Exploring the Future of Polyhydroxyalkanoate Composites with Organic Fillers: A Review of Challenges and Opportunities.

Biopolymers from renewable materials are promising alternatives to the traditional petroleum-based plastics used today, although they face limitations in terms of performance and processability. Natural fillers have been identified as a strategic route to create sustainable composites, and natural fillers in the form of waste by-products have received particular attention. Consequently, the primary focus of this article is to offer a broad overview of recent breakthroughs in environmentally friendly Polhydroxyalkanoate (PHA) polymers and their composites. PHAs are aliphatic polyesters obtained by bacterial fermentation of sugars and fatty acids and are considered to play a key role in addressing sustainability challenges to replace traditional plastics in various industrial sectors. Moreover, the article examines the potential of biodegradable polymers and polymer composites, with a specific emphasis on natural composite materials, current trends, and future market prospects. Increased environmental concerns are driving discussions on the importance of integrating biodegradable materials with natural fillers in our daily use, emphasizing the need for clear frameworks and economic incentives to support the use of these materials. Finally, it highlights the indispensable need for ongoing research and development efforts to address environmental challenges in the polymer sector, reflecting a growing interest in sustainable materials across all industries.

An UltraMNIST classification benchmark to train CNNs for very large images.

Current convolutional neural networks (CNNs) are not designed for large scientific images with rich multi-scale features, such as in satellite and microscopy domain. A new phase of development of CNNs especially designed for large images is awaited. However, application-independent high-quality and challenging datasets needed for such development are still missing. We present the 'UltraMNIST dataset' and associated benchmarks for this new research problem of 'training CNNs for large images'. The dataset is simple, representative of wide-ranging challenges in scientific data, and easily customizable for different levels of complexity, smallest and largest features, and sizes of images. Two variants of the problem are discussed: standard version that facilitates the development of novel CNN methods for effective use of the best available GPU resources and the budget-aware version to promote the development of methods that work under constrained GPU memory. Several baselines are presented and the effect of reduced resolution is studied. The presented benchmark dataset and baselines will hopefully trigger the development of new CNN methods for large scientific images.

Deep Learning Approaches for Medical Image Analysis and Diagnosis.

In addition to enhancing diagnostic accuracy, deep learning techniques offer the potential to streamline workflows, reduce interpretation time, and ultimately improve patient outcomes. The scalability and adaptability of deep learning algorithms enable their deployment across diverse clinical settings, ranging from radiology departments to point-of-care facilities. Furthermore, ongoing research efforts focus on addressing the challenges of data heterogeneity, model interpretability, and regulatory compliance, paving the way for seamless integration of deep learning solutions into routine clinical practice. As the field continues to evolve, collaborations between clinicians, data scientists, and industry stakeholders will be paramount in harnessing the full potential of deep learning for advancing medical image analysis and diagnosis. Furthermore, the integration of deep learning algorithms with other technologies, including natural language processing and computer vision, may foster multimodal medical data analysis and clinical decision support systems to improve patient care. The future of deep learning in medical image analysis and diagnosis is promising. With each success and advancement, this technology is getting closer to being leveraged for medical purposes. Beyond medical image analysis, patient care pathways like multimodal imaging, imaging genomics, and intelligent operating rooms or intensive care units can benefit from deep learning models.

Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.

Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory "folded" conformation, due to intrinsic sequence effects. Here we investigated the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a novel thermodynamic cycle involving many (n=108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation "DFG-out Activation Loop Folded", is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modes in trans and additional modes of regulation in cis for TKs.

Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.

Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches - tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory "folded" conformation, due to intrinsic sequence effects. Here we investigated the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a novel thermodynamic cycle involving many (n=108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation "DFG-out Activation Loop Folded", is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modes in trans and additional modes of regulation in cis for TKs.

Potts Hamiltonian Models and Molecular Dynamics Free Energy Simulations for Predicting the Impact of Mutations on Protein Kinase Stability.

Single-point mutations in kinase proteins can affect their stability and fitness, and computational analysis of these effects can provide insights into the relationships among protein sequence, structure, and function for this enzyme family. To assess the impact of mutations on protein stability, we used a sequence-based Potts Hamiltonian model trained on a kinase family multiple-sequence alignment (MSA) to calculate the statistical energy (fitness) effects of mutations and compared these against relative folding free energies (ΔΔGs) calculated from all-atom molecular dynamics free energy perturbation (FEP) simulations in explicit solvent. The fitness effects of mutations in the Potts model (ΔEs) showed good agreement with experimental thermostability data (Pearson r = 0.68), similar to the correlation we observed with ΔΔGs predicted from structure-based relative FEP simulations. Recognizing the possible advantages of using Potts models to rapidly estimate protein stability effects of kinase mutations seen in cancer genomics data, we used the Potts statistical energy model to estimate the stability effects of 65 conservative and nonconservative mutations across three distinct kinases (Wee1, Abl1, and Cdc7) with somatic mutations reported in the Genomic Data Commons (GDC) database. The ΔEs of these mutations calculated from the Potts model are consistent with the corresponding ΔΔGs from FEP simulations (Pearson ratio of 0.72). The agreement between these methods suggests that the Potts model may be used as a sequence-based tool for high-throughput screening of mutational effects as part of a computational pipeline for predicting the stability effects of mutations. We also demonstrate how the scalability of the fitness-based Potts model calculations permits analyses that are not easily accessed using FEP simulations. To this end, we employed site-saturation mutagenesis in the Potts model in order to investigate the relative stability effects of mutations seen in different cancer evolutionary scenarios. We used this approach to analyze the effects of drug pressure in Abl kinase by contrasting the relative fitness penalties of somatic mutations seen in miscellaneous cancer types with those calculated for mutations associated with cancer drug resistance. We observed that, in contrast to somatic mutations of Abl seen in various tumors that appear to have evolved neutrally, cancer mutations that evolved under drug pressure in Abl-targeted therapies tend to preserve enzyme stability.

Tuning Caco-2 permeability by cocrystallization: Insights from molecular dynamics simulation.

Emerging evidence suggests that intestinal permeability can be potentially enhanced through cocrystallization. However, a mechanism for this effect remains to be established. In this study, we first demonstrate the enhancement in intestinal permeability, evaluated by the Caco-2 cell permeability assay, of acetazolamide (ACZ) in the presence of a conformer, p-aminobenzoic acid (PABA), delivered in the form of a 1:1 cocrystal. The binding strength of ACZ and PABA with the Pgp efflux transporter, either alone or as a mixture, was calculated using molecular dynamics simulation. Results show that PABA weakens the binding of ACZ with Pgp, which leads to a lower efflux ratio and elevated permeability of ACZ. This work provides molecular-level insights into a potentially effective strategy to improve the intestinal permeability of drugs. If the same cocrystal also exhibits higher solubility, oral bioavailability of BCS IV drugs can likely be improved by forming a cocrystal with a Pgp inhibitor.

SELEX based aptamers with diagnostic and entry inhibitor therapeutic potential for SARS-CoV-2.

Frequent mutation and variable immunological protection against vaccination is a common feature for COVID-19 pandemic. Early detection and confinement remain key to controlling further spread of infection. In response, we have developed an aptamer-based system that possesses both diagnostic and therapeutic potential towards the virus. A random aptamer library (~ 1017 molecules) was screened using systematic evolution of ligands by exponential enrichment (SELEX) and aptamer R was identified as a potent binder for the SARS-CoV-2 spike receptor binding domain (RBD) using in vitro binding assay. Using a pseudotyped viral entry assay we have shown that aptamer R specifically inhibited the entry of a SARS-CoV-2 pseudotyped virus in HEK293T-ACE2 cells but did not inhibit the entry of a Vesicular Stomatitis Virus (VSV) glycoprotein (G) pseudotyped virus, hence establishing its specificity towards SARS-CoV-2 spike protein. The antiviral potential of aptamers R and J (same central sequence as R but lacking flanked primer regions) was tested and showed 95.4% and 82.5% inhibition, respectively, against the SARS-CoV-2 virus. Finally, intermolecular interactions between the aptamers and the RBD domain were analyzed using in silico docking and molecular dynamics simulations that provided additional insight into the binding and inhibitory action of aptamers R and J.

An Abnormal ECG Finding in a Patient With COVID-19.

This case report presents the electrocardiogram findings of a patient in their 50s with severe COVID-19 pneumonia, hypertension, and diabetes.

Allogenic adipose derived mesenchymal stem cells are effective than antibiotics in treating endometritis.

Endometritis is a uterine inflammatory disease that causes reduced livestock fertility, milk production and lifespan leading to significant economic losses to the dairy industry. Mesenchymal stem cells (MSC) may act as an alternative for inefficacy of antibiotics and rising antibiotic resistance in endometritis. The present study aimed to cure the chronic endometritic buffaloes using allogenic adipose-derived MSCs (AD-MSC). AD-MSCs were isolated from buffalo adipose tissue and characterized by multilineage differentiation as well as MSC-specific markers. The in vivo safety and efficacy were assessed after infusion of AD-MSCs. In safety trial, cells were administered in healthy buffaloes via different routes (IV and IC) followed by examination of clinical and hematological parameters. In efficacy study, AD-MSCs treatments (IV and IC) and antibiotic therapy (ABT) in endometritic buffaloes were comparatively evaluated. AD-MSCs did not induced any immunological reaction in treated buffaloes. PMN count, CRP levels and VDS were significantly (p ≤ 0.05) reduced after AD-MSCs infusions in IV and IC groups and no significant difference was observed in antibiotic group. The IV group was marked with 50% absolute risk reduction in endometritis and 50% live calf births after artificial insemination in comparison with ABT group. Anti-inflammatory cytokines (IL4 and IL10) and anti-microbial peptides (PI3, CATHL4, LCN2 and CST3) expressions were significantly (p ≤ 0.05) upregulated in IV group. The calf delivery rate after the treatments in IV group was higher (50%, 3 calves) than the other groups (IC: 33.3%, 2 calves; ABT: 16.6%, 1 calf). In conclusion, the administration of AD-MSCs through IV route was found to be safe and efficacious for alleviating chronic endometritis in dairy buffaloes.

Coronary Stent Infections - A Systematic Review and Meta-Analysis.

BACKGROUND: Coronary stent infection (CSI) represents a rare but potentially fatal complication of percutaneous coronary interventions (PCI). A systematic review and meta-analysis of published reports was performed to profile CSI and its management strategies. METHODS: Online database searches were performed using MeSH and keywords. The primary outcome of the study was in-hospital mortality. A unique Artificial Intelligence-based predictive model was developed for need for delayed surgery and probability of survival on medical therapy alone. RESULTS: A total of 79 subjects were included in the study. Twenty eight (35.0 %) patients had type 2 diabetes mellitus. Subjects most commonly reported symptoms within the first week of the procedure (43 %). Fever was the most common initial symptom (72 %). Thirty eight percent of patients presented with acute coronary syndrome. The presence of mycotic aneurysms was described in 62 % of patients. Staphylococcus species were the most common (65 %) isolated organism. The primary outcome of in-hospital mortality was seen in a total of 24 patients out of 79 (30.3 %). A comparative univariate analysis comparing those encountering in-hospital mortality versus otherwise revealed the presence of structural heart disease (83 % mortality vs 17 % survival, p = 0.009), and the presence of non ST elevation acute coronary syndrome (11 % mortality vs 88 % survival, p = 0.03), to be a statistically significant factor predicting in-hospital mortality. In an analysis between patients with successful versus failed initial medical therapy, patients from private teaching hospitals (80.0 % vs 20.0 %; p = 0.01, n = 10) had a higher survival with medical therapy alone. CONCLUSION: CSI is a highly under-studied disease entity with largely unknown risk factors and clinical outcomes. Larger studies are needed to further define the characteristics of CSI. (PROSPERO ID CRD42021216031).

Septic arthritis by Nocardia farcinica: Case report and literature review.

Nocardiosis is a bacterial infection caused by organisms of the Nocardia genus. The disease typically involves the skin, central nervous system or pulmonary system. Very rarely nocardiosis can cause disease of other organs including bone and joints. Nocardiosis is typically a chronic, somewhat indolent infection, occurring in patients with defective cell mediated immunity. We describe a 78-year-old female with right shoulder septic arthritis resulting from Nocardia farcinica with associated involvement of her skin and lungs as well. She was treated with surgical debridement and combination antibiotic therapy. We also share a literature review of bone and joint infection caused by the N. farcinica species, highlighting its rarity. Understanding uncommon manifestations of nocardiosis allows for early recognition and treatment of the condition and optimal patient care.

Evolutionary divergence in the conformational landscapes of tyrosine vs serine/threonine kinases.

Inactive conformations of protein kinase catalytic domains where the DFG motif has a "DFG-out" orientation and the activation loop is folded present a druggable binding pocket that is targeted by FDA-approved 'type-II inhibitors' in the treatment of cancers. Tyrosine kinases (TKs) typically show strong binding affinity with a wide spectrum of type-II inhibitors while serine/threonine kinases (STKs) usually bind more weakly which we suggest here is due to differences in the folded to extended conformational equilibrium of the activation loop between TKs vs. STKs. To investigate this, we use sequence covariation analysis with a Potts Hamiltonian statistical energy model to guide absolute binding free-energy molecular dynamics simulations of 74 protein-ligand complexes. Using the calculated binding free energies together with experimental values, we estimated free-energy costs for the large-scale (~17-20 Å) conformational change of the activation loop by an indirect approach, circumventing the very challenging problem of simulating the conformational change directly. We also used the Potts statistical potential to thread large sequence ensembles over active and inactive kinase states. The structure-based and sequence-based analyses are consistent; together they suggest TKs evolved to have free-energy penalties for the classical 'folded activation loop' DFG-out conformation relative to the active conformation, that is, on average, 4-6 kcal/mol smaller than the corresponding values for STKs. Potts statistical energy analysis suggests a molecular basis for this observation, wherein the activation loops of TKs are more weakly 'anchored' against the catalytic loop motif in the active conformation and form more stable substrate-mimicking interactions in the inactive conformation. These results provide insights into the molecular basis for the divergent functional properties of TKs and STKs, and have pharmacological implications for the target selectivity of type-II inhibitors.

Stage specific gene expression of folate mediated one-carbon metabolism enzymes and transporters in buffalo oocytes and pre-implantation embryos.

DNA synthesis and methylations are crucial during pre-implantation embryonic development, and are mediated by one-carbon metabolism of folates. Folates, transported into the cells via folate receptors (FOLR1 and FOLR2) and carriers (SLC19A1), are metabolized by various enzymes involved in folate-methionine cycle. However, the variations in temporal expression of folate transporters and folate-methionine cycle enzymes during pre-implantation embryo development is obscure. Thus, the present study aimed to investigate the differential expression of the genes for folate transporters and folate-methionine cycle enzymes. We also examined the expression of folate transport proteins in different pre-implantation development stages. Immature buffalo oocytes were matured in maturation medium followed by in vitro fertilization and culture at standard culture conditions. The temporal pattern of gene expression in buffalo, when compared to previous studies, indicated an inter-specific variation. The transcripts of some enzymes and folate transporters were significantly upregulated after zygotic genome activation. The transcripts as well as proteins for FOLR1, FOLR2 and SLC19A1 were present in oocytes and all the pre-implantation embryo stages. FOLR1 was present in the nuclei of different stages of developing embryos but not in the metaphase (MII) oocytes. As a result, the present study advocates the existence of active folate transport in buffalo oocytes and pre-implantation embryos. The data provided by the analysis of differential gene expression of folate transporters and metabolic enzymes would likely contribute to a better understanding of the role of folates in embryo development as well as advancements in assisted reproductive technologies.

Unravelling the role of hemp straw derived cellulose in CMC/PVA hydrogel for sustained release of fluoroquinolone antibiotic.

Cellulose fibres derived from hemp stalks, a prevalent biowaste in Northern India, were effectively converted into carboxymethyl cellulose (HS-CMC). Novel environmentally benign hydrogels were synthesized from HS-CMC and polyvinyl alcohol (PVA) using citric acid, a green crosslinker employing freeze-drying method. The HS-CMC/PVA hydrogels were successfully used for sustained release of fluoroquinolone antibiotic, norfloxacin. The hydrogels were characterized using FTIR, XRD, FE-SEM, EDS and thermal stability and evaluated for their carbonyl content, swelling ratio, in-vitro drug release behaviour and bactericidal properties. Successful isolation of cellulose from hemp stalks and its conversion into hydrogel with the presence of ester and carbonyl linkages was confirmed by FTIR. Thermal stability was impaired when cellulose fibres were converted into HS-CMC via carboxymethylation, as the crystalline structure was utterly disrupted. For the hydrogel, the equilibrium swelling ratios at pH -1.2 and 7.4 were assessed as 378.4 % and 538.7 %, respectively, higher than reported CMC hydrogels. The norfloxacin (NFX) encapsulated hydrogels exhibited good bactericidal properties with zone of inhibition of 19.2 ± 0.3 mm against E. coli and 16.4 ± 0.4 mm against S. aureus. The in-vitro release of NFX at pH 1.2 was 91 %, higher than pH 7.4 at 82 % with strong adherence to Higuchi kinetics model signifying that the release of NFX is via dissolution and diffusion. The release kinetics at different pH revealed Fickian behaviour establishing the potential of HS-CMC hydrogel for sustained release of norfloxacin.

Hesitancy and reactogenicity to mRNA-based COVID-19 vaccines-Early experience with vaccine rollout in a multi-site healthcare system.

BACKGROUND: Hesitancy and incomplete vaccination against coronavirus disease 2019 (COVID-19) remains an obstacle to achieving herd immunity. Because of fear of vaccine reactions, patients with medical and allergic co-morbidities express heightened hesitancy. Limited information is available to guide these patients. We sought to identify factors associated with mRNA-based COVID-19 vaccines hesitancy and reactogenicity. METHODS: We surveyed employees of a multi-site health system in central Pennsylvania who were offered the COVID-19 vaccine (N = 18,740) inquiring about their experience with the Moderna and Pfizer-BioNTech mRNA-based vaccines. The survey was administered online using the REDCap platform. We used multivariable regression analysis to determine whether a particular factor(s) (e.g., demographics, selected co-morbid allergic and medical conditions, vaccine brand, and prior COVID-19) were associated with vaccine reactogenicity including the occurrence and severity of local and systemic reactions. We also explored factors and reasons associated with vaccine hesitancy. RESULTS: Of the 5709 who completed the survey (response rate, 30.4%), 369 (6.5%) did not receive the vaccine. Black race and allergy to other vaccines were associated with vaccine hesitancy. Reaction intensity following the first vaccine dose and allergic co-morbidities were associated with incomplete vaccination. Older individuals (>60 years) experienced less reactogenicity. Females had higher odds of local and systemic reactions and reported more severe reactions. Asians reported more severe reactions. As compared to Pfizer-BioNTech, the Moderna vaccine was associated with higher odds of vaccine reactions of higher severity. Prior COVID-19 resulted in more severe reactions following the first dose, but less severe reactions following the second dose. CONCLUSIONS: Targeted campaigns to enhance vaccination acceptance should focus on Black individuals, females, and those with allergic co-morbidities. Prior COVID-19 caused more severe reactions after the first but not the second vaccine dose. Moderna vaccine caused more vaccine reactions. Lessons learned from the early rollout of COVID-19 vaccine may serve to inform future novel vaccine experiences.

Statin and aspirin as adjuvant therapy in hospitalised patients with SARS-CoV-2 infection: a randomised clinical trial (RESIST trial).

BACKGROUND: Statins and aspirin have been proposed for treatment of COVID-19 because of their anti-inflammatory and anti-thrombotic properties. Several observational studies have shown favourable results. There is a need for a randomised controlled trial. METHODS: In this single-center, open-label, randomised controlled trial, 900 RT-PCR positive COVID-19 patients requiring hospitalisation, were randomly assigned to receive either atorvastatin 40 mg (Group A, n = 224), aspirin 75 mg (Group B, n = 225), or both (Group C, n = 225) in addition to standard of care for 10 days or until discharge whichever was earlier or only standard of care (Group D, n = 226). The primary outcome variable was clinical deterioration to WHO Ordinal Scale for Clinical Improvement ≥ 6. The secondary outcome was change in serum C-reactive protein, interleukin-6, and troponin I. RESULTS: The primary outcome occurred in 25 (2.8%) patients: 7 (3.2%) in Group A, 3 (1.4%) in Group B, 8 (3.6%) in Group C, and 7 (3.2%) in Group D. There was no difference in primary outcome across the study groups (P = 0.463). Comparison of all patients who received atorvastatin or aspirin with the control group (Group D) also did not show any benefit [Atorvastatin: HR 1.0 (95% CI 0.41-2.46) P = 0.99; Aspirin: HR 0.7 (95% CI 0.27-1.81) P = 0.46]. The secondary outcomes revealed lower serum interleukin-6 levels among patients in Groups B and C. There was no excess of adverse events. CONCLUSIONS: Among patients admitted with mild to moderate COVID-19 infection, additional treatment with aspirin, atorvastatin, or a combination of the two does not prevent clinical deterioration. Trial Registry Number CTRI/2020/07/026791 ( http://ctri.nic.in ; registered on 25/07/2020).

Minimally-Invasive Plate Osteosynthesis for Clavicle Fractures.

Objective To analyze the radiological, clinical, and functional outcomes of clavicle fractures treated with the minimally-invasive plate osteosynthesis (MIPO) technique. Methods From June 2018 to July 2019, 17 cases of clavicular fractures were managed using the MIPO technique under C-arm fluoroscopy. The functional outcomes were assessed using the Constant-Murley score and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. The clinical results of union, the complications, the operative time, the hospital stay, as well as infection, were analyzed. Results The mean follow-up time was of 10.41 ± 1.75 months (range: 8 to 14 months). There were 11 male and 6 female patients, with a mean age of 39.05 ± 10.76 years (range: 22 to 57 years). All fractures united on the mean time of 15.35 ± 3.08 weeks (range: 12 to 20 weeks). The mean operative time was of 98.11 ± 13.83 minutes (range: 70 to 130 minutes), and the mean length of the hospital stay was of 4.7 ± 1.12 days (range: 3 to 7 days). The mean Constant-Murley score was of 74.82 ± 6.36 in 4 th postoperstive month, and of 92.35 ± 5.48 in the 8 th postoperative month, which was statistically significant. The mean DASH score was of 9.94 ± 1.55 in the 4 th postoperative month, and of 5.29 ± 1.85 in the 8 th postoperative month, which was also statistically significant. One patient had superficial skin infection at the site of the incision. Conclusions The MIPO technique is an alternative method for the fixation of clavicle fractures, but it is technically more demanding, and requires well-equipped operating room facilities.