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Coronavirus disease 2019 (COVID-19) produced devastating health and economic impacts worldwide. While progress has been made in vaccine development, effective antiviral treatments remain limited, particularly those targeting the papain-like protease (PLpro) of SARS-CoV-2. PLpro plays a key role in viral replication and immune evasion, making it an attractive yet underexplored target for drug repurposing. In this study, we combined machine learning, molecular dynamics, and molecular docking to identify potential PLpro inhibitors in existing drugs. We performed long-timescale molecular dynamics simulations on PLpro–ligand complexes at two known binding sites, followed by structural clustering to capture representative structures. These were used for molecular docking, including a training set of 127 compounds and a library of 1107 FDA-approved drugs. A random forest model, trained on the docking scores of the representative conformations, yielded 76.4% accuracy via leave-one-out cross-validation. Applying the model to the drug library and filtering results based on prediction confidence and the applicability domain, we identified five drugs as promising candidates for repurposing for COVID-19 treatment. Our findings demonstrate the power of integrating computational modeling with machine learning to accelerate drug repurposing against emerging viral targets.

Forward propulsion during walking is generated by different joints and biomechanical mechanisms depending on environmental and task demands. Although propulsion can be modulated by feedback, it is unclear whether extrinsic and intrinsic feedback generate similar propulsion or promote different joint-level strategies during split-belt walking. The purpose of this study was to investigate strategies used by non-impaired individuals to generate greater propulsion using different feedback to reach targeted levels of propulsion force during split-belt walking. Fifteen young adults walked on a split-belt treadmill with the dominant leg on the fast belt at their comfortable walking speed and the non-dominant leg on the slow belt at half speed. They performed trials with extrinsic via visual feedback of propulsive force (targeting 5 and 10% body weight) and with intrinsic feedback via a backward resistive force at the center of mass (5 and 10% body weight). Primary outcome was propulsion accuracy, measured as average propulsion error relative to target levels. Secondary analyses examined explanatory biomechanical variables related to propulsion generation. Outcomes were analyzed using two-way repeated measures ANOVA with Bonferroni correction. Participants achieved similar target propulsion across feedback types ( = 0.66). However, biomechanical strategies differed. Visual feedback increased trailing limb angle (TLA) at 5% ( = 0.0011) and 10% ( < 0.0001) and increased ankle moment at 5% ( = 0.0005) and 10% ( < 0.0001). In contrast, backward resistive force increased (BRF) hip moment at 5% ( = 0.0018) and 10% ( < 0.0001), and hip power at both 5 and 10% ( < 0.0001). Ankle power did not differ between feedback types at 5% ( = 0.0754) but was greater under BRF at 10% ( < 0.0001). While both feedback types generate similar propulsion to achieve different target levels during split-belt treadmill walking, they engaged distinct biomechanical strategies. Our results indicate that participants increased TLA and ankle moment under visual feedback. However, they increased hip moment and hip power under BRF, with ankle power adjustments depending on the target level. The findings highlight motor abundance in gait and suggest tailoring rehabilitation strategies in populations with impaired propulsion.

The COVID-19 pandemic, driven by the novel coronavirus SARS-CoV-2, has drastically reshaped global health and socioeconomic landscapes. The papain-like protease (PLpro) plays a critical role in viral polyprotein cleavage and immune evasion, making it a prime target for therapeutic intervention. Numerous compounds have been identified as inhibitors of SARS-CoV-2 PLpro, with many characterized through crystallographic studies. To date, over 70 three-dimensional (3D) structures of PLpro complexed ligands have been deposited in the Protein Data Bank, offering valuable insight into ligand-binding features that could aid the discovery and development of effective COVID-19 treatments targeting PLpro. In this study, we reviewed and analyzed these 3D structures, focusing on the key residues involved in ligand interactions. Our analysis revealed that most inhibitors bind to PLpro’s substrate recognition sites S3/S4 and SUb2. While these sites are highly attractive and have been extensively explored, other potential binding regions, such as SUb1 and the Zn(II) domain, are less explored and may hold untapped potential for future COVID-19 drug discovery and development. Our structural analysis provides insights into the molecular features of PLpro that could accelerate the development of novel therapeutics targeting this essential viral enzyme.

The opioid crisis in the United States is a significant public health issue, with a nearly threefold increase in opioid-related fatalities between 1999 and 2014. In response to this crisis, society has made numerous efforts to mitigate its impact. Recent advancements in understanding the structural intricacies of the κ opioid receptor (KOR) have improved our knowledge of how opioids interact with their receptors, triggering downstream signaling pathways that lead to pain relief. This review concentrates on the KOR, offering crucial structural insights into the binding mechanisms of both agonists and antagonists to the receptor. Through comparative analysis of the atomic details of the binding site, distinct interactions specific to agonists and antagonists have been identified. These insights not only enhance our understanding of ligand binding mechanisms but also shed light on potential pathways for developing new opioid analgesics with an improved risk-benefit profile.

Primary urethral carcinomas are rare genitourinary malignancies and squamous cell carcinoma is a less common subtype. Presentation is often non-specific in urethral cancers. A single lytic skeletal metastasis is rare with urethral carcinomas, diagnosis of which is pivotal for prognosis and management necessitating biopsy confirmation. While penile squamous cell carcinomas commonly present as ulcers or ulceroproliferative growths originating from the penile skin or foreskin, an exophytically growing squamous cell carcinoma centred in the corpus spongiosum without any skin ulceration is a rare presentation of urethral malignancy. MRI, being exceptional in delineating the anatomy of penis and urethra, can give a possible solution to the origin of an advanced penile mass, which in our case pointed towards a primary urethral carcinoma. Histological diagnosis of solitary bone metastasis is also imperative as it has a significant prognostic value guiding further management.

Nail lacquers or nail paints may be defined as viscous or semi-liquid preparations that are intended for the decoration of the nails of the fingers and toes. Nail lacquers form the most commonly used the most popular type of manicure preparations. It can help our nails grow longer and stronger. It has become an essential step for many self-care routines. An attempt was made to prepare nail lacquer containing natural antifungal agent obtained from extract of pomegranate (Punica granatum) peel which are employed for the treatment of onychomycosis, a fungal infection of nail. This was expected to improve chemical efficacy and improve patient compliance. The film forming polymer, permeation enhancer and solvent, along with extract was optimized for component release, stability and convenience of application. The formulation was prepared by simple mixing and using magnetic stirrer which was analyzed for nonvolatile content, gloss, smoothness to flow, drying time, viscosity, adhesion, permeation studies and antifungal studies. Among all the formulations of nail lacquer prepared, F5 exhibited good nonvolatile content and zone of inhibition. Pomegranate peel extract nail lacquer can be used irrespective of the sex of patient for the treatment of onychomycosis.

An electrocardiogram (ECG) plays a crucial role in identifying and classifying cardiac arrhythmia. Traditional methods employ handcrafted features, and more recently, deep learning methods use convolution and recursive structures to classify heart signals. Considering the time sequence nature of the ECG signal, a transformer-based model with its high parallelism is proposed to classify ECG arrhythmia. The DistilBERT transformer model, pre-trained for natural language processing tasks, is used in the proposed work. The signals are denoised and then segmented around the R peak and oversampled to get a balanced dataset. The input embedding step is skipped, and only positional encoding is done. The final probabilities are obtained by adding a classification head to the transformer encoder output. The experiments on the MIT-BIH dataset show that the suggested model is excellent in classifying various arrhythmias. The model achieved 99.92% accuracy, 0.99 precision, sensitivity, and F1 score on the augmented dataset with a ROC-AUC score of 0.999.

  Significant progress has been made in the effort to develop a national LF program in Haiti, thanks to the highly motivated staff of the Ministry of Public Health and the Population (MSPP) and partners and critical funding support from the Bill & Melinda Gates Foundation, the United States Agency for International Development (USAID), the Centers for Disease Control and Prevention (CDC), CBM, the Inter-American Development Bank (IDB), the Abbott Foundation, PepsiCo, the Frank Eck Family Foundation, and other private donors. Acknowledgments We thank the dedicated LF teams in Léogâne, Milot, and Port-au-Prince, the committed staff and trainees from all of the partners, the community volunteers around the country, GlaxoSmithKline (GSK) for the generous donation of albendazole, and the Bill & Melinda Gates Foundation, CDC, UND, IMA World Health (IMAWH), Abbott and Abbvie funds, USAID, RTI International, Partners for Philanthropic Change, Frank Eck Family Foundation, Inter-American Development Bank, and PepsiCo Foundation for supporting program development.

Enzymes are biological macromolecules, typically proteins, that efficiently accelerate the rate of chemical reactions. Their remarkable catalytic power plays a vital role in essential processes across all kingdoms of life. Nowadays, computational chemistry methods provide valuable insights into enzymatic functions aiding our understanding of biological processes and providing advancements in fields such as biomedical sciences, biomimetic catalysis, drug design and biotechnology. This dissertation employs multilevel computational chemistry methods to investigate the structure-function relationships and the catalytic mechanisms of two metalloenzymes -Zn(II)-dependent matrix metalloproteinase-1 (MMP-1) and non-heme Fe(II)/2-oxoglutarate (2OG) dependent fat-mass and obesity-associated (FTO) enzyme. Chapter 2 explores the role of catalytic and structural Zn(II) ions in the long-range dynamics and overall stability of the MMP-1•triple-helical peptide (THP) ES complex. The results identified catalytic (CAT) domain residues arginine195 (R195) and methionine217 (M217) as crucial for preserving the integrity of the active site. Additionally, the studies show that both Zn(II) ions are critical to maintain effective communication between the S'10 exosite of the hemopexin (HPX) domain and the S'10 specificity loop (extensive target for drug design) of the CAT domain. Chapter 3 discusses the impact of the removal of THP substrate from MMP-1 ES complex and the effect of in silico replacement of the catalytic Zn(II) ion by Co(II) on the geometry of catalytic site, the overall structure, and dynamics of MMP-1•THP complex. The results highlight that the removal of THP induces slightly increased flexibility in the CAT domain and along with the catalytic Zn(II), influences the stabilizing interactions of the S'1 subsite of MMP-1. Chapter 4 is focused on the catalytic mechanism of MMP-1 catalyzed collagenolysis. Our proposed mechanism involves the participation of an additional water molecule (wat2) in the catalytic site that aids in catalysis. The results reveal that the rate-determining step is the water-mediated nucleophilic attack. Furthermore, the calculations show the consecutive and concerted route for the following hydrogen-bond rearrangement and proton transfer steps. Chapter 5 delineates the catalytic mechanism of FTO with pentanucleotide single-stranded RNA (ssRNA) with N6-methyladenine (m6A) substrate and the effects of clinically relevant mutations Arginine316Glutamine (R316Q) and Serine319Phenylalanine (S319F) on the second-coordination sphere (SCS) interactions, dynamics and different stages of the catalytic cycle. The results reveal the different networks of residues that stabilize the TS of the rate-determining hydrogen atom transfer (HAT) step. Additionally, the mutations R316Q and S319F were identified to influence the interactions of the jelly-roll motif and various loops in FTO and, in particular, the S319F affects the pentanucleotide ssRNA(m6A) binding by FTO. Overall, the results of this dissertation provide advanced insights into the intricate relationship between the enzyme structure and function and contribute to an in-depth understanding of the enzymatic mechanism of MMP-1 and FTO. These insights serve as valuable guidelines in enzyme redesign or selective design of inhibitors.

Internal carotid artery [ICA] dissection is a rare cause of vocal cord palsy. This cause is not always considered in the initial differential diagnosis and such cases often get classed as idiopathic. We report a case of right ICA dissection, where the patient had presented with symptoms of right vocal cord palsy. This was a 52-year-old woman who presented to ENT department with a 3 week history of hoarse voice, sore throat and dysphagia. She was found to have a right vocal cord palsy and oropharyngeal dysphagia. Her neurological examination at the time of assessment was normal except for a mild reduced elevation of right side of her palate. At that time, the aetiology was thought to be idiopathic. Due to an incidental sphenoid wing meningioma on the CT head and neck, she underwent an MRI head, which demonstrated a thrombosed right ICA. Subsequently, her CT images were reconstructed to demonstrate a rat-tail stenosis of the lower right ICA consistent with dissection, for which she was started on clopidogrel. Therefore an internal carotid artery dissection should be considered in a case of ‘idiopathic’ vocal cord palsy, as they may not necessarily be idiopathic.