Predicting lysine methylation sites using a convolutional neural network.

Protein lysine methylation is a particular type of post translational modification that plays an important role in both histone and non-histone function regulation in proteins. Deregulation caused by lysine methyltransferases has been identified as the cause of several diseases including cancer as well as both mental and developmental disorders. Identifying lysine methylation sites is a critical step in both early diagnosis and drug design. This study proposes a new Machine Learning method called CNN-Meth for predicting lysine methylation sites using a convolutional neural network (CNN). Our model is trained using evolutionary, structural, and physicochemical-based presentation along with binary encoding. Unlike previous studies, instead of extracting handcrafted features, we use CNN to automatically extract features from different presentations of amino acids to avoid information loss. Automated feature extraction from these representations of amino acids as well as CNN as a classifier have never been used for this problem. Our results demonstrate that CNN-Meth can significantly outperform previous methods for predicting methylation sites. It achieves 96.0%, 85.1%, 96.4%, and 0.65 in terms of Accuracy, Sensitivity, Specificity, and Matthew's Correlation Coefficient (MCC), respectively. CNN-Meth and its source code are publicly available at https://github.com/MLBC-lab/CNN-Meth.

Nephrotic Syndrome and Posterior Reversible Encephalopathy Syndrome as Clinical Presentations of Gemcitabine-Induced Thrombotic Micro-Angiopathy.

Gemcitabine-induced thrombotic micro-angiopathy (GiTMA) is a very rare pathology of micro-vascular occlusion with a poor prognosis. In this case report, we present a young male with pancreatic carcinoma who received gemcitabine as adjuvant chemotherapy and developed thrombotic micro-angiopathy (TMA) manifesting as nephrotic syndrome with renal dysfunction and posterior reversible encephalopathy syndrome (PRES). The case was successfully managed with discontinuation of the drug and conservative management. The pathogenesis of GiTMA might be direct endothelial dysfunction with consequent activation of the clotting system. The role of plasma exchanges and monoclonal antibodies is unclear in drug-induced TMA.

Antimicrobial Potential of Polyphenols: An Update on Alternative for Combating Antimicrobial Resistance.

The last decade has encountered an increasing demand for plant-based natural antibiotics. This demand has led to more research-based investigations for natural sources of antimicrobial agents and published reports demonstrating that plant extracts are widely applied in modern medicine, reporting potential activity that may be due to polyphenol compounds. Interestingly, the effects of polyphenols on the sensitivity of bacteria to antibiotics have not been well-studied. Hence, the current review encompasses the prospective application of plant-based phenolic extracts from plants of Indian origin. The emergence of resistance to antimicrobial agents has increased the inefficacy of many antimicrobial drugs. Several strategies have been developed in recent times to overcome this issue. A combination of antimicrobial agents is employed for the failing antibiotics, which restores the desirable effect but may have toxicity-related issues. Phytochemicals such as some polyphenols have demonstrated their potent activity as antimicrobial agents of natural origin to work against resistance issues. These agents alone or in combination with certain antibiotics have been shown to enhance the antimicrobial activity against a spectrum of microbes. However, the information regarding the mechanisms and structure-activity relationships remains elusive. The present review also focuses on the possible mechanisms of natural compounds based on their structure- activity relationships for incorporating polyphenolic compounds in the drug-development processes. Besides this work, polyphenols could reduce drug dosage and may diminish the unhidden or hidden side effects of antibiotics. Pre-clinical findings have provided strong evidence that polyphenolic compounds, individually and in combination with already approved antibiotics, work well against the development of resistance. However, more studies must focus on in vivo results, and clinical research needs to specify the importance of polyphenol-based antibacterials in clinical trials.

Severity of muscle impairment and its progression assessed using musculoskeletal magnetic resonance imaging and diffusion tension imaging in 78 boys with Duchenne muscular dystrophy: a retrospective study.

Purpose: Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy. Current diagnostic tests like genetic testing, needle electromyography, and muscle biopsy are either not easily available or invasive, and they are impractical for assessing disease progression and treatment outcomes. Therefore, there is a need for a non-invasive and accurate investigative modality for DMD. In recent years, musculoskeletal magnetic resonance imaging (MRI-MSK) along with fractional anisotropy (FA) and diffusion tensor imaging (DTI) have become major non-invasive tools. Material and methods: T1-weighted MRI-MSK and FA measures of DTI of 78 DMD patients were retrospectively studied to identify the distinct pattern of muscle involvement and fatty infiltration as age and/or disease progresses. Correlation analysis was performed between MRI-MSK grade score vs. age, muscle strength, and Vignos scale. Spearman's rank correlation coefficient was used. Results: As age increased, the MRI grade score and Vignos score increased. There was a statistically significant high positive correlation between MRI-MSK grade score and age, and low positive correlation with Vignos scores. With increasing age, the muscle strength on manual muscle testing (MMT) and FA value decreased. There was high negative correlation with muscle strength on MMT and low positive correlation between FA values and MMT score. Conclusions: On T1-weighted MRI, a distinct pattern, extent, and distribution of lower limb muscle involvement can be seen. MRI-MSK grade score worsens with progressing age, reducing strength, and increasing functional impairment. FA alone may not be an accurate marker in assessing progression of DMD. MRI-MSK and other DTI measures should be further explored as diagnostic and prognostic tools for DMD.

Smart Materials Design for Antibacterial Application.

In response to the escalating issue of antibiotic-resistant bacteria adhering to and thriving on medical equipment, scientists are pioneering innovative "intelligent" materials and coatings. These advancements entail the targeted release of antimicrobial substances, specifically activated when bacteria are detected. The next section discusses three revolutionary substances: hydrogels, nanoparticles, and thin films. Furthermore, intelligent antibacterial materials are divided into 2 groups based on the triggering source: those that react to biological stimuli and those that react to non-biological ones, like temperature and electric cues associated with bacterial presence, such as pH shifts or bacterial enzyme discharge. Moreover, because of their simple construction technique, outstanding biocompatibility, and robust antibacterial characteristics derived from polyphenols and metal ions, metallic-polyphenolic nanoparticles (MPNs) have obtained substantial interest in tackling antimicrobial infections. This article presents an introduction to several MPN-centered biomaterials (like nanoparticles, coatings, capsules, and hydrogels) and highlights the latest advancements in research in its applications for addressing microbial threats in the field of biomedicine. Furthermore, the usage of smart materials is classified based on their application domains, encompassing medical implants, waste reduction, and nano-engineered systems.

IgG4-Related Kidney Disease: A Diagnostic Conundrum Successfully Treated With Steroids and Rituximab.

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that has been recognized as a unified systemic disease that links many individual organ conditions that were previously considered to be unrelated. The pathological hallmark of the disease is an abundant IgG4-positive plasma cell infiltration in the affected tissues and fibrosis. It is a great mimicker of neoplastic, inflammatory, and infectious conditions. We report a 72-year-old man who presented to our hospital with dyspnea and oliguria. Detailed evaluation revealed that he was treated at multiple places for right-sided loin pain over the past 10 months and was found to have right-sided hydronephrosis, renal dysfunction, and multiple enlarged lymph nodes. A search for underlying malignancy previously was unyielding and he had rapid worsening of renal function prior to the current presentation. He was uremic and was initiated on hemodialysis. Kidney biopsy revealed features of IgG4-related tubulointerstitial nephritis. Despite tubular atrophy and interstitial fibrosis involving more than 50% of the sampled cortex, he showed a good response to steroids and rituximab (RTX) and became dialysis-independent. This report underscores the masquerading presentation of IgG4-RD which can hinder timely diagnosis and demonstrates the usefulness of a regimen of steroids and RTX in its treatment.

Comprehensive Review on Herbal Medicine: Emphasis on Current Therapy and Role of Phytoconstituents for Cancer Treatment.

INTRODUCTION: Cancer poses a significant public health challenge in both developed and developing nations, with a rising global incidence of patients facing the threat of death due to abnormal cell proliferation. AIM: Review explores the utilization of different parts of herbal medicinal plants and their active pharmaceutical constituents in the prevention and treatment of various types of cancer. METHODOLOGY: Various anticancer medicinal plants have been identified, demonstrating their therapeutic effects by inhibiting cancer-stimulating enzymes and hormones, activating DNA repair processes, boosting the synthesis of protective stimulants, reducing the formation of free radicals, and enhancing individual immunity. Data for this study were gathered from diverse online bibliographic and databases, including Google, Google Scholar, Mendeley, Springer Link, Research Gate, and PubMed. RESULT: Herbal drugs have a huge contribution to the inhibition of the progression of cancer.A large volume of clinical studies has reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL) of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. CONCLUSION: The latest medicines for the clinical purpose (Above 50 %) are derived from herbal products. Furthermore, combination of these herbs with nanotechnology shows promise in treating specific carcinomas.

Exploring Scientific Validation of Millets in Contemporary Healthcare: A Traditional Food Supplement.

Millets, small-seeded grasses, are gaining interest for their nutrition and health benefits. This abstract provides a comprehensive overview of millets' pharmacological activities, highlighting their rich bioactive compounds. These compounds, including phenolic compounds, flavonoids, and dietary fibers, contribute to antioxidant effects, safeguarding against chronic diseases. Millets also possess anti-inflammatory properties, potentially alleviating conditions, like arthritis and asthma. They show anti-carcinogenic potential, possibly preventing various cancers' development through mechanisms, like apoptosis induction and inhibiting tumor growth. Moreover, millets offer hypolipidemic and hypoglycemic effects, beneficial for managing conditions, such as dyslipidemia and diabetes. Their high dietary fiber and resistant starch content regulate blood lipids and glucose, reducing the cardiovascular risk. Additionally, millets act as antimicrobials, inhibiting pathogens and serving as natural alternatives to synthetic antimicrobials. They exhibit immunomodulatory effects, enhancing immune function and response. Overall, millets' pharmacological properties, including antioxidant, antiinflammatory, anti-carcinogenic, hypolipidemic, hypoglycemic, antimicrobial, and immunomodulatory traits, position them as functional foods with varied health benefits. Further research can integrate millets into preventive and therapeutic approaches for diverse diseases.

Revealing the mechanism of action of a first-in-class covalent inhibitor of KRASG12C (ON) and other functional properties of oncogenic KRAS by 31P NMR.

Individual oncogenic KRAS mutants confer distinct differences in biochemical properties and signaling for reasons that are not well understood. KRAS activity is closely coupled to protein dynamics and is regulated through two interconverting conformations: state 1 (inactive, effector binding deficient) and state 2 (active, effector binding enabled). Here, we use 31P NMR to delineate the differences in state 1 and state 2 populations present in WT and common KRAS oncogenic mutants (G12C, G12D, G12V, G13D, and Q61L) bound to its natural substrate GTP or a commonly used nonhydrolyzable analog GppNHp (guanosine-5'-[(ß,γ)-imido] triphosphate). Our results show that GppNHp-bound proteins exhibit significant state 1 population, whereas GTP-bound KRAS is primarily (90% or more) in state 2 conformation. This observation suggests that the predominance of state 1 shown here and in other studies is related to GppNHp and is most likely nonexistent in cells. We characterize the impact of this differential conformational equilibrium of oncogenic KRAS on RAF1 kinase effector RAS-binding domain and intrinsic hydrolysis. Through a KRAS G12C drug discovery, we have identified a novel small-molecule inhibitor, BBO-8956, which is effective against both GDP- and GTP-bound KRAS G12C. We show that binding of this inhibitor significantly perturbs state 1-state 2 equilibrium and induces an inactive state 1 conformation in GTP-bound KRAS G12C. In the presence of BBO-8956, RAF1-RAS-binding domain is unable to induce a signaling competent state 2 conformation within the ternary complex, demonstrating the mechanism of action for this novel and active-conformation inhibitor.

Modulation in gene expression and enzyme activity suggested the roles of monodehydroascorbate reductase in development and stress response in bread wheat.

Monodehydroascorbate reductase (MDHAR) is a crucial enzymatic antioxidant of the ascorbate-glutathione pathway involved in reactive oxygen species scavenging. Herein, we identified 15 TaMDHAR genes in bread wheat. Phylogenetic analysis revealed their clustering into three groups, which are also related to the subcellular localization in the peroxisome matrix, peroxisome membrane, and chloroplast. Each TaMDHAR protein consisted of two conserved domains; Pyr_redox and Pyr_redox_2 of the pyridine nucleotide disulfide oxidoreductase family. The occurrence of diverse groups of cis-regulatory elements in the promoter region and their interaction with numerous transcription factors suggest assorted functions of TaMDHARs in growth and development and in light, phytohormones, and stress responses. Expression analysis in various tissues further revealed their importance in vegetative and reproductive development. In addition, the differential gene expression and enhanced enzyme activity during drought, heat, and salt treatments exposed their role in abiotic stress response. Interaction of MDHARs with various antioxidant enzymes and biochemicals related to the ascorbate-glutathione cycle exposed their synchronized functioning. Interaction with auxin indicated the probability of cross-talk between antioxidants and auxin signaling. The miR168a, miR169, miR172 and others interaction with various TaMDHARs further directed their association with developmental processes and stress responses. The current study provides extensive information about the importance of TaMDHARs, moreover, the precise role of each gene needs to be established in future studies.

Multifaceted Neuroprotective Role of Punicalagin: A Review.

Millions of people worldwide are currently afflicted with neurologic conditions like a seizure, depression, stress, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, the precise etiopathology of these diseases is still unknown. Substantial studies are being conducted to discover more treatments against these disorders because many patients do not experience the therapeutic benefits that would be expected from using existing pharmaceutical strategies. Herbal medicines which have been used in traditional medicine for millennia to treat various neurological problems are also being investigated and scientifically assessed. Punicalagin is a known polyphenol that has significant antioxidant, anti-inflammatory, anti-viral, anti-proliferative, and anti-cancer properties. Around the world, traditional use of herbal drugs is gaining wider acceptance as a part of complementary and alternative medicine. The scientific community should pay attention to these many neuroprotective pharmacodynamic activities of Punicalagin to create effective pharmacotherapeutic plans, as evidenced by mounting data in pre-clinical research investigations. The current review describes the recent studies on the pharmacological effects of Punicalagin in a variety of neurological illnesses and paves the way for further study in this field.

Scientific and Regulatory Policy Committee Technical Review: Biology and Pathology of Ganglia in Animal Species Used for Nonclinical Safety Testing.

Dorsal root ganglia (DRG), trigeminal ganglia (TG), other sensory ganglia, and autonomic ganglia may be injured by some test article classes, including anti-neoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, nerve growth factor inhibitors, and aminoglycoside antibiotics. This article reviews ganglion anatomy, cytology, and pathology (emphasizing sensory ganglia) among common nonclinical species used in assessing product safety for such test articles (TAs). Principal histopathologic findings associated with sensory ganglion injury include neuron degeneration, necrosis, and/or loss; increased satellite glial cell and/or Schwann cell numbers; and leukocyte infiltration and/or inflammation. Secondary nerve fiber degeneration and/or glial reactions may occur in nerves, dorsal spinal nerve roots, spinal cord (dorsal and occasionally lateral funiculi), and sometimes the brainstem. Ganglion findings related to TA administration may result from TA exposure and/or trauma related to direct TA delivery into the central nervous system or ganglia. In some cases, TA-related effects may need to be differentiated from a spectrum of artifactual and/or spontaneous background changes.

PepCNN deep learning tool for predicting peptide binding residues in proteins using sequence, structural, and language model features.

Protein-peptide interactions play a crucial role in various cellular processes and are implicated in abnormal cellular behaviors leading to diseases such as cancer. Therefore, understanding these interactions is vital for both functional genomics and drug discovery efforts. Despite a significant increase in the availability of protein-peptide complexes, experimental methods for studying these interactions remain laborious, time-consuming, and expensive. Computational methods offer a complementary approach but often fall short in terms of prediction accuracy. To address these challenges, we introduce PepCNN, a deep learning-based prediction model that incorporates structural and sequence-based information from primary protein sequences. By utilizing a combination of half-sphere exposure, position specific scoring matrices from multiple-sequence alignment tool, and embedding from a pre-trained protein language model, PepCNN outperforms state-of-the-art methods in terms of specificity, precision, and AUC. The PepCNN software and datasets are publicly available at https://github.com/abelavit/PepCNN.git .

The Role of Ultrasound in Cancer and Cancer-Related Pain-A Bibliometric Analysis and Future Perspectives.

Ultrasound has a deep penetrating ability with minimal or no tissue injury, while cancer-mediated complications during diagnosis, therapy, and surgery have become a serious challenge for clinicians and lead to the severity of the primary condition (cancer). The current study highlights the importance of ultrasound imaging and focused ultrasound therapy during cancer diagnosis, pain reduction, guidance for surgical resection of cancer, and the effectiveness of chemotherapy. We performed the bibliometric analysis on research domains involving ultrasound, cancer management, pain, and other challenges (chemotherapy, surgical guidance, and postoperative care), to observe the trend by which the research field has grown over the years and propose a possible future trend. The data was obtained from the Web of Science, processed, and exported as plain text files for analysis in the Bibliometrix R web interface using the Biblioshiny package. A total of 3248 documents were identified from 1100 journal sources. A total of 390 articles were published in 2022, with almost a 100% growth rate from previous years. Based on the various network analysis, we conclude that the outcome of the constant research in this domain will result in better patient care during the management of various diseases, including cancer and other co-morbidities.

Scientific and Regulatory Policy Committee Points to Consider: Sampling, Processing, Evaluation, Interpretation, and Reporting of Test Article-Related Ganglion Pathology for Nonclinical Toxicity Studies.

Certain biopharmaceutical products consistently affect dorsal root ganglia, trigeminal ganglia, and/or autonomic ganglia. Product classes targeting ganglia include antineoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, and anti-nerve growth factor agents. This article outlines "points to consider" for sample collection, processing, evaluation, interpretation, and reporting of ganglion findings; these points are consistent with published best practices for peripheral nervous system evaluation in nonclinical toxicity studies. Ganglion findings often occur as a combination of neuronal injury (e.g., degeneration, necrosis, and/or loss) and/or glial effects (e.g., increased satellite glial cell cellularity) with leukocyte accumulation (e.g., mononuclear cell infiltration or inflammation). Nerve fiber degeneration and/or glial reactions may be seen in nerves, dorsal spinal nerve roots, spinal cord, and occasionally brainstem. Interpretation of test article (TA)-associated effects may be confounded by incidental background changes or experimental procedure-related changes and limited historical control data. Reports should describe findings at these sites, any TA relationship, and the criteria used for assigning severity grades. Contextualizing adversity of ganglia findings can require a weight-of-evidence approach because morphologic changes of variable severity occur in ganglia but often are not accompanied by observable overt in-life functional alterations detectable by conventional behavioral and neurological testing techniques.

Post COVID-19 AA amyloidosis of the kidneys with rapidly progressive renal failure.

Coronavirus disease 2019 (COVID-19) pandemic has taken the world by a storm, posing a gruelling challenge to the medical fraternity globally. Besides its very high infectivityinfectivity, significant organ dysfunction occurs in critically ill COVID-19 patients, leading to severe morbidity and mortality. Pulmonary involvement is the leading cause of death in these patients to be followed by the cardiovascular involvement. Kidney involvement due to COVID-19 is becoming more discernible with AKI adversely affecting the outcome. Besides AKI, a few cases of collapsing FSGS in genetically vulnerable patients and thrombotic microangiopathies have been reported as well. We report a case of AA amyloidosis of the kidney with a rapidly progressive renal failure and congestive heart failure with preserved left ventricular functions, which complicated a moderate COVID-19 pneumonia providing some clues to a possible association of this novel virus disease with this complication, which needs to be confirmed in future studies.

Expression of TaNCL2-A ameliorates cadmium toxicity by increasing calcium and enzymatic antioxidants activities in arabidopsis.

Cadmium (Cd) is a heavy metal that occurs naturally in the environment and is toxic to both animals and plants. The impact of Cd toxicity is shown to be reduced by the exogenous application of calcium (Ca) in crop plants. The sodium/calcium exchanger-like (NCL) protein is involved in Ca enrichment in the cytoplasm by transporting it from the vacuole in the exchange of cytosolic sodium (Na). However, it has not been utilized to ameliorate the Cd toxicity, to date. An elevated expression of TaNCL2-A gene in the root and shoot tissues of bread wheat seedlings, and a higher growth rate of recombinant yeast cells, suggested its role in Cd stress response. The TaNCL2-A expressing transgenic Arabidopsis lines exhibited significant Cd tolerance with increased Ca (∼10-fold) accumulation. The proline content and antioxidant enzymes activities were increased while oxidative stress-related molecules such as H2O2 and MDA were reduced in the transgenic lines. In addition, the growth and yield parameters of transgenic lines such as seed germination rate, root length, leaf biomass, leaf area index, rosette diameter, leaf length and width, and silique count, along with various physiological indicators like chlorophyll, carotenoid, and relative water contents were also improved in comparison to the control plants. Further, the transgenic lines exhibited significant salinity and osmotic stress tolerance, as well. Taken together, these results suggested that the TaNCL2-A could mitigate Cd toxicity along with salinity and osmotic stress. This gene may also be utilized for phytoremediation and Cd sequestration in future studies.

Membranous Nephropathy in Syphilis is Associated with Neuron-Derived Neurotrophic Factor.

SIGNIFICANCE STATEMENT: Syphilis is a common worldwide sexually transmitted infection. Proteinuria may occur in patients with syphilis. Membranous nephropathy (MN) is the most common cause of proteinuria in syphilis. The target antigen of MN in syphilis is unknown. This study shows that MN in syphilis is associated with a novel target antigen called neuron-derived neurotrophic factor (NDNF). NDNF-associated MN has distinctive clinical and pathologic manifestations and NDNF appears to be the target antigen in syphilis-associated MN. BACKGROUND: Syphilis is a common sexually transmitted infection. Membranous nephropathy (MN) is a common cause of proteinuria in syphilis. The target antigen is not known in most cases of syphilis-associated MN. METHODS: We performed laser microdissection of glomeruli and mass spectrometry (MS/MS) in 250 cases (discovery cohort) of phospholipase A2 receptor-negative MN to identify novel target antigens. This was followed by immunohistochemistry/confocal microscopy to localize the target antigen along the glomerular basement membrane (GBM). Western blot analyses using IgG eluted from frozen biopsy tissue were performed to detect binding to target antigen. RESULTS: MS/MS studies of the discovery cohort revealed high total spectral counts of a novel protein, neuron-derived neurotrophic factor (NDNF), in three patients: one each with syphilis and hepatitis B, HIV (syphilis status not known), and lung tumor. Next, MS/MS studies of five cases of syphilis-MN (validation cohort) confirmed high total spectral counts of NDNF (average 45±20.4) in all (100%) cases. MS/MS of 14 cases of hepatitis B were negative for NDNF. All eight cases of NDNF-associated MN were negative for known MN antigens. Electron microscopy showed stage I MN in all cases, with superficial and hump-like deposits without GBM reaction. IgG1 was the dominant IgG subtype on MS/MS and immunofluorescence microscopy. Immunohistochemistry/confocal microscopy showed granular staining and colocalization of NDNF and IgG along GBM. Western blot analyses using eluate IgG of NDNF-MN showed binding to both nonreduced and reduced NDNF, while IgG eluate from phospholipase A2 receptor-MN showed no binding. CONCLUSION: NDNF is a novel antigenic target in syphilis-associated MN.

DeepInsight-3D architecture for anti-cancer drug response prediction with deep-learning on multi-omics.

Modern oncology offers a wide range of treatments and therefore choosing the best option for particular patient is very important for optimal outcome. Multi-omics profiling in combination with AI-based predictive models have great potential for streamlining these treatment decisions. However, these encouraging developments continue to be hampered by very high dimensionality of the datasets in combination with insufficiently large numbers of annotated samples. Here we proposed a novel deep learning-based method to predict patient-specific anticancer drug response from three types of multi-omics data. The proposed DeepInsight-3D approach relies on structured data-to-image conversion that then allows use of convolutional neural networks, which are particularly robust to high dimensionality of the inputs while retaining capabilities to model highly complex relationships between variables. Of particular note, we demonstrate that in this formalism additional channels of an image can be effectively used to accommodate data from different omics layers while implicitly encoding the connection between them. DeepInsight-3D was able to outperform other state-of-the-art methods applied to this task. The proposed improvements can facilitate the development of better personalized treatment strategies for different cancers in the future.