The pathophysiological and immunological background of the monkeypox virus infection: An update.

In addition to the COVID-19 waves, the globe is facing global monkeypox (MPX) outbreak. MPX is an uncommon zoonotic infection characterized by symptoms similar to smallpox. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus that belongs to the genus Orthopoxvirus (OPXV). MPXV, which causes human disease, has been confined to Africa for many years, with only a few isolated cases in other areas. Outside of Africa, the continuing MPXV outbreak in multiple countries in 2022 is the greatest in recorded history. The current outbreak, with over 10 000 confirmed cases in over 50 countries between May and July 2022, demonstrates that MPXV may travel rapidly among humans and pose a danger to human health worldwide. The rapid spread of such outbreaks in recent times has elevated MPX to the status of a rising zoonotic disease with significant epidemic potential. While the MPXV is not as deadly or contagious as the variola virus that causes smallpox, it poses a threat because it could evolve into a more potent human pathogen. This review assesses the potential threat to the human population and provides a brief overview of what is currently known about this reemerging virus. By analyzing the biological effects of MPXV on human health, its shifting epidemiological footprint, and currently available therapeutic options, this review has presented the most recent insights into the biology of the virus. This study also clarifies the key potential causes that could be to blame for the present MPX outbreak and draw attention to major research questions and promising new avenues for combating the current MPX epidemic.

The interplay of arsenic, silymarin, and NF-ĸB pathway in male reproductive toxicity: A review.

Arsenic toxicity is one of the most trending reasons for several malfunctions, particularly reproductive toxicity. The exact mechanism of arsenic poisoning is a big question mark. Exposure to arsenic reduces sperm count, impairs fertilization, and causes inflammation and genotoxicity through interfering with autophagy, epigenetics, ROS generation, downregulation of essential protein expression, metabolite changes, and hampering several signaling cascades, particularly by the alteration of NF-ĸB pathway. This work tries to give a clear idea about the different aspects of arsenic resulting in male reproductive complications, often leading to infertility. The first part of this article explains the implications of arsenic poisoning and the crosstalk of the NF-ĸB pathway in male reproductive toxicity. Silymarin is a bioactive compound that exerts anti-cancer and anti-inflammatory properties and has demonstrated hopeful outcomes in several cancers, including colon cancer, breast cancer, and skin cancer, by downregulating the hyperactive NF-ĸB pathway. The next half of this article thus sheds light on silymarin's therapeutic potential in inhibiting the NF-ĸB signaling cascade, thus offering protection against arsenic-induced male reproductive toxicity.

Acetic Acid-Catalyzed Regioselective C(sp2)-H Bond Functionalization of Indolizines: Concomitant Involvement of Synthetic and Theoretical Studies.

An atom economical and environmentally benign protocol has been developed for the regioselective C(sp2)-H bond functionalization of indolizines. The acetic acid-catalyzed cross-coupling reaction proceeds under metal-free conditions, producing a wide range of synthetically useful indolizine derivatives. The present protocol showed good functional group tolerance and broad substrate scope in good to excellent yields. Quantum mechanical investigation using density functional theory (DFT) has played a crucial role in understanding that acetic acid is the key player in determining the actual pathway as the catalyst and its ultrafast nature. Different pathways involving inter- and intramolecular proton transfer, with or without acetic acid, were investigated. Calculated results revealed that a proton shuttle mechanism is involved for the least energetic, most favorable acetic acid-catalyzed pathway. Furthermore, regioselectivity has also been explained theoretically.

A knowledge graph embedding based approach to predict the adverse drug reactions using a deep neural network.

Recently Artificial Intelligence(AI) has not only been used to diagnose the disease but also to cure the disease. Researchers started using AI for drug discovery. Predicting the Adverse Drug Reactions(ADRs) caused by the drug in the manufacturing stage or in the clinical trial stage is a very important problem in drug discovery. ADRs have become a major concern resulting in injuries and also becoming fatal sometimes. Drug safety has gained much importance over the years propelling to the forefront investigation of predicting the ADRs. Although prior studies have queried diverse approaches to predict ADRs, very few were found to be effective. Also, the problem of having fewer reports makes the prediction of ADRs more difficult. To tackle this problem effectively, a novel method has been proposed in this paper. The proposed method is based on Knowledge Graph(KG) embedding. Using the KG embedding, we designed and trained a custom-made Deep Neural Network(DNN) called KGDNN(Knowledge Graph DNN) for predicting the ADRs. A KG has been constructed with 6 types of entities: drugs, ADRs, target proteins, indications, pathways, and genes. Using the Node2Vec algorithm, each node has been embedded into a feature space. Using those embeddings, the ADRs are classified by the KGDNN model. The proposed method has obtained an AUROC score of 0.917 and significantly outperformed the existing methods. Two case studies on drugs causing liver injury and COVID-19 recommended drugs have been performed to illustrate the model efficacy.

Mixed Contaminants: Occurrence, Interactions, Toxicity, Detection, and Remediation.

The ever-increasing rate of pollution has attracted considerable interest in research. Several anthropogenic activities have diminished soil, air, and water quality and have led to complex chemical pollutants. This review aims to provide a clear idea about the latest and most prevalent pollutants such as heavy metals, PAHs, pesticides, hydrocarbons, and pharmaceuticals-their occurrence in various complex mixtures and how several environmental factors influence their interaction. The mechanism adopted by these contaminants to form the complex mixtures leading to the rise of a new class of contaminants, and thus resulting in severe threats to human health and the environment, has also been exhibited. Additionally, this review provides an in-depth idea of various in vivo, in vitro, and trending biomarkers used for risk assessment and identifies the occurrence of mixed contaminants even at very minute concentrations. Much importance has been given to remediation technologies to understand our current position in handling these contaminants and how the technologies can be improved. This paper aims to create awareness among readers about the most ubiquitous contaminants and how simple ways can be adopted to tackle the same.

Misuse of Cardiac Lipid upon Exposure to Toxic Trace Elements-A Focused Review.

Heavy metals and metalloids like cadmium, arsenic, mercury, and lead are frequently found in the soil, water, food, and atmosphere; trace amounts can cause serious health issues to the human organism. These toxic trace elements (TTE) affect almost all the organs, mainly the heart, kidney, liver, lungs, and the nervous system, through increased free radical formation, DNA damage, lipid peroxidation, and protein sulfhydryl depletion. This work aims to advance our understanding of the mechanisms behind lipid accumulation via increased free fatty acid levels in circulation due to TTEs. The increased lipid level in the myocardium worsens the heart function. This dysregulation of the lipid metabolism leads to damage in the structure of the myocardium, inclusive fibrosis in cardiac tissue, myocyte apoptosis, and decreased contractility due to mitochondrial dysfunction. Additionally, it is discussed herein how exposure to cadmium decreases the heart rate, contractile tension, the conductivity of the atrioventricular node, and coronary flow rate. Arsenic may induce atherosclerosis by increasing platelet aggregation and reducing fibrinolysis, as exposure interferes with apolipoprotein (Apo) levels, resulting in the rise of the Apo-B/Apo-A1 ratio and an elevated risk of acute cardiovascular events. Concerning mercury and lead, these toxicants can cause hypertension, myocardial infarction, and carotid atherosclerosis, in association with the generation of free radicals and oxidative stress. This review offers a complete overview of the critical factors and biomarkers of lipid and TTE-induced cardiotoxicity useful for developing future protective interventions.

O-GlcNAcylation of High Mobility Group Box 1 (HMGB1) Alters Its DNA Binding and DNA Damage Processing Activities.

Protein O-GlcNAcylation is an essential and dynamic regulator of myriad cellular processes, including DNA replication and repair. Proteomic studies have identified the multifunctional nuclear protein HMGB1 as O-GlcNAcylated, providing a potential link between this modification and DNA damage responses. Here, we verify the protein's endogenous modification at S100 and S107 and found that the major modification site is S100, a residue that can potentially influence HMGB1-DNA interactions. Using synthetic protein chemistry, we generated site-specifically O-GlcNAc-modified HMGB1 at S100 and characterized biochemically the effect of the sugar modification on its DNA binding activity. We found that O-GlcNAc alters HMGB1 binding to linear, nucleosomal, supercoiled, cruciform, and interstrand cross-linked damaged DNA, generally resulting in enhanced oligomerization on these DNA structures. Using cell-free extracts, we also found that O-GlcNAc reduces the ability of HMGB1 to facilitate DNA repair, resulting in error-prone processing of damaged DNA. Our results expand our understanding of the molecular consequences of O-GlcNAc and how it affects protein-DNA interfaces. Importantly, our work may also support a link between upregulated O-GlcNAc levels and increased rates of mutations in certain cancer states.

A review on modern and smart technologies for efficient waste disposal and management.

In the current scenario, the word waste management holds much importance in every individual's life. Pollution and the generation of vast waste quantities with no proper waste management process have become one of humanity's biggest threats. This review article provides a complete review of the innovative technologies currently employed to handle and dispose of the waste successfully. This work aims to include the different solid, liquid, gaseous, and radioactive waste management processes. The novel and improved plasma gasification concepts, transmutation, incineration, bio-refineries, microbial fuel cells (MFC) have been thoroughly explained. In addition, some new techniques like Mr. Trash Wheel and the Smart bin approach provide much hope of adequately managing waste. The work's novelty lies in adopting several successful methods of various countries for waste disposal and management. To incorporate or improve India'sIndia's same techniques and processes, we have to tackle the ever-increasing waste disposal problems and find economic and eco-friendly ways of waste management.

HMGB1 interacts with XPA to facilitate the processing of DNA interstrand crosslinks in human cells.

Many effective agents used in cancer chemotherapy cause DNA interstrand crosslinks (ICLs), which covalently link both strands of the double helix together resulting in cytotoxicity. ICLs are thought to be processed by proteins from a variety of DNA repair pathways; however, a clear understanding of ICL recognition and repair processing in human cells is lacking. Previously, we found that the high mobility group box 1 (HMGB1) protein bound to triplex-directed psoralen ICLs (TFO-ICLs) in vitro, cooperatively with NER damage recognition proteins, promoted removal of UVC-induced lesions and facilitated error-free repair of TFO-ICLs in mouse fibroblasts. Here, we demonstrate that HMGB1 recognizes TFO-ICLs in human cells, and its depletion increases ICL-induced mutagenesis in human cells without altering the mutation spectra. In contrast, HMGB1 depletion in XPA-deficient human cells significantly altered the ICL-induced mutation spectrum from predominantly T→A to T→G transversions. Moreover, the recruitment of XPA and HMGB1 to the ICLs is co-dependent. Finally, we show that HMGB1 specifically introduces negative supercoils in ICL-containing plasmids in HeLa cell extracts. Taken together, our data suggest that in human cells, HMGB1 functions in association with XPA on ICLs and facilitates the formation of a favorable architectural environment for ICL repair processing.

Quantitative assessment of cardiac mechanical dyssynchrony and prediction of response to cardiac resynchronization therapy in patients with non-ischaemic dilated cardiomyopathy using equilibrium radionuclide angiography.

AIMS: The aim of this study was to evaluate equilibrium radionuclide angiography (ERNA) in prediction of response to cardiac resynchronization therapy (CRT) in non-ischaemic dilated cardiomyopathy (DCM) patients. METHODS AND RESULTS: Thirty-two patients (23 males, 57.5 ± 12.1 years) were prospectively included. Equilibrium radionuclide angiography and clinical evaluation were performed before and 3 months after CRT implantation. Standard deviation of left ventricle mean phase angle (SD LVmPA) and difference between LV and right ventricle mPA (LV-RVmPA) expressed in degrees (°) were used to quantify left intraventricular synchrony and interventricular synchrony, respectively. Left ventricular ejection fraction (LVEF) was also evaluated. At the baseline, mean NYHA class was 3.3 ± 0.5, LVEF 22.5 ± 5.6%, mean QRS duration 150.3 ± 18.2 ms, SD LVmPA 43.5 ± 18°, and LV-RVmPA 30.4 ± 15.6°. At 3-month follow-up, 22 patients responded to CRT with improvement in NYHA class ≥1 and EF >5%. Responders had significantly larger SD LVmPA (51.2 ± 13.9 vs. 26.5 ± 14°) and LV-RVmPA (35.8 ± 13.7 vs. 18.4 ± 13°) than non-responders. Receiver-operating characteristic curve analysis demonstrated 95% sensitivity and 80% specificity at a cut-off value of 30° for SD LVmPA, and 81% sensitivity and 80% specificity at a cut-off value of 23° for LV-RVmPA in prediction of response to CRT. CONCLUSION: Baseline SD LVmPA and LV-RVmPA derived from ERNA are useful for prediction of response to CRT in non-ischaemic DCM patients.

Serum proteomics of hepatitis C virus infection reveals retinol-binding protein 4 as a novel regulator.

Persistent infection of hepatitis C virus (HCV) can lead to liver cirrhosis and hepatocellular carcinoma, which are currently diagnosed by invasive liver biopsy. Approximately 15-20 % of cases of chronic liver diseases in India are caused by HCV infection. In North India, genotype 3 is predominant, whereas genotype 1 is predominant in southern parts of India. The aim of this study was to identify differentially regulated serum proteins in HCV-infected Indian patients (genotypes 1 and 3) using a two-dimensional electrophoresis approach. We identified eight differentially expressed proteins by MS. Expression levels of one of the highly upregulated proteins, retinol-binding protein 4 (RBP4), was validated by ELISA and Western blotting in two independent cohorts. We also confirmed our observation in the JFH1 infectious cell culture system. Interestingly, the HCV core protein enhanced RBP4 levels and partial knockdown of RBP4 had a positive impact on HCV replication, suggesting a possible role for this cellular protein in regulating HCV infection. Analysis of RBP4-interacting partners using a bioinformatic approach revealed novel insights into the possible involvement of RBP4 in HCV-induced pathogenesis. Taken together, this study provided information on the proteome profile of the HCV-infected Indian population, and revealed a link between HCV infection, RBP4 and insulin resistance.

Potential role of 18F-FDG PET/CT in patients with fungal infections.

OBJECTIVE: Combined anatomic and functional imaging with (18)F-FDG PET/CT is slowly gaining foothold in the management of various infective pathologic abnormalities. However, limited literature is available regarding the role of FDG PET/CT in patients with fungal infections. CONCLUSION: Here, we briefly review the available literature and highlight the potential role that FDG PET/CT can play in the diagnosis and management of fungal infections.

Arsenic-induced prostate cancer: an enigma.

Arsenic exhibits varying degrees of toxicity depending on its many chemical forms. The carcinogenic properties of arsenic have already been established. However, the precise processes underlying the development of diseases following acute or chronic exposure to arsenic remain poorly known. Most of the existing investigation has focused on studying the occurrence of cancer following significant exposure to elevated levels of arsenic. Nevertheless, multiple investigations have documented diverse health consequences from prolonged exposure to low levels of arsenic. Inorganic arsenic commonly causes lung, bladder, and skin cancer. Some investigations have shown an association between arsenic in drinking water and prostate cancer, but few investigations have focused on exploring this connection. There is currently a lack of relevant animal models demonstrating a clear link between inorganic arsenic exposure and the development of prostate cancer. Nevertheless, studies using cellular model systems have demonstrated that arsenic can potentially promote the malignant transformation of human prostate epithelial cells in vitro. The administration of elevated levels of arsenic has been demonstrated to elicit cell death in instances of acute experimental exposure. Conversely, in cases of chronic exposure, arsenic prompts cellular proliferation and sustains cellular viability, thereby circumventing the constraints imposed by telomere shortening and apoptosis. Furthermore, cells consistently exposed to the stimulus exhibit an augmented ability to invade surrounding tissues and an enhanced potential to form tumors. This review aims to portray mechanistic insights into arsenic-induced prostate cancer.

Anti-sperm Antibodies as an Increasing Threat to Male Fertility: Immunological Insights, Diagnostic and Therapeutic Strategies.

It is a fact that sperm possess antigenic properties. Substantial scientific research suggests that specific antibodies that attach to sperm antigens can induce infertility in both humans and other species. Antisperm antibodies (ASA) represent a significant etiology of infertility in humans, leading to immunoinfertility. The association between ASA and infertility is multifaceted. The observation of sperm agglutination, although not conclusive for the diagnosis of immunological infertility, may suggest the presence of ASA. Nevertheless, ASA may also manifest in the lack of any sperm agglutination. Managing ASA from an andrological perspective depends on the underlying cause and the specific approaches healthcare professionals adopt. The precise etiology of male infertility resulting from ASA remains unclear. Current research has examined the impact of ASA and its prevalence among infertile males to understand the relationship between ASA and changes in semen parameters. However, the findings have been inconclusive. Numerous techniques have been documented for the management of immunoinfertility. This review examines the importance of ASA in the context of infertility, encompassing the postulated mechanisms underlying the development of ASA, the various assays employed for detecting them, and the available treatments.

Somatostatin receptor-based PET/CT of intracranial tumors: a potential area of application for 68 Ga-DOTA peptides?

OBJECTIVE: Similar to neuroendocrine tumors (NETs) at other sites, a wide array of intracranial tumors also express somatostatin receptors (SSTRs). This expression can be exploited for both imaging and therapy. The introduction of (68)Ga-labeled tetraazacyclododecanetetraacetic acid (DOTA)-peptide PET/CT has given new dimension to SSTR-based imaging because of its improved sensitivity and excellent spatial resolution. CONCLUSION: However, in contrast to gastropancreatic and bronchopulmonary NETs, limited literature is available regarding the use of (68)Ga-DOTA-peptide PET/CT in intracranial tumors. Here, we briefly review the available literature and highlight the potential role that (68)Ga-DOTA-peptide PET/CT can play in the management of intracranial tumors.

Economic geography of contagion: a study of COVID-19 outbreak in India.

We propose a mechanism based on regional inequality in economic activity to explain the heterogeneity in the spread of COVID-19 and test it using data from India. Contagion is expected to spread at a higher rate in regions characterized by greater movement of goods and services. We argue that mobility is higher in regions with greater degree of intra-regional inequality in economic activity. Such regions are usually characterized by a core-periphery economic structure in which the periphery is dependent on the core for the supply of jobs, goods, and services. Such dependence leads to a greater degree of mobility between the core and periphery, which in turn leads to higher rate of contagion. Using nightlight data to measure regional inequality, we find evidence in support of our hypothesis. Using mobility data, we provide direct evidence in support of our proposed channel; the positive relationship between regional inequality and COVID-19 infection is driven by mobility. Our findings suggest that policy responses to contain COVID-19 contagion need to be heterogeneous across India, where the priority areas can be chosen ex ante based on a regional inequality-based criterion. Supplementary Information: The online version contains supplementary material available at 10.1007/s00148-022-00935-9.

Dynamic correlations in the conserved Manna sandpile.

We study dynamic correlations for current and mass, as well as the associated power spectra, in the one-dimensional conserved Manna sandpile. We show that, in the thermodynamic limit, the variance of cumulative bond current up to time T grows subdiffusively as T^{1/2-µ} with the exponent µ≥0 depending on the density regimes considered and, likewise, the power spectra of current and mass at low frequency f varies as f^{1/2+µ} and f^{-3/2+µ}, respectively. Our theory predicts that, far from criticality, µ=0 and, near criticality, µ=(ß+1)/2ν_{⊥}z>0 with ß, ν_{⊥}, and z being the order parameter, correlation length, and dynamic exponents, respectively. The anomalous suppression of fluctuations near criticality signifies a "dynamic hyperuniformity," characterized by a set of fluctuation relations, in which current, mass, and tagged-particle displacement fluctuations are shown to have a precise quantitative relationship with the density-dependent activity (or its derivative). In particular, the relation, D_{s}(ρ[over ¯])=a(ρ[over ¯])/ρ[over ¯], between the self-diffusion coefficient D_{s}(ρ[over ¯]), activity a(ρ[over ¯]) and density ρ[over ¯] explains a previous simulation observation [Eur. Phys. J. B 72, 441 (2009)10.1140/epjb/e2009-00367-0] that, near criticality, the self-diffusion coefficient in the Manna sandpile has the same scaling behavior as the activity.

The mechanistic insights of the antioxidant Keap1-Nrf2 pathway in oncogenesis: a deadly scenario.

The Nuclear factor erythroid 2-related factor 2 (Nrf2) protein has garnered significant interest due to its crucial function in safeguarding cells and tissues. The Nrf2 protein is crucial in preserving tissue integrity by safeguarding cells against metabolic, xenobiotic and oxidative stress. Due to its various functions, Nrf2 is a potential pharmacological target for reducing the incidence of diseases such as cancer. However, mutations in Keap1-Nrf2 are not consistently favored in all types of cancer. Instead, they seem to interact with specific driver mutations of tumors and their respective tissue origins. The Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway mutations are a powerful cancer adaptation that utilizes inherent cytoprotective pathways, encompassing nutrient metabolism and ROS regulation. The augmentation of Nrf2 activity elicits significant alterations in the characteristics of neoplastic cells, such as resistance to radiotherapy and chemotherapy, safeguarding against apoptosis, heightened invasiveness, hindered senescence, impaired autophagy and increased angiogenesis. The altered activity of Nrf2 can arise from diverse genetic and epigenetic modifications that instantly impact Nrf2 regulation. The present study aims to showcase the correlation between the Keap1-Nrf2 pathway and the progression of cancers, emphasizing genetic mutations, metabolic processes, immune regulation, and potential therapeutic strategies. This article delves into the intricacies of Nrf2 pathway anomalies in cancer, the potential ramifications of uncontrolled Nrf2 activity, and therapeutic interventions to modulate the Keap1-Nrf2 pathway.

Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms.

Because the overexpression of histone deacetylase enzymes (HDACs) has been linked to numerous diseases, including various cancers and neurodegenerative disorders, HDAC inhibitors have emerged as promising therapeutic agents. However, most HDAC inhibitors lack both subclass and isoform selectivity, which leads to potential toxicity. Unlike classical hydroxamate HDAC inhibitors, slow-binding HDAC inhibitors form tight and prolonged bonds with HDAC enzymes. This distinct mechanism of action improves both selectivity and toxicity profiles, which makes slow-binding HDAC inhibitors a promising class of therapeutic agents for various diseases. Therefore, the development of slow-binding HDAC inhibitors that can effectively target a wide range of HDAC isoforms is crucial. This Perspective provides valuable insights into the potential and progress of slow-binding HDAC inhibitors as promising drug candidates for the treatment of various diseases.

Unlocking the mystery associated with infertility and prostate cancer: an update.

Male-specific reproductive disorders and cancers have increased intensely in recent years, making them a significant public health problem. Prostate cancer (PC) is the most often diagnosed cancer in men and is one of the leading causes of cancer-related mortality. Both genetic and epigenetic modifications contribute to the development and progression of PC, even though the exact underlying processes causing this disease have yet to be identified. Male infertility is also a complex and poorly understood phenomenon believed to afflict a significant portion of the male population. Chromosomal abnormalities, compromised DNA repair systems, and Y chromosome alterations are just a few of the proposed explanations. It is becoming widely accepted that infertility shares a link with PC. Much of the link between infertility and PC is probably attributable to common genetic defects. This article provides an overview of PC and spermatogenic abnormalities. This study also investigates the link between male infertility and PC and uncovers the underlying reasons, risk factors, and biological mechanisms contributing to this association.