching in forestalling resistance, and epigenetic reprogramming to combat resistance.

Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins.

Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, nonkinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here, we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically relevant ROS1 RTK fusion oncoproteins. SDC4-ROS1 and SLC34A2-ROS1 fusion oncoproteins resided on endosomes and activated the MAPK pathway. CD74-ROS1 variants that localized instead to the endoplasmic reticulum (ER) showed compromised activation of MAPK. Forced relocalization of CD74-ROS1 from the ER to endosomes restored MAPK signaling. ROS1 fusion oncoproteins that better activate MAPK formed more aggressive tumors. Thus, differential subcellular localization controlled by the N-terminal fusion partner regulates the oncogenic mechanisms and output of certain RTK fusion oncoproteins. SIGNIFICANCE: ROS1 fusion oncoproteins exhibit differential activation of MAPK signaling according to subcellular localization, with ROS1 fusions localized to endosomes, the strongest activators of MAPK signaling.

Revelation of ZnS Nanoparticles Induces Follicular Atresia and Apoptosis in the Ovarian Preovulatory Follicles in the Catfish Mystus tengara (Hamilton, 1822).

Important physicochemical characteristics of water like dissolved oxygen content, pH, and so forth were found to change in a dose dependent manner, showing a negative correlation with the nanoparticle concentration, when ZnS nanoparticle (NP) was exposed to water. This observation could be attributed to the enhanced photooxidation property associated with ZnS in its NP form. Under this situation, the catfish Mystus tengara was forced to live in hypoxia in its habitat. This condition was found to hamper the natural oogenesis process of the fish. Due to exposure at relatively lower concentration of ZnS NPs (250 µg/L), most of the maturing follicles of M. tengara failed to complete the process of vitellogenesis properly and underwent preovulatory atresia followed by oocytic apoptosis. For relatively higher concentration of ZnS nanoparticles (500 µg/L), the previtellogenic process continued with increasing number of apoptotic cells; however the vitellogenic process was found to be totally blocked. This unusual reproductive behaviour in female M. tengara can be attributed to the decreased metabolism of the fishes under ZnS nanoparticle induced hypoxia.

SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells.

The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor.

Stepwise nucleosome translocation by RSC remodeling complexes.

The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1-2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome.

An Analytic Contemplation of the Conspicuous Vicissitudes in the Histomorphology of Corpuscles of Stannius of a Freshwater Catfish Mystus tengara (Hamilton, 1822) due to the Exposure of ZnS Nanoparticles.

Enhanced surface photooxidation property associated with the ZnS nanoparticles caused the reduction of dissolved oxygen content in water in a dose dependent manner, when ZnS nanoparticles of different sizes are exposed to the water in various concentrations. This property was more prominent for ZnS nanoparticles with smaller sizes. Mystus tengara, exposed to ZnS nanoparticles, responded to hypoxia with varied behavioural, physiological, and cellular responses in order to maintain homeostasis and organ function in an oxygen-depleted environment. The histomorphology of corpuscles of Stannius of the fish showed conspicuous vicissitudes under exposure of ZnS nanoparticles. The population of the cell type with granular cytoplasm showed significant increase at the expense of the other that consisted of agranular cytoplasm with increasing nanoparticle concentration. This can be explained as the defence mechanism of the fish against ZnS nanoparticle induced hypoxia and environmental acidification. The altering histomorphology has been studied employing an analytical approach.