A review of methods for predicting DNA N6-methyladenine sites.

Deoxyribonucleic acid(DNA) N6-methyladenine plays a vital role in various biological processes, and the accurate identification of its site can provide a more comprehensive understanding of its biological effects. There are several methods for 6mA site prediction. With the continuous development of technology, traditional techniques with the high costs and low efficiencies are gradually being replaced by computer methods. Computer methods that are widely used can be divided into two categories: traditional machine learning and deep learning methods. We first list some existing experimental methods for predicting the 6mA site, then analyze the general process from sequence input to results in computer methods and review existing model architectures. Finally, the results were summarized and compared to facilitate subsequent researchers in choosing the most suitable method for their work.

Long-Term Efficacy and Safety of Low-Dose Rituximab in Patients with Refractory Myasthenia Gravis.

INTRODUCTION: Rituximab is a monoclonal chimeric antibody against CD20+ B cells. We aimed to assess the long-term efficacy and safety of CD20+ B cell-guided treatment with low-dose rituximab in refractory myasthenia gravis patients. METHODS: Patients with refractory myasthenia gravis treated with rituximab for more than 2 years were included. Rituximab was administered when CD20+ B cells were greater than 1%. We analysed the efficacy of rituximab, treatment interval, side effects, prognosis, and treatment course. RESULTS: A total of 22 patients were included. All patients received 2-12 doses of rituximab, and the median follow-up time was 48.5 months. The scores of the Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Composite were significantly lower than those at baseline (p < 0.05). MGFA-PIS was significantly improved in 21 (95.45%) patients and 14 (63.64%) patients have reached MGFA-PIS minimal manifestations. The average daily dose of prednisone and pyridostigmine bromide and the proportion of immunosuppressants were significantly lower (p < 0.05). Seven patients suffered from 14 worsenings. Eight patients terminated rituximab due to good efficacy. Most patients tolerated rituximab well, although 1 patient had opportunistic infection and hypogammaglobulinemia, 1 patient had an intracranial mass. CONCLUSION: Long-term CD20+ B-cell-guided low-dose rituximab showed good efficacy and tolerance in patients with refractory myasthenia gravis.

Multimorbidity and polypharmacy in hospitalized older patients: a cross-sectional study.

BACKGROUND: The growing trend of ageing population has become a worldwide concern. In comparison with the youth, older people are more likely to suffer from multimorbidity and polypharmacy, both of which are associated with adverse outcomes and increased healthcare costs. This study aimed to investigate the status of multimorbidity and polypharmacy in a large sample of hospitalized older patients aged 60 years and over. METHODS: A retrospective cross-sectional study was conducted among 46,799 eligible patients aged 60 years and over, who were hospitalized from January 1, 2021 to December 31, 2021. Multimorbidity was defined as the presence of 2 or more morbidities in one patient during the stay in hospital, and polypharmacy as prescription of 5 or more different oral medications. Spearman rank correlation analysis was used to assess the relationship of factors with the number of morbidities or oral medications. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated from logistic regression models to determine the predictors for polypharmacy and all-cause death. RESULTS: The prevalence of multimorbidity was 91.07% and increased with age. The prevalence of polypharmacy was 56.32%. Older age, polypharmacy, prolonged length of stay (LOS), higher cost on medications were significantly associated with an increased number of morbidities (all P < 0.01). The number of morbidities (OR = 1.29, 95% CI: 1.208-1.229) and LOS (OR = 1.171, 95% CI: 1.166-1.177) were potential risk factors for polypharmacy. As for all-cause death, age (OR = 1.107, 95% CI: 1.092-1.122), number of morbidities (OR = 1.495, 95% CI: 1.435-1.558) and LOS (OR = 1.020, 95% CI: 1.013-1.027) were the potential risk factors, but the number of medications (OR = 0.930, 95% CI: 0.907-0.952) and polypharmacy (OR = 0.764, 95% CI: 0.608-0.960) were associated with a reduction of mortality. CONCLUSION: Morbidities and LOS might be predictors for polypharmacy and all-cause death. The number of oral medications was inversely associated with the risk of all-cause mortality. Appropriate polypharmacy was beneficial for the clinical outcomes of older patients during hospitalization.

Modular Entry to Functionalized Tetrahydrobenzo[b]azepines via the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-Modified Norbornene.

Tetrahydrobenzo[b]azepines (THBAs) are commonly found in many bioactive compounds; however, the modular preparation of functionalized THBAs remains challenging to date. Here, we report a straightforward method to synthesize THBAs directly from simple aryl iodides via palladium/norbornene (Pd/NBE) cooperative catalysis. Capitalizing on an olefin-tethered electrophilic amine reagent, an ortho amination followed by 7-exo-trig Heck cyclization furnishes the seven-membered heterocycle. To overcome the difficulty with ortho-unsubstituted aryl iodide substrates, we discovered a unique C7-bromo-substituted NBE (N1) to offer the desired reactivity and selectivity. In addition to THBAs, synthesis of other benzo-seven-membered ring compounds can also be promoted by N1. Combined experimental and computational studies show that the C7-bromo group in N1 plays an important and versatile role in this catalysis, including promoting ß-carbon elimination, suppressing benzocyclobutene formation, and stabilizing reaction intermediates. The mechanistic insights gained could guide future catalyst design. The synthetic utility has been demonstrated in a streamlined synthesis of tolvaptan and forming diverse pharmaceutically relevant THBA derivatives. Finally, a complementary and general catalytic condition to access C6-substituted THBAs from ortho-substituted aryl iodides has also been developed.

Selective CO2 Electrochemical Reduction Enabled by a Tricomponent Copolymer Modifier on a Copper Surface.

Electrochemical CO2 reduction over Cu could provide value-added multicarbon hydrocarbons and alcohols. Despite recent breakthroughs, it remains a significant challenge to design a catalytic system with high product selectivity. Here we demonstrate that a high selectivity of ethylene (55%) and C2+ products (77%) could be achieved by a highly modular tricomponent copolymer modified Cu electrode, rivaling the best performance using other modified polycrystalline Cu foil catalysts. Such a copolymer can be conveniently prepared by a ring-opening metathesis polymerization, thereby offering a new degree of freedom for tuning the selectivity. Control experiments indicate all three components are essential for the selectivity enhancement. A surface characterization showed that the incorporation of a phenylpyridinium component increased the film robustness against delamination. It was also shown that its superior performance is not due to a morphology change of the Cu underneath. Molecular dynamics (MD) simulations indicate that a combination of increased local CO2 concentration, increased porosity for gas diffusion, and the local electric field effect together contribute to the increased ethylene and C2+ product selectivity.

Palladium/Norbornene Cooperative Catalysis.

Palladium/norbornene cooperative catalysis has emerged as a distinct approach to construct polyfunctionalized arenes from readily available starting materials. This Review provides a comprehensive overview of this field, including the early stoichiometric investigations, catalytic reaction developments, as well as the applications in the syntheses of bioactive compounds and polymers. The section of catalytic reactions is divided into two parts according to the reaction initiation mode: Pd(0)-initiated reactions and Pd(II)-initiated reactions.

Clinical characteristics and impacts of traditional Chinese medicine treatment on the convalescents of COVID-19.

Objectives: A significant proportion of discharged COVID-19 patients still have some symptoms. Traditional Chinese medicine (TCM) has played an important role in the treatment of COVID-19, but whether it is helpful for discharged patients is still unknown. The aim of this study was to retrospectively analyze the impacts of TCM treatment on the convalescents of COVID-19. Methods: A total of 372 COVID-19 convalescents from February 21 to May 3 in Shenzhen, China were retrospectively analyzed, 291 of them accepted clinically examined at least once and 191 convalescents accepted TCM. Results: After retrospective analysis of the clinical data of convalescents accepted TCM treatment or not, we found that the white blood cell count, as well as serum interleukin-6 and procalcitonin decreased in TCM group. Serum γ-glutamyl transpeptidase was significantly decreased, while prealbumin and albumin increased in TCM group. Red blood cell, hemoglobin, and platelet count increased in TCM group. The mechanisms of TCM treatment might be the overall regulations, including balanced immune response, improved hematopoiesis and coagulation systems, enhanced functions of liver and heart, increased nutrient intake and lipid metabolism. Conclusions: This study suggested that TCM treatment would be beneficial for discharged COVID-19 patients. However, long-term medical observation and further study with randomized trial should be done to confirm this result. Besides, the potential molecular mechanisms of TCM treatment should be further revealed.

Liver function recovery of COVID-19 patients after discharge, a follow-up study.

Objective: The aim of this study was to observe the liver function recovery of COVID-19 patients after discharge. Patients and Methods: A total of 253 discharged COVID-19 patients in Shenzhen city, China were selected. The clinical characteristics of these patients were assessed. A 2-month follow-up and laboratory hematology test were performed to examine the status of patients' liver function. Results: Patients combined with liver diseases, especially fatty liver, are more likely to progress to severe condition (P<0.05). Patients in severe condition and those with liver diseases have higher rates of liver injuries during hospitalization, characterized by a significant increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST, P<0.01). The ALT, AST/ALT, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total protein (TP), albumin (ALB), and A/G levels showed significant differences in comparison with the control group (P<0.05, and P<0.001); and the outlier ratio of A/G, ALT, GGT and ALP of patients remained abnormal higher within 14 days after discharge (P<0.001). Liver injuries of COVID-19 patients may be related to the epidemiological characteristics, clinical indexes, basic diseases, symptoms, drug treatment during hospitalization and the complications. Indicators of liver function were correlated with cardiac function, renal function, thyroid function, lipid metabolism, glucose metabolism, immune index, leukocyte, erythrocyte, hemoglobin and platelet related indexes. The outlier ratio of TP, ALB and GLB remained extremely low throughout the follow-up period; the outlier ratio of ALT, AST and GGT decreased below 10% from a high level at 40 days after discharged. However, the outlier ratio of A/G, AST/ALT and ALP remained high during the follow-up period. Conclusions: Abnormal liver function might indicate worse recovery of COVID-19 patients. Changes in liver function should be emphasized during long-term follow-up of COVID-19 patients after hospital discharge; the necessity of employing appropriate interventions for liver function repair should be emphasized.

Clinical characteristics and follow-up analysis of 324 discharged COVID-19 patients in Shenzhen during the recovery period.

Objectives: Research on recovering COVID-19 patients could be helpful for containing the pandemic and developing vaccines, but we still do not know much about the clinical features, recovery process, and antibody reactions during the recovery period. Methods: We retrospectively analysed the epidemiological information, discharge summaries, and laboratory results of 324 patients. Results: In all, 15 (8.62%) patients experienced chest distress/breath shortness, where 8 of the 15 were severely ill. This means severely ill patients need an extended amount of time to recover after discharge; next, 20 (11.49%) patients experienced anxiety and 21 (12.07%) had headache/insomnia and a small fraction of them complained of anosmia/ageusia, indicating that these patients need treatment for mental and psychological health issues. Regarding the re-positive patients, their CT and laboratory test results showed no obvious evidence of illness progress or infectivity but a high anti-SARS-CoV-2 antibody expression. Conclusion: Recovered COVID-19 patients need psychological and physiological care and treatment, re-positivity can occur in any person, but juveniles, females, and patients with mild/moderate existing symptoms have higher rates of re-positivity, While there is no evidence that turning re-positive has an impact on their infectivity, but it still alerted us that we need differentiate them in the following managements.

Effects of a Serum Heating Procedure for Inactivating COVID-19 on Common Biochemical Tests.

BACKGROUND: COVID-19 has recently been declared an epidemic by the WHO, and there is an urgent need for affected countries and laboratories to assess and treat people at risk of COVID-19. A heat procedure has been suggested for specimen inactivation. This study was designed to evaluate the effect of serum heating on biochemical indexes, and providing a basis for accurate detection results of the COVID-19 patients. METHODS: We collected 29 normal cases of two tubes of 5 mL whole blood. One tube was analyzed directly, and the other was analyzed after heating at 56°C 30 minutes. RESULTS: A total of 34 serum biochemical index quantitative results were obtained, 28/34 indexes were not significantly affected by the heat inactivation and remained clinically interpretable. As the thermal inactivation for these indexes showed good correlation, ALB (p = 0.04, Pearson R = 0.91, 2.6% mean increase), CysC (p = 0.03, Pearson R = 0.98, 9.9% mean increase), CO2CP (p < 0.001, Pearson R = 0.96, 13% mean decrease), they were still inter-pretable. Four biochemical indexes ALP, CK, CK-MB, and insulin were inactivated and showed significant statistical differences (p < 0.001). CONCLUSIONS: Our study showed CK, CK-MB, ALP, and insulin were sensitive to heat and will be inhibited or degrade after heating, indicating that the rapid decrease of this indexes in the COVID-19 patients may be caused by sample heat inactivation. For safety and diagnostic accuracy, we recommend the use of a point-of-care device for blood gases, electrolytes, troponin, and liver and renal function tests within a ISL 2 or above biosafety cabinet with level 3 or above biosafety laboratory practice.

The SALT-Readout ASIC for Silicon Strip Sensors of Upstream Tracker in the Upgraded LHCb Experiment.

SALT, a new dedicated readout Application Specific Integrated Circuit (ASIC) for the Upstream Tracker, a new silicon detector in the Large Hadron Collider beauty (LHCb) experiment, has been designed and developed. It is a 128-channel chip using an innovative architecture comprising a low-power analogue front-end with fast pulse shaping and a 40 MSps 6-bit Analog-to-Digital Converter (ADC) in each channel, followed by a Digital Signal Processing (DSP) block performing pedestal and Mean Common Mode (MCM) subtraction and zero suppression. The prototypes of SALT were fabricated and tested, confirming the full chip functionality and fulfilling the specifications. A signal-to-noise ratio of about 20 is achieved for a silicon sensor with a 12 pF input capacitance. In this paper, the SALT architecture and measurements of the chip performance are presented.

Entry to 1,2,3,4-Tetrasubstituted Arenes through Addressing the "Meta Constraint" in the Palladium/Norbornene Catalysis.

Arenes with four different contiguous substituents, i.e. 1,2,3,4-tetrasubstituted arenes, are commonly found in bioactive compounds, but they are nontrivial to access via conventional methods. Through addressing the "meta constraint" in the palladium/norbornene (Pd/NBE) cooperative catalysis, which is the difficulty of tolerating a sizable meta substituent in aryl halide substrates, here a modular and regioselective approach is realized for preparing 1,2,3,4-tetrasubstituted arenes. One key is the use of a C2-amide-substituted NBE, and a combined experimental and computational study reveals its role in promoting the NBE insertion and the ortho C-H metalation steps. The scope is broad: a variety of electrophiles and nucleophiles could be introduced to the ortho and ipso positions, respectively, with 1,4-disubstituted aryl halides, leading to diverse unsymmetrical contiguous tetrasubstituted arenes. Application of this approach has been demonstrated in streamlined syntheses of several bioactive compounds.

FBW7 protects against spinal cord injury by mitigating inflammation-associated neuronal apoptosis in mice.

Spinal cord injury (SCI) leads to severe and long-lasting neurological disability. Presently, the lack of effective therapies for SCI is largely attributable to an incomplete understanding of its pathogenesis. F-box and WD repeat domain-containing protein 7 (FBW7, also known as FBXW7) is a type of E3 ubiquitin ligase complex, and plays essential roles in regulating different pathological and physiological processes. In this study, we attempted to explore the effects of FBW7 on SCI progression by the in vivo and in vitro experiments. SCI mice showed significantly reduced expression of FBW7 in spinal cord tissues. Promoting FBW7 expression via intrathecal injection of AAV9/FBW7 effectively improved locomotor function in SCI mice. Neuronal death in spinal cords of SCI mice was obviously ameliorated by FBW7 over-expression, along with greatly decreased expression of cleaved Caspase-3. In addition, microglial activation in spinal cord specimens was detected in SCI mice through increasing Iba-1 expression levels, which was, however, attenuated in SCI mice injected with AAV9/FBW7. Additionally, FBW7 over-expression dramatically restrained inflammatory response in spinal cord tissues of SCI mice, as evidenced by the down-regulated expression of tumor necrosis factor-α (TNF-α) and interleukin 1ß (IL-1ß) through blocking the activation of nuclear factor-κB (NF-κB) signaling. These anti-inflammatory effects of FBW7 were confirmed in LPS-stimulated mouse microglial BV2 cells. Finally, our in vitro studies showed that conditional medium (CM) collected from LPS-incubated BV2 cells markedly induced apoptosis in the isolated primary spinal neurons; However, this effect was overtly ameliorated by CM from LPS-exposed BV2 cells over-expressing FBW7. Thus, FBW7-regulated inflammation in microglial cells was involved in the amelioration of neuronal apoptosis during SCI development. Collectively, these findings illustrated that FBW7 expression was down-regulated in spinal cords of SCI mice, and promoting its expression could effectively mitigate SCI progression by repressing microglial inflammation and neuronal death.

Correlation between immune response and self-reported depression during convalescence from COVID-19.

Self-reported depression has been observed in coronavirus disease-2019 (COVID-19) patients, infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), during discharge from the hospital. However, the cause of this self-reported depression during the convalescent period remains unclear. Here, we report the mental health status of 96 convalescent COVID-19 patients who were surveyed using an online questionnaire at the Shenzhen Samii Medical Center from March 2 to March 12, 2020 in Shenzhen, China. After obtaining their informed consent, we retrospectively analyzed the clinical characteristics of patients, including routine blood and biochemical data. The results suggested that patients with self-reported depression exhibited increased immune response, as indicated by increased white blood cell and neutrophil counts, as well as neutrophil-to-lymphocyte ratio. However, the mechanism linking self-reported depression to these cellular changes needs further study. In conclusion, self-reported depression occurred at an early stage in convalescent COVID-19 patients, and changes in immune function were apparent during short-term follow-up of these patients after discharge. Appropriate psychological interventions are necessary, and changes in immune function should be emphasized during long-term follow up of these patients.

Psychological Distress and Its Correlates Among COVID-19 Survivors During Early Convalescence Across Age Groups.

OBJECTIVE: To examine the psychological distress and the associated predictor factors of the 2019 corona-virus disease (COVID-19) on survivors in the early convalescence in Shenzhen. METHOD: A survey questionnaire consisting of post-traumatic stress disorder self-rating scale (PTSD-SS), self-rating depression scale (SDS), and self-rating anxiety scale (SAS) was presented to COVID-19 survivors still in quarantine. Scores of each scale and subscale were dependent variables in the Mann-Whitney test and stepwise regression analysis. RESULTS: A total of 126 subjects were included in the study, the mean scores of PTSD-SS, SDS, and SAS were 45.5 ± 18.9, 47.3 ± 13.1, and 43.2 ± 10.2, respectively, meanwhile, 9 (31.0%), 28 (22.2%), and 48 (38.1%) of the survivors met the cut-score for clinical significant symptoms of stress response, anxiety, and depression, respectively. Infected family members, and postinfection physical discomforts were significantly associated with scores on all three scales. Social support, retirement, and being female had significant associations with the PTSD-SS score. The survivors aged 60 or above experienced less severe stress response symptoms, fewer emotional symptoms of depression, and fewer anxiety symptoms than younger survivors. CONCLUSION: The occurrence rate of psychological distress among the COVID-19 survivors in early convalescence was high, highlighting the need for all COVID-19 survivors to be screened for psychological distress regularly for timely intervention. The predictors indicated by the current study may help to identify those at high-risk. Besides, the results indicated the older survivors suffered less emotional reactivity and fewer stress response symptoms from infectious diseases than the younger ones.

Simultaneous determination of eight flavonoids in Sedum sarmentosum Bunge from different areas by UHPLC with triple quadrupole MS/MS.

Sedum sarmentosum Bunge (SSB) is a traditional Chinese herbal medicine containing multiple components that has been extensively used clinically to treat chronic viral hepatitis and some inflammatory diseases. Total flavonoids are major pharmacologically active components of SSB. To gain a deeper understanding of SSB resources, we analyzed eight chemical constituents in 33 batches of SSB from 11 regions in China. An accurate, precise and sensitive ultra-high-performance liquid chromatography coupled with triple quadrupole electrospray tandem mass spectrometry method was developed for the determination of eight flavonoids in SSB. Under the optimized chromatographic conditions, good separation for the eight target components was obtained on an Agilent Zobax SB C18 (50 × 2.1 mm, 5 µm) column within 4 min. The established methods were validated with good linearity (r ≥ 0.9988), precision (RSD ≤ 2.68%), stability (1.43-3.28%) and repeatability (1.14-2.89%). Moreover, the average recoveries were 95.91-100.68%, and the RSDs were 1.50-3.80%. In addition, the analytical conditions of UPLC-ESI-MS/MS provided better sensitivity with a shorter analysis time when compared with the HPLC-DAD method. Hierarchical clustering analysis and principal component analysis were performed to estimate and classify these samples based on the contents of the eight chemical constituents. This study provided the theoretical basis and scientific evidence for the development and utilization of SSB resources.

Palladium/Norbornene-Catalyzed Indenone Synthesis from Simple Aryl Iodides: Concise Syntheses of Pauciflorol†F and Acredinone†A.

To show the synthetic utility of palladium/norbornene (Pd/NBE) cooperative catalysis, here we report concise syntheses of indenone-based natural products, pauciflorol F and acredinone A, which are enabled by direct annulation between aryl iodides and unsaturated carboxylic acid anhydrides. Compared to the previous indenone-preparation approaches, this method allows simple aryl iodides to be used as substrates with complete control of the regioselectivity. The total synthesis of acredinone A features two different Pd/NBE-catalyzed ortho acylation reactions for constructing penta-substituted arene cores, including the development of a new ortho acylation/ipso borylation.

Suzuki-Miyaura Coupling of Simple Ketones via Activation of Unstrained Carbon-Carbon Bonds.

Here, we describe that simple ketones can be efficiently employed as electrophiles in Suzuki-Miyaura coupling reactions via catalytic activation of unstrained C-C bonds. A range of common ketones, such as cyclopentanones, acetophenones, acetone and 1-indanones, could be directly coupled with various arylboronates in high site-selectivity, which offers a distinct entry to more functionalized aromatic ketones. Preliminary mechanistic study suggests that the ketone α-C-C bond was cleaved via oxidative addition.

Modular ipso/ ortho Difunctionalization of Aryl Bromides via Palladium/Norbornene Cooperative Catalysis.

Palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a useful tool for preparing poly substituted arenes; however, its substrate scope has been largely restricted to aryl iodides. While aryl bromides are considered as standard substrates for Pd-catalyzed cross coupling reactions, their use in Pd/NBE catalysis remains elusive. Here we describe the development of general approaches for aryl bromide-mediated Pd/NBE cooperative catalysis. Through careful tuning the phosphine ligands and quenching nucleophiles, ortho amination, acylation and alkylation of aryl bromides have been realized in good efficiency. Importantly, various heteroarene substrates also work well and a wide range of functional groups are tolerated. In addition, the utility of these methods has been demonstrated in sequential cross coupling/ ortho functionalization reactions, consecutive Pd/NBE-catalyzed difunctionalization to construct penta-substituted aromatics and two-step meta functionalization reactions. Moreover, the origin of the ligand effect in ortho amination reactions has been explored through DFT studies. It is expected that this effort would significantly expand the reaction scope and enhance the synthetic potential for Pd/NBE catalysis in preparing complex aromatic compounds.

Study of the instability of the Poiseuille flow using a thermodynamic formalism.

The stability of the plane Poiseuille flow is analyzed using a thermodynamic formalism by considering the deterministic Navier-Stokes equation with Gaussian random initial data. A unique critical Reynolds number, Rec ≈ 2,332, at which the probability of observing puffs in the solution changes from 0 to 1, is numerically demonstrated to exist in the thermodynamic limit and is found to be independent of the noise amplitude. Using the puff density as the macrostate variable, the free energy of such a system is computed and analyzed. The puff density approaches zero as the critical Reynolds number is approached from above, signaling a continuous transition despite the fact that the bifurcation is subcritical for a finite-sized system. An action function is found for the probability of observing puffs in a small subregion of the flow, and this action function depends only on the Reynolds number. The strategy used here should be applicable to a wide range of other problems exhibiting subcritical instabilities.