Identifying Drug Candidates for COVID-19 with Large-Scale Drug Screening.

Papain-like protease (PLpro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PLpro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The three best compounds all had better estimated binding energy than those of the drug candidates proposed in previous studies. By analyzing the docking results for the drug candidates identified in this and previous studies, we demonstrate that the critical interactions between the compounds and PLpro proposed by the computational approaches are consistent with those proposed by the biological experiments. In addition, the predicted binding energies of the compounds in the dataset showed a similar trend as their IC50 values. The predicted ADME and drug-likeness properties also suggested that these identified compounds can be used for COVID-19 treatment.

Research trends of Janus Kinase inhibitors: a bibliometric and visualized study from 2012 to 2023.

OBJECTIVE: Janus Kinase (JAK) inhibitors have been extensively evaluated for their potential in the management of various diseases. Despite previous research on this topic, there is a lack of bibliometric analysis that summarizes research trends on JAK inhibitors. This study aims to provide a comprehensive overview of the top 100 most frequently cited studies on JAK inhibitors over the last ten years. MATERIALS AND METHODS: The Web of Science database was used to screen and extract relevant studies on JAK inhibitors. The top 100 studies most cited within the JAK inhibitor-related research were identified and evaluated, and various data such as the year of publication, study focus and keywords, author information, and number of citations were extracted and analyzed for further examination. RESULTS: In the top 100 most cited studies of JAK inhibitors, more than 70% of studies focused on the role of JAK inhibitors in disease treatments, with 42% of these studies focused on using JAK inhibitors as treatment for autoimmune diseases and 19 of them focused on the treatment of neoplasms. Time trend analysis revealed that the keywords "tofacitinib", "atopic dermatitis", and "rheumatoid arthritis" were widely mentioned in 2016, while new trends emerged in 2018, with "ruxolitinib" and "baricitinib" being more commonly mentioned. CONCLUSIONS: The top 100 most frequently cited studies on JAK inhibitors focused primarily on the safety and efficacy of these inhibitors in the management of various diseases, particularly inflammatory diseases and neoplasms. The results can serve as a valuable reference for rheumatologists and immunologists interested in the development of JAK inhibitors and expanding future research fields.

DeepFlu: a deep learning approach for forecasting symptomatic influenza A infection based on pre-exposure gene expression.

BACKGROUND AND OBJECTIVE: Not everyone gets sick after an exposure to influenza A viruses (IAV). Although KLRD1 has been identified as a potential biomarker for influenza susceptibility, it remains unclear whether forecasting symptomatic flu infection based on pre-exposure host gene expression might be possible. METHOD: To examine this hypothesis, we developed DeepFlu using the state-of-the-art deep learning approach on the human gene expression data infected with IAV subtype H1N1 or H3N2 viruses to forecast who would catch the flu prior to an exposure to IAV. RESULTS: The results indicated that such forecast is possible and, in other words, gene expression could reflect the strength of host immunity. In the leave-one-person-out cross-validation, DeepFlu based on deep neural network outperformed the models using convolutional neural network, random forest, or support vector machine, achieving 70.0% accuracy, 0.787 AUROC, and 0.758 AUPR for H1N1 and 73.8% accuracy, 0.847 AUROC, and 0.901 AUPR for H3N2. In the external validation, DeepFlu also reached 71.4% accuracy, 0.700 AUROC, and 0.723 AUPR for H1N1 and 73.5% accuracy, 0.732 AUROC, and 0.749 AUPR for H3N2, surpassing the KLRD1 biomarker. In addition, DeepFlu which was trained only by pre-exposure data worked the best than by other time spans and mixed training data of H1N1 and H3N2 did not necessarily enhance prediction. DeepFlu is available at https://github.com/ntou-compbio/DeepFlu. CONCLUSIONS: DeepFlu is a prognostic tool that can moderately recognize individuals susceptible to the flu and may help prevent the spread of IAV.

Polyphenols as Potential Inhibitors of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp).

An increasing number of studies have demonstrated the antiviral nature of polyphenols, and many polyphenols have been proposed to inhibit SARS-CoV or SARS-CoV-2. Our previous study revealed the inhibitory mechanisms of polyphenols against DNA polymerase α and HIV reverse transcriptase to show that polyphenols can block DNA elongation by competing with the incoming NTPs. Here we applied computational approaches to examine if some polyphenols can also inhibit RNA polymerase (RdRp) in SARS-CoV-2, and we identified some better candidates than remdesivir, the FDA-approved drug against RdRp, in terms of estimated binding affinities. The proposed compounds will be further examined to develop new treatments for COVID-19.

Polyphenols as alternative treatments of COVID-19.

Although scientists around the world have put lots of effort into the development of new treatments for COVID-19 since the outbreak, no drugs except Veklury (remdesivir) have been approved by FDA. There is an urgent need to discover some alternative antiviral treatment for COVID-19. Because polyphenols have been shown to possess antiviral activities, here we conducted a large-scale virtual screening for more than 400 polyphenols. Several lead compounds such as Petunidin 3-O-(6″-p-coumaroyl-glucoside) were identified to have promising binding affinities and convincing binding mechanisms. Analyzing the docking results and ADME properties sheds light on the potential efficacy of the top-ranked drug candidates and pinpoints the key residues on the target proteins for the future of drug development.

DeepDISE: DNA Binding Site Prediction Using a Deep Learning Method.

It is essential for future research to develop a new, reliable prediction method of DNA binding sites because DNA binding sites on DNA-binding proteins provide critical clues about protein function and drug discovery. However, the current prediction methods of DNA binding sites have relatively poor accuracy. Using 3D coordinates and the atom-type of surface protein atom as the input, we trained and tested a deep learning model to predict how likely a voxel on the protein surface is to be a DNA-binding site. Based on three different evaluation datasets, the results show that our model not only outperforms several previous methods on two commonly used datasets, but also demonstrates its robust performance to be consistent among the three datasets. The visualized prediction outcomes show that the binding sites are also mostly located in correct regions. We successfully built a deep learning model to predict the DNA binding sites on target proteins. It demonstrates that 3D protein structures plus atom-type information on protein surfaces can be used to predict the potential binding sites on a protein. This approach should be further extended to develop the binding sites of other important biological molecules.

Structural and Functional Enrichment Analyses for Antimicrobial Peptides.

Whether there is any inclination between structures and functions of antimicrobial peptides (AMPs) is a mystery yet to be unraveled. AMPs have various structures associated with many different antimicrobial functions, including antibacterial, anticancer, antifungal, antiparasitic and antiviral activities. However, none has yet reported any antimicrobial functional tendency within a specific category of protein/peptide structures nor any structural tendency of a specific antimicrobial function with respect to AMPs. Here, we examine the relationships between structures categorized by three structural classification methods (CATH, SCOP, and TM) and seven antimicrobial functions with respect to AMPs using an enrichment analysis. The results show that antifungal activities of AMPs were tightly related to the two-layer sandwich structure of CATH, the knottin fold of SCOP, and the first structural cluster of TM. The associations with knottin and TM Cluster 1 even sustained through the AMPs with a low sequence identity. Moreover, another significant mutual enrichment was observed between the third cluster of TM and anti-Gram-positive-bacterial/anti-Gram-negative-bacterial activities. The findings of the structure-function inclination further our understanding of AMPs and could help us design or discover new therapeutic potential AMPs.

In silico identification of drug candidates against COVID-19.

The COVID-19 pandemic has caused unprecedented health and economic crisis throughout the world. However, there is no effective medication or therapeutic strategy for treatment of this disease currently. Here, to elucidate the inhibitory effects, we first tested binding affinities of 11 HIV-1 protease inhibitors or their pharmacoenhancers docked onto SARS-CoV-2 main protease (M pro ), and 12 nucleotide-analog inhibitors docked onto RNA dependent RNA polymerase (RdRp). To further obtain the effective drug candidates, we screened 728 approved drugs via virtual screening on SARS-CoV-2 M pro . Our results demonstrate that remdesivir shows the best binding energy on RdRp and saquinvir is the best inhibitor of M pro . Based on the binding energies, we also list 10 top-ranked approved drugs which can be potential inhibitors for M pro . Overall, our results do not only propose drug candidates for further experiments and clinical trials but also pave the way for future lead optimization and drug design.

Qubit Measurement by Multichannel Driving.

We theoretically propose and experimentally implement a method of measuring a qubit by driving it close to the frequency of a dispersively coupled bosonic mode. The separation of the bosonic states corresponding to different qubit states begins essentially immediately at maximum rate, leading to a speedup in the measurement protocol. Also the bosonic mode can be simultaneously driven to optimize measurement speed and fidelity. We experimentally test this measurement protocol using a superconducting qubit coupled to a resonator mode. For a certain measurement time, we observe that the conventional dispersive readout yields close to 100% higher average measurement error than our protocol. Finally, we use an additional resonator drive to leave the resonator state to vacuum if the qubit is in the ground state during the measurement protocol. This suggests that the proposed measurement technique may become useful in unconditionally resetting the resonator to a vacuum state after the measurement pulse.

Depressive Symptoms in Newly Diagnosed Lung Carcinoma: Prevalence and Associated Risk Factors.

BACKGROUND: Depression is a recognized complication of lung cancer underreported in developing countries such as Malaysia. Treating and identifying depression in cancer patients increases survival and quality of life. Our objectives are to study prevalence of depressive symptoms in newly diagnosed lung carcinoma, and examine the relationship of depressive symptoms with other influencing risk factors. METHODS: A 2-year, cross sectional study February 2015-February 2017, was conducted at Hospital Tengku Ampuan Afzan, and Penang General Hospital. One hundred and three patients with newly diagnosed, biopsy confirmed primary lung carcinoma were recruited. Self-rated patient's identification sheet, validated Center for Epidemiologic Studies Depression (CES-D), and Dukes University Religion Index score from three different main languages were used. RESULTS: Prevalence of current depressive symptoms (CES-D total score ≥16) is 37.9%. The result suggests prevalence of those at high risk of moderate to major depression, may need treatment. Multivariate analysis reveals those with good Eastern Cooperation Oncology Group factor (η2=0.24, p<0.001) married (η=0.14, p<0.001) with intrinsic religiosity (IR) (η=0.07, p<0.02) are more resistant to depression. CONCLUSION: One in three of lung carcinoma patients, are at increased risk for depression. Clinicians should be aware that risk is highest in those with poor performance status, single, and with poor IR. We suggest routine screening of depression symptoms as it is feasible, to be performed during a regular clinic visit with immediate referral to psychiatrist when indicated.

Trends in regional cancer mortality in Taiwan 1992-2014.

BACKGROUND: Although the cancer mortality rate in Taiwan has been declining in recent years, no study has yet reported any regional differences in cancer mortality rates in Taiwan. We hypothesized that regional cancer mortality rates in Taiwan, an ethnically homogeneous society, exhibited no significant variations. METHODS: We investigated the trends in Taiwan regional cancer mortality between 1992 and 2014. We analyzed regional age-standardized cancer mortality rates for lung, liver, colon, stomach, oral, breast, and prostate cancers using the Taiwan Longitudinal Health Insurance Database and Demographic Database. Furthermore, we applied Joinpoint regression analysis to evaluate the trends across different regions. RESULTS: There are clear regional variations in mortality rates for liver, stomach, and oral cancers, but not for lung, colon, breast, and prostate cancers. The regional death rates of oral cancer, especially for eastern Taiwan, not only elevate the fastest (APC = 14.78% per year, P < 0.001) but also show the largest disparities between men and women. Regional death rates for stomach cancer, which declined most rapidly, are converging in both general and gender groups. Liver cancer is the only one with regional variations whose trends do not all go in the same direction. We also demonstrated that northern Taiwan has significant regional advantages with respect to cancer mortality. CONCLUSIONS: Some but not all cancers in Taiwan show regional disparities. Liver, stomach, and oral cancers in Taiwan exhibit clear regional variations in mortality rates. In particular, the regional variations in oral cancer mortality rates are consistent with those in alcohol consumption.

Associations between Water Quality Measures and Chronic Kidney Disease Prevalence in Taiwan.

To determine the relationships between exposure to environmental contaminants in water and chronic kidney disease (CKD), we investigated the associations of 61 water attributes with the prevalence of CKD and End-Stage Renal Disease (ESRD) using data from 2005 to 2011 from all 22 counties and cities in the main island of Taiwan. We acquired patient information from the Taiwan Longitudinal Health Insurance Database to calculate the age-standardized CKD and ESRD prevalence rates and linked the patients' residences to the water quality monitoring data, which were sampled periodically for a total of over 45,000 observations obtained from the Taiwan Environmental Water Quality Information Database. The association analysis adjusting for gender, age, and annual effects showed that the zinc (Zn), ammonia, chemical oxygen demand (COD), and dissolved oxygen in rivers were weakly correlated with CKD (τ = 0.268/0.250/0.238/-0.267, p = 6.01×10-6/2.52×10-5/6.05×10-5/3.30×10-5, respectively), but none for ESRD. The importances of Zn and COD in rivers were also demonstrated in a CKD regression model. Moreover, an unusually high CKD prevalence was related to arsenic contamination in groundwater. A further prospective cohort study would improve our understanding of what level of environmental water with risky properties could affect the development of CKD.

CD83 Antibody Inhibits Human B Cell Responses to Antigen as well as Dendritic Cell-Mediated CD4 T Cell Responses.

Anti-CD83 Ab capable of Ab-dependent cellular cytotoxicity can deplete activated CD83+ human dendritic cells, thereby inhibiting CD4 T cell-mediated acute graft-versus-host disease. As CD83 is also expressed on the surface of activated B lymphocytes, we hypothesized that anti-CD83 would also inhibit B cell responses to stimulation. We found that anti-CD83 inhibited total IgM and IgG production in vitro by allostimulated human PBMC. Also, Ag-specific Ab responses to immunization of SCID mice xenografted with human PBMC were inhibited by anti-CD83 treatment. This inhibition occurred without depletion of all human B cells because anti-CD83 lysed activated CD83+ B cells by Ab-dependent cellular cytotoxicity and spared resting (CD83-) B cells. In cultured human PBMC, anti-CD83 inhibited tetanus toxoid-stimulated B cell proliferation and concomitant dendritic cell-mediated CD4 T cell proliferation and expression of IFN-γ and IL-17A, with minimal losses of B cells (<20%). In contrast, the anti-CD20 mAb rituximab depleted >80% of B cells but had no effect on CD4 T cell proliferation and cytokine expression. By virtue of the ability of anti-CD83 to selectively deplete activated, but not resting, B cells and dendritic cells, with the latter reducing CD4 T cell responses, anti-CD83 may be clinically useful in autoimmunity and transplantation. Advantages might include inhibited expansion of autoantigen- or alloantigen-specific B cells and CD4 T cells, thus preventing further production of pathogenic Abs and inflammatory cytokines while preserving protective memory and regulatory cells.

Observation of microwave absorption and emission from incoherent electron tunneling through a normal-metal-insulator-superconductor junction.

We experimentally study nanoscale normal-metal-insulator-superconductor junctions coupled to a superconducting microwave resonator. We observe that bias-voltage-controllable single-electron tunneling through the junctions gives rise to a direct conversion between the electrostatic energy and that of microwave photons. The measured power spectral density of the microwave radiation emitted by the resonator exceeds at high bias voltages that of an equivalent single-mode radiation source at 2.5 K although the phonon and electron reservoirs are at subkelvin temperatures. Measurements of the generated power quantitatively agree with a theoretical model in a wide range of bias voltages. Thus, we have developed a microwave source which is compatible with low-temperature electronics and offers convenient in-situ electrical control of the incoherent photon emission rate with a predetermined frequency, without relying on intrinsic voltage fluctuations of heated normal-metal components or suffering from unwanted losses in room temperature cables. Importantly, our observation of negative generated power at relatively low bias voltages provides a novel type of verification of the working principles of the recently discovered quantum-circuit refrigerator.

Large-Scale Analysis of Antimicrobial Activities in Relation to Amphipathicity and Charge Reveals Novel Characterization of Antimicrobial Peptides.

It has been unclear to which antimicrobial activities (e.g., anti-gram-positive bacterial, anti-gram-negative bacterial, antifungal, antiparasitic, and antiviral activities) of antimicrobial peptides (AMPs) a given physiochemical property matters most. This is the first computational study using large-scale AMPs to examine the relationships between antimicrobial activities and two major physiochemical properties of AMPs-amphipathicity and net charge. The results showed that among all kinds of antimicrobial activities, amphipathicity and net charge best differentiated between AMPs with and without anti-gram-negative bacterial activities. In terms of amphipathicity and charge, all the AMPs whose activities were significantly associated with amphipathicity and net charge were alike except those with anti-gram-positive bacterial activities. Furthermore, the higher the amphipathic value, the greater the proportion of AMPs possessing both antibacterial and antifungal activities. This dose-response-like pattern suggests a possible causal relationship-dual antibacterial and antifungal activities of AMPs may be attributable to amphipathicity. These novel findings could be useful for identifying potent AMPs computationally.

Flux-tunable phase shifter for microwaves.

We introduce a magnetic-flux-tunable phase shifter for propagating microwave photons, based on three equidistant superconducting quantum interference devices (SQUIDs) on a transmission line. We experimentally implement the phase shifter and demonstrate that it produces a broad range of phase shifts and full transmission within the experimental uncertainty. Together with previously demonstrated beam splitters, this phase shifter can be utilized to implement arbitrary single-qubit gates for qubits based on propagating microwave photons. These results complement previous demonstrations of on-demand single-photon sources and detectors, and hence assist in the pursuit of an all-microwave quantum computer based on propagating photons.

Patients with chronic periodontitis present increased risk for osteoporosis: A population-based cohort study in Taiwan.

OBJECTIVES: Chronic periodontitis is a bone destructive inflammatory disease with an adverse impact on general health and suggested underlying factors in common with osteoporosis. A few studies have examined the possible relationship between chronic periodontitis and osteoporosis; however, the results remain inconclusive. This longitudinal follow-up study investigated the possible risk of patients with chronic periodontitis to present osteoporosis by using a population-based national health insurance data set in Taiwan. MATERIAL AND METHODS: A random sample consisting of 1 million individuals was collected from Taiwan's national health insurance data set. From the sample, a total of 29 463 patients with newly diagnosed periodontitis from 2002 to 2008 were recruited and compared with a matched cohort of 58 926 patients without periodontitis. All patients were tracked until an osteoporosis diagnosis, or death, until the end of 2011. Associated factors, such as gender, age and comorbidities were examined. Cox proportional-hazards regression was performed to examine the risk of osteoporosis for patients with or without periodontitis. RESULTS: Within the 6-year follow-up period, the incidence rates of osteoporosis in the periodontitis cohort and comparison group were 2.72 and 1.66 per 1000 person-years, respectively. Mild, moderate and severe periodontitis were found to have 1.56, 2.09 and 2.08 times the risk of osteoporosis respectively compared to patients without periodontitis. Log-rank analysis revealed that patients with periodontitis had significantly higher cumulative incidence rates of osteoporosis than the control group (P<.0001). CONCLUSION: This study found that patients with periodontitis had a higher risk of being diagnosed with osteoporosis.

Idiopathic thrombocytopenic purpura in childhood, Langerhans cell histiocytosis in adulthood: More than a chance association?

Described herein, a case of Langerhans cell histiocytosis (LCH) in an adult with Idiopathic Thrombocytopenic Purpura (ITP) diagnosed at age ten. She presented with cranial diabetes insipidus, later developed hypogonadotrophic hypogonadism and multiple cervical lympadenopathy from which histopathology of excisional biopsy confirmed LCH. Magnetic resonance imaging showed thickened pituitary stalk. Association of ITP and LCH is unknown but the question of LCH presenting as isolated thrombocytopenia in childhood only to be discovered in adulthood when there was pituitary and bone involvement remains. It reemphasizes the need for high index of suspicion and the challenges in diagnosing LCH at the outset.

Structural correlates of trait impulsivity in patients with bipolar disorder and healthy controls: a surface-based morphometry study.

BACKGROUND: Patients with bipolar disorder (BD) frequently exhibit impulsive behaviors independent of their mood state, and trait impulsivity is increasingly recognized as a crucial BD biomarker. This study aimed to investigate structural correlates of trait impulsivity measured using the Barratt Impulsiveness Scale (BIS) in healthy controls (HCs) and patients with BD. METHOD: We recruited 59 patients diagnosed with BD I or BD II (35.3 ± 8.5 years) and 56 age- and sex-matched HCs (33.9 ± 7.4 years). Participants underwent structural magnetic resonance imaging and clinical evaluations, and their BIS scores were evaluated. An automated surface-based method (FreeSurfer) was used to measure cortical thickness and generate thickness maps for each participant. Brain-wise regression analysis of the association between cortical thickness and BIS scores was performed separately for BD and HC groups by using a general linear model. RESULTS: Patients with BD obtained significantly higher BIS scores than HCs. In HCs, higher BIS scores were associated with a thinner cortex in the left inferior, middle and medial frontal cortices. By contrast, in BD patients, higher BIS scores were associated with a thicker cortex in the right insula. Patients with BD showed a thinner cortex than HCs in all these four structures. CONCLUSIONS: The findings indicate that the left prefrontal cortex plays a cardinal role in trait impulsivity of healthy individuals. Patients with BD have a different structural correlate of trait impulsivity in the right insula. However, the use of various psychotropics in patients with BD may limit our interpretation of BD findings.

Peptidomic analysis of type 1 diabetes associated HLA-DQ molecules and the impact of HLA-DM on peptide repertoire editing.

HLA-DM and class II associated invariant chain (Ii) are key cofactors in the MHC class II (MHCII) antigen processing pathway. We used tandem mass spectrometry sequencing to directly interrogate the global impact of DM and Ii on the repertoire of MHCII-bound peptides in human embryonic kidney 293T cells expressing HLA-DQ molecules in the absence or presence of these cofactors. We found that Ii and DM have a major impact on the repertoire of peptides presented by DQ1 and DQ6, with the caveat that this technology is not quantitative. The peptide repertoires of type 1 diabetes (T1D) associated DQ8, DQ2, and DQ8/2 are altered to a lesser degree by DM expression, and these molecules share overlapping features in their peptide binding motifs that are distinct from control DQ1 and DQ6 molecules. Peptides were categorized into DM-resistant, DM-dependent, or DM-sensitive groups based on the mass spectrometry data, and representative peptides were tested in competitive binding assays and peptide dissociation rate experiments with soluble DQ6. Our data support the conclusion that high intrinsic stability of DQ-peptide complexes is necessary but not sufficient to confer resistance to DM editing, and provide candidate parameters that may be useful in predicting the sensitivity of T-cell epitopes to DM editing.