Biology subjects

Kim, B.

Publications and source records attributed to Kim, B..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Speckle contrast optical spectroscopy improves cuffless blood pressure estimation compared to photoplethysmography

Continuous and non-invasive blood pressure (BP) monitoring has the potential to greatly improve hypertension diagnosis and management, along with enabling valuable personal health monitoring in the population at large. Existing methods rely on cuff-based sphygmomanometers, which are cumbersome and disrupt sleep. Despite extensive research utilizing photoplethysmography (PPG), which is integrated into many consumer wearables, errors in continuous BP estimation are generally considered unacceptable for general use. We developed a high-speed (390 Hz) Speckle Contrast Optical Spectroscopy (SCOS) system to measure the cardiac blood flow waveform simultaneously with the PPG signal at high temporal resolution. The system utilized high speed multiplexed detection of optical speckle patterns on the wrist and finger, enabling the extraction of novel features related to BP. In comparison to PPG alone, SCOS demonstrated a notable 31% improvement (p = 3.45 * 10-7) in systolic BP estimation when integrated into subject-specific machine-learning models. The resulting errors were remarkably low (systolic BP: 0.06+/- 2.88 mmHg, diastolic BP: 0.09 +/-2.14 mmHg) across a wide range of BP variations (range SBP: 89-284 mmHg). Importantly, this improvement was sustained several weeks later within a re-measured cohort, indicating highly robust BP predictions. Looking ahead, the use of SCOS for blood flow measurements holds the potential to substantially enhance BP estimations compared to conventional PPG-based methods.

bioengineering↗

bioRxiv2024

Rapid protein evolution by few-shot learning with a protein language model

Directed evolution of proteins is critical for applications in basic biological research, therapeutics, diagnostics, and sustainability. However, directed evolution methods are labor intensive, cannot efficiently optimize over multiple protein properties, and are often trapped by local maxima. In silico-directed evolution methods incorporating protein language models (PLMs) have the potential to accelerate this engineering process, but current approaches fail to generalize across diverse protein families. We introduce EVOLVEpro, a few-shot active learning framework to rapidly improve protein activity using a combination of PLMs and protein activity predictors, achieving improved activity with as few as four rounds of evolution. EVOLVEpro substantially enhances the efficiency and effectiveness of in silico protein evolution, surpassing current state-of-the-art methods and yielding proteins with up to 100-fold improvement of desired properties. We showcase EVOLVEpro for five proteins across three applications: T7 RNA polymerase for RNA production, a miniature CRISPR nuclease, a prime editor, and an integrase for genome editing, and a monoclonal antibody for epitope binding. These results demonstrate the advantages of few-shot active learning with small amounts of experimental data over zero-shot predictions. EVOLVEpro paves the way for broader applications of AI-guided protein engineering in biology and medicine.

bioengineering↗

bioRxiv2024

3D in-situ characterization reveals the instability-induced auxetic behavior of collagen scaffolds for tissue engineering

Collagen scaffolds seeded with human chondrocytes have shown great potential for cartilage repair and regeneration. However, these porous scaffolds buckle under low compressive forces, creating regions of highly localized deformations that can cause cell death and deteriorate the integrity of the engineered tissue. We perform three-dimensional (3D) tomography-based characterization to track the evolution of collagen scaffolds microstructure under large deformation. The results illustrate how instabilities produce a spatially varying compaction across the specimens, with more pronounced collapse near the free boundaries. We discover that, independent of differences in pore-size distributions, all collagen scaffolds examined displayed strong auxetic behavior i.e., their transverse area contracts under compression, as a result of the instability cascade. This feature, typically characteristic of engineered metamaterials, is of critical importance for the performance of collagen scaffolds in tissue engineering, especially regarding the persistent challenge of lateral integration in cartilage constructs.

bioengineering↗

bioRxiv2024

Identification of 17 novel epigenetic biomarkers associated with anxiety disorders using differential methylation analysis followed by machine learning-based validation

BackgroundThe changes in DNA methylation patterns may reflect both physical and mental well-being, the latter being a relatively unexplored avenue in terms of clinical utility for psychiatric disorders. In this study, our objective was to identify the methylation-based biomarkers for anxiety disorders and subsequently validate their reliability. MethodsA comparative differential methylation analysis was performed on whole blood samples from 94 anxiety disorder patients and 296 control samples using targeted bisulfite sequencing. Subsequent validation of identified biomarkers employed an artificial intelligence- based risk prediction models: a linear calculation-based methylation risk score model and two tree-based machine learning models: Random Forest and XGBoost. Results17 novel epigenetic methylation biomarkers were identified to be associated with anxiety disorders. These biomarkers were predominantly localized near CpG islands, and they were associated with two distinct biological processes: 1) cell apoptosis and mitochondrial dysfunction and 2) the regulation of neurosignaling. We further developed a robust diagnostic risk prediction system to classify anxiety disorders from healthy controls using the 17 biomarkers. Machine learning validation confirmed the robustness of our biomarker set, with XGBoost as the best-performing algorithm, an area under the curve of 0.876. ConclusionOur findings support the potential of blood liquid biopsy in enhancing the clinical utility of anxiety disorder diagnostics. This unique set of epigenetic biomarkers holds the potential for early diagnosis, prediction of treatment efficacy, continuous monitoring, health screening, and the delivery of personalized therapeutic interventions for individuals affected by anxiety disorders.

bioinformatics↗

bioRxiv2024

HIF2α-dependent inhibition of mitochondrial clustering of glutaminase suppresses clear cell renal cell carcinoma

Clear cell renal cell carcinomas (ccRCC) are largely driven by HIF2 and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2 inhibition, recently FDA-approved for treatment of ccRCC, shows great but incomplete benefits, underscoring the need to better understand the roles of glutamine and HIF2 in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria across diverse cell types, but not in ccRCC. GLS1 clustering is rapid (1-3 hours) and reversible, is specifically driven by reduced intracellular glutamate, and is mediated by mitochondrial fission. Clustered GLS1 markedly enhances glutaminase activity and promotes cell death under glutamine-deprived conditions. HIF2 prevents GLS1 clustering, independently of its transcriptional activity, thereby protecting ccRCC cells from cell death induced by glutamine deprivation. Reversing this protection, by genetic expression of GLS1 mutants that constitutively cluster, enhances ccRCC cell death in culture and suppresses ccRCC growth in vivo. These findings provide multiple insights into cellular glutamine handling, including a novel metabolic pathway by which HIF2 promotes ccRCC, and reveals a potential therapeutic avenue to synergize with HIF2 inhibition in the treatment of ccRCC.

cancer biology↗

bioRxiv2024

Control of OPC proliferation and repopulation by the intellectual disability gene PAK1 under homeostatic and demyelinating conditions

Appropriate proliferation and repopulation of oligodendrocyte progenitor cells (OPCs) determine successful (re)myelination in homeostatic and demyelinating brains. Activating mutations in p21-activated kinase 1 (PAK1) cause intellectual disability, neurodevelopmental abnormality, and white matter anomaly in children. It remains unclear if and how PAK1 regulates oligodendroglial development. Here, we report that PAK1 controls proliferation and regeneration of OPCs. Unlike differentiating oligodendrocytes, OPCs display high PAK1 activity which maintains them in a proliferative state by modulating PDGFRa-mediated mitogenic signaling. PAK1-deficient or kinase-inhibited OPCs reduce their proliferation capacity and population expansion. Mice carrying OPC-specific PAK1 deletion or kinase inhibition are populated with fewer OPCs in the homeostatic and demyelinated CNS than control mice. Together, our findings suggest that kinase-activating PAK1 mutations stall OPCs in a progenitor state, impacting timely oligodendroglial differentiation in the CNS of affected children and that PAK1 is a potential molecular target for replenishing OPCs in demyelinating lesions.

neuroscience↗

bioRxiv2024

Conserved DNA Methylation Signatures in The Prefrontal Cortex of Newborn and Juvenile Guinea Pigs Following Antenatal Corticosteroid Exposure

Antenatal corticosteroids (ACS) are provided to improve perinatal survival when there is risk of preterm birth. Though evidence suggests increased risk of developing neurobehavioural disorders in exposed offspring, the mechanisms that mediate this relationship remain largely unknown. Here, we investigated the DNA methylation patterns in the prefrontal cortex (PFC) of exposed offspring. We hypothesized that differential methylation will be evident at both newborn and juvenile ages. Pregnant guinea pigs were administered saline or betamethasone (1mg/kg) on gestational days 50/51 to mimic a single course of ACS. gDNA was isolated from the PFC of term-born offspring on postnatal day 1 (PND1) and PND14 to identify differentially methylated CpG sites (DMCs) using reduced representative bisulfite sequencing. In the PND1 PFC, 1521 DMCs, annotating to 145 genes were identified following ACS. Identified genes were involved in pathways regulating developmental cellular process. In the PND14 PFC, 776 DMCs representing 46 genes were identified, and were enriched in synaptic signalling pathways. Though no individual DMCs were identified at both PND1 and PND14, differential methylation was consistently observed at the binding sites of transcription factors PLAGL1, TFAP2C, ZNF263, and SP1 at both ages. In this study, we identified an altered DNA methylome in the PFC of ACS-exposed guinea pig offspring at both newborn and juvenile ages. Notably, a unique methylation signature was consistently observed at four key transcription factor binding sites at multiple post-natal time points, indicating a persistent change which may predispose the development of altered neurobehavioural phenotypes that have been described in exposed offspring.

developmental biology↗

bioRxiv2024

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1(Y99H/A128T IN) variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. While both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCDY99H/A128T + PIR complex. Consequently, full-length INY99H/A128T was substantially less susceptible to the PIR induced hyper-multimerization than the WT protein, and HIV-1(Y99H/A128T IN) conferred >150- fold resistance to the inhibitor compared to the WT virus. By rationally modifying PIR we have developed its analog EKC110, which readily induced hyper-multimerization of INY99H/A128T in vitro and was [~]14-fold more potent against HIV-1(Y99H/A128T IN) than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use. IMPORTANCEAntiretroviral therapies save the lives of millions of people living with HIV (PLWH). However, evolution of multi-drug-resistant viral phenotypes is a major clinical problem, and there are limited or no treatment options for heavily treatment-experienced PLWH. Allosteric HIV-1 integrase inhibitors (ALLINIs) are a novel class of antiretroviral compounds which work by a unique mechanism of binding to the non-catalytic site on the viral protein and inducing aberrant integrase multimerization. Accordingly, ALLINIs potently inhibit both wild type HIV-1 and all drug-resistant viral phenotypes that have so far emerged against currently used therapies. Pirmitegravir, a highly potent and safe investigational ALLINI, is currently advancing through clinical trials. Here we have elucidated structural and mechanistic bases behind the emergence of HIV-1 integrase mutations in infected cell that confer resistance to pirmitegravir. In turn, our findings allowed us to rationally develop an improved ALLINI with substantially enhanced potency against the pirmitegravir resistant virus.

microbiology↗

bioRxiv2024

Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19

BackgroundCardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19. MethodsRadiotelemetry in conscious animals was used to non-invasively record electrocardiograms and subpleural pressures after intranasal SARS-CoV-2 infection. Cardiac cytokines, interferon-stimulated gene expression, and macrophage infiltration of the CCS, were assessed at 4 days and 4 weeks post-infection. A double-stranded RNA mimetic, polyinosinic:polycytidylic acid (PIC), was used in vivo and in vitro to activate viral pattern recognition receptors in the absence of SARS-CoV-2 infection. ResultsCOVID-19 induced pronounced tachypnea and severe cardiac conduction system (CCS) dysfunction, spanning from bradycardia to persistent atrioventricular block, although no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped after the pulmonary infection was resolved, indicating persistent CCS injury. Increased cardiac cytokines, interferon-stimulated gene expression, and macrophage remodeling in the CCS accompanied the electrophysiological abnormalities. Interestingly, the arrhythmia phenotype was reproduced by cardiac injection of PIC in the absence of virus, indicating that innate immune activation was sufficient to drive the response. PIC also strongly induced cytokine secretion and robust interferon signaling in hearts, human iPSC-derived cardiomyocytes (hiPSC-CMs), and engineered heart tissues, accompanied by alterations in electrical and Ca2+ handling properties. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by in vivo inhibition of JAK/STAT signaling or by a mitochondrially-targeted antioxidant. ConclusionsThe findings indicate that long term dysfunction and immune cell remodeling of the CCS is induced by COVID-19, arising indirectly from oxidative stress and excessive activation of cardiac innate immune responses during infection, with implications for long COVID Syndrome.

pathology↗

bioRxiv2023

Circuit mechanism underlying fragmented sleep and memory deficits in 16p11.2 deletion mouse model of autism

Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further exacerbates sleep disturbances in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings demonstrate that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.

neuroscience↗

bioRxiv2023

A population code for spatial representation in the larval zebrafish telencephalon

The vertebrate telencephalon is the site of complex cognitive processes, such as spatial cognition. The larval zebrafish telencephalon is a compact circuit of only [~]10,000 neurons that contains potentially homologous structures to the mammalian basal ganglia and limbic system (e.g., the hippocampus). However, despite long-standing evidence that spatial navigation and learning in zebrafish requires an intact telencephalon, cells believed to underlie spatial cognition in the mammalian hippocampus (e.g., place cells) have yet to be established in any fish species. Using a tracking microscope to image brain-wide activity at cellular resolution in freely swimming larval zebrafish, we compute the spatial information of neurons throughout the zebrafish brain. Strikingly, in every animal we recorded, cells with the highest spatial specificity are enriched in the zebrafish telencephalon. These cells form a population code of space, from which we can decode the animals spatial location across time. By continuous recording of population-level activity, we find that the activity manifold of place cells gradually untangles over time. Through systematic manipulation of allothetic and idiothetic cues, we demonstrate that place cells in the zebrafish telencephalon integrate multiple sources of information. By analysis of neighborhood distance between cells across environments, we find that the spatial representation in the zebrafish telencephalon partially generalizes across environments, suggesting that preconfigured network states may have been a feature of spatial computation that emerged early in vertebrate evolution.

neuroscience↗

bioRxiv2023

Gene editing of SAMHD1 in macrophage-like cells reveals complex relationships between SAMHD1 phospho-regulation, HIV-1 restriction and cellular dNTP levels

Sterile motif (SAM) and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphate triphosphohydrolase (dNTPase) and a potent restriction factor for immunodeficiency virus 1 (HIV-1), active in myeloid and resting CD4+ T cells. The anti-viral activity of SAMHD1 is regulated by dephosphorylation of the residue T592. However, the impact of T592 phosphorylation on dNTPase activity is still under debate. Whether additional cellular functions of SAMHD1 impact anti-viral restriction is not completely understood. We report BLaER1 cells as a novel human macrophage HIV-1 infection model combined with CRISPR/Cas9 knock-in (KI) introducing specific mutations into the SAMHD1 locus to study mutations in a physiological context. Transdifferentiated BLaER1 cells harbor active dephosphorylated SAMHD1 that blocks HIV-1 reporter virus infection. As expected, homozygous T592E mutation, but not T592A, relieved a block to HIV-1 reverse transcription. Co-delivery of VLP-Vpx to SAMHD1 T592E KI mutant cells did not further enhance HIV-1 infection indicating the absence of an additional SAMHD1-mediated antiviral activity independent of T592 de-phosphorylation. T592E KI cells retained dNTP levels similar to WT cells indicating uncoupling of anti-viral and dNTPase activity of SAMHD1. The integrity of the catalytic site in SAMHD1 was critical for anti-viral activity, yet poor correlation of HIV-1 restriction and global cellular dNTP levels was observed in cells harboring catalytic core mutations. Together, we emphasize the complexity of the relationship between HIV-1 restriction, SAMHD1 enzymatic function and T592 phospho-regulation and provide novel tools for investigation in an endogenous and physiological context. ImportanceWe introduce BLaER1 cells as an alternative myeloid cell model in combination with CRISPR/Cas9-mediated gene editing to study the influence of SAMHD1 T592 Mophosphorylation on anti-viral restriction and the control of cellular dNTP levels in an endogenous, physiological relevant context. Proper understanding of the mechanism of the anti-viral function of SAMHD1 will provide attractive strategies aiming at selectively manipulating SAMHD1 without affecting other cellular functions. Even more, our toolkit may inspire further genetic analysis and investigation of restriction factors inhibiting retroviruses, their cellular function and regulation, leading to a deeper understanding of intrinsic anti-viral immunity.

microbiology↗

bioRxiv2023

Enhanced functionalities of immune cells separated by microfludic lattice: assessment based on holotomography

The isolation of white blood cells (WBCs) from whole blood constitutes a pivotal process for immunological studies, diagnosis of hematologic disorders, and the facilitation of immunotherapy. Despite the ubiquity of density gradient centrifugation in WBC isolation, its influence on WBC functionality remains inadequately understood. This research employs holotomography to explore the effects of two distinct WBC separation techniques, namely conventional centrifugation and microfluidic separation, on the functionality of the isolated cells. We utilize three-dimensional refractive index distribution and time-lapse dynamics to conduct an in-depth analysis of individual WBCs, focusing on their morphology, motility, and phagocytic capabilities. Our observations highlight that centrifugal processes negatively impacts WBC motility and phagocytic capacity, whereas microfluidic separation yields a more favorable outcome in preserving WBC functionality. These findings emphasize the potential of microfluidic separation techniques as a viable alternative to traditional centrifugation for WBC isolation, potentially enabling more precise analyses in immunology research and improving the accuracy of hematologic disorder diagnoses.

biophysics↗

bioRxiv2023

Correlation of two different devices for the evaluation of primary implant stability depending on dental implant length and bone density: an in vitro study

Non-invasive objective implant stability measurements are needed to determine the appropriate timing of prosthetic fitting after implant placement. We compared the early implant stability results obtained using resonance frequency analysis (RFA) and damping capacity analysis (DCA) depending on the implant length and bone density. Total 60, 4.0 mm diameter implants of various lengths (7.3 mm, 10 mm, and 13 mm) were used. Group I and Group II had implants placed in an artificial bone model with a uniform density of 15 PCF (0.24 g/cm3) and 30 PCF (0.48 g/cm3), respectively. RFA was performed using an Osstell(R) Beacon+; DCA was performed using Anycheck(R). Measurements were repeated five times for each implant. Statistical significance was set at P <0.05. In Group I, bone density and primary implant stability were positively correlated, while implant length and primary implant stability were positively correlated. In Group II, the implant stability quotient (ISQ) and implant stability test (IST) values in did not change significantly above a certain length. Primary implant stability was positively correlated with bone density and improved with increasing implant length at low bone densities. Compared with the Osstell(R) Beacon+, the simplicity of Anycheck(R) was easy to use and accessible.

bioengineering↗

bioRxiv2023

Human Intelligence and the Connectome are Driven by Structural Brain Network Control

Research in network neuroscience demonstrates that human intelligence is shaped by the structural brain connectome, which enables a globally coordinated and dynamic architecture for general intelligence. Building on this perspective, the network neuroscience theory proposes that intelligence arises from system-wide network dynamics and the capacity to flexibly transition between network states. According to this view, network flexibility is made possible by network controllers that move the system into specific network states, enabling solutions to familiar problems by accessing nearby, easy-to-reach network states and adapting to novel situations by engaging distant, difficult-to-reach network states. Although this framework predicts that general intelligence depends on network controllability, the specific cortical regions that serve as network controllers and the nature of their control operations remain to be established. We therefore conducted a comprehensive investigation of the relationship between regional measures of network controllability and general intelligence within a sample of 275 healthy young adults using structural and diffusion-weighted MRI data. Our findings revealed significant associations between intelligence and network controllers located within the frontal, temporal and parietal cortex. Furthermore, we discovered that these controllers collectively enable access to both easy- and difficult-to-reach network states, aligning with the predictions made by the network neuroscience framework. Additionally, our research demonstrated that the identified network controllers are primarily localized within the left hemisphere and do not reside within regions or connections that possess the highest capacity for structural control in general. This discovery suggests that the identified regions may facilitate specialized control operations and motivates further exploration of the network topology and dynamics underlying intelligence in the human brain. SummaryThis study examines the relationship between regional measures of network controllability and general intelligence within a sample of 275 healthy young adults using structural and diffusion-weighted MRI data. We report that individual differences in general intelligence are associated average and modal controllability in specific left-hemisphere cortical regions, and further show that controller regions associated with intelligence are distinct from regions with the highest, centrality, controllability, or communication. These findings reveal a significant structural role for individual regions in controlling the trajectory of the connectome, advancing our understanding of the nature and mechanisms of network controllability in general intelligence.

neuroscience↗

bioRxiv2023

In vitro broad-spectrum antiviral activity of MIT-001, a mitochondria-targeted reactive oxygen species scavenger, against severe acute respiratory syndrome coronavirus 2 and multiple zoonotic viruses

The COVID-19 pandemic caused by SARS-CoV-2 becomes a serious threat to global health and requires the development of effective antiviral therapies. Current therapies that target viral proteins have limited efficacy with side effects. In this study, we investigated the antiviral activity of MIT-001, a small molecule reactive oxygen species (ROS) scavenger targeting mitochondria, against SARS-CoV-2 and other zoonotic viruses in vitro. The antiviral activity of MIT-001 was quantified by RT-qPCR and plaque assay. We also evaluated the functional analysis of MIT-001 by JC-1 staining to measure mitochondrial depolarization, total RNA sequencing to investigate gene expression changes, and immunoblot to quantify protein expression levels. The results showed that MIT-001 effectively inhibited the replication of B.1.617.2 and BA.1 strains, Zika virus, Seoul virus, and Vaccinia virus. Treatment with MIT-001 restored the expression of heme oxygenase-1 (HMOX1) and NAD(P)H: quinone oxidoreductase 1 (NqO1) genes, anti-oxidant enzymes reduced by SARS-CoV-2, to normal levels. The presence of MIT-001 also alleviated mitochondrial depolarization caused by SARS-CoV-2 infection. These findings highlight the potential of MIT-001 as a broad-spectrum antiviral compound that targets for zoonotic RNA and DNA viruses, providing a promising therapeutic approach to combat viral infection.

microbiology↗

bioRxiv2023

Identification of Therapeutic Leads from Ficus hispida Fruit Phytochemicals against Prostate Cancer Using Pharmacoinformatic and Molecular Dynamics Simulation Approach

Prostate cancer is one of the leading causes of death and the most common cancer type in men. In this study, potential leads from the phytochemicals of Ficus hispida fruit were screened using in silico tools against androgen receptor (AR), a known target for prostate cancer. PASS online and ADMET tools were used to screen specific phytochemicals that are relevant to prostate cancer treatment and have drug-like properties. Of 13, a total of 10 phytochemicals passed PASS online and ADMET screening. Next, a total of three phytochemicals, including nodakenetin (CID: 26305), isowigtheone hydrate (CID: 66728267), and 7-hydroxycoumarin (CID: 5281426) were selected based on their docking scores (-9.946 to -7.653 kcal/mol) and relevance to selective bioactivity. The MD simulation further confirmed the binding stability of these three phytochemicals with their target AR protein and determined that the main amino acid residues mainly responsible for this stability including RMSD, RMSF, and post simulation binding free energies. These findings suggest that these three phytochemicals of Ficus hispida fruit can further be developed as prospective therapeutics against prostate cancer.

bioinformatics↗

bioRxiv2023

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion.

The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that ATR is dispensable for the viability of G0-arrested naive B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently in early S phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that suppress origin firing, such as downregulation of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.

genetics↗