Amyloid beta peptide （Aβ） is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein （APP）, by β- and y-secretases. Aβ accumulation in the brain is proposed ...to be an early toxic event in the pathogenesis of Alzheimer＇s disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer＇s disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer＇s disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer＇s disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ inhibitors or modulators of β- and y-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.
Fast radio bursts (FRBs) are millisecond-duration radio transients
of unknown origin. Two possible mechanisms that could generate extremely coherent emission from FRBs invoke neutron star ...magnetospheres
or relativistic shocks far from the central energy source
. Detailed polarization observations may help us to understand the emission mechanism. However, the available FRB polarization data have been perplexing, because they show a host of polarimetric properties, including either a constant polarization angle during each burst for some repeaters
or variable polarization angles in some other apparently one-off events
. Here we report observations of 15 bursts from FRB 180301 and find various polarization angle swings in seven of them. The diversity of the polarization angle features of these bursts is consistent with a magnetospheric origin of the radio emission, and disfavours the radiation models invoking relativistic shocks.
Since December 2019, the novel coronavirus disease 2019 (COVID-19) that emerged in Wuhan city has spread rapidly around the world. The risk for poor outcome dramatically increases once a patient ...progresses to the severe or critical stage. The present study aims to investigate the risk factors for disease progression in individuals with mild to moderate COVID-19.
We conducted a cohort study that included 1007 individuals with mild to moderate COVID-19 from three hospitals in Wuhan. Clinical characteristics and baseline laboratory findings were collected. Patients were followed up for 28 days for observation of disease progression. The end point was the progression to a more severe disease stage.
During a follow up of 28 days, 720 patients (71.50%) had recovered or were symptomatically stable, 222 patients (22.05%) had progressed to severe disease, 22 patients (2.18%) had progressed to the critically ill stage and 43 patients (4.27%) had died. Multivariate Cox proportional hazards models identified that increased age (hazard ratio (HR) 2.56, 95% CI 1.97–3.33), male sex (HR 1.79, 95% CI 1.41–2.28), presence of hypertension (HR 1.44, 95% CI 1.11–1.88), diabetes (HR 1.82, 95% CI 1.35–2.44), chronic obstructive pulmonary disease (HR 2.01, 95% CI 1.38–2.93) and coronary artery disease (HR 1.83, 95% CI 1.26–2.66) were risk factors for disease progression. History of smoking was protective against disease progression (HR 0.56, 95% CI 0.34–0.91). Elevated procalcitonin (HR 1.72, 95% CI 1.02–2.90), urea nitrogen (HR 1.72, 95% CI 1.21–2.43), α-hydroxybutyrate dehydrogenase (HR 3.02, 95% CI 1.26–7.21) and D-dimer (HR 2.01, 95% CI 1.12–3.58) at baseline were also associated with risk for disease progression.
This study identified a panel of risk factors for disease progression in individuals with mild to moderate COVID-19.
The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, ...identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global pandemic. Although great efforts have been made to develop ...effective therapeutic interventions, only the nucleotide analog remdesivir was approved for emergency use against COVID-19. Remdesivir targets the RNA-dependent RNA polymerase (RdRp), an essential enzyme for viral RNA replication and a promising drug target for COVID-19. Recently, several structures of RdRp in complex with substrate RNA and remdesivir were reported, providing insights into the mechanisms of RNA recognition by RdRp. These structures also reveal the mechanism of RdRp inhibition by nucleotide inhibitors and offer a molecular template for the development of RdRp-targeting drugs. This review discusses the recognition mechanism of RNA and nucleotide inhibitor by RdRp, and its implication in drug discovery.
Summary
Background
Coronavirus disease 2019 (COVID-19) is a global pandemic but the follow-up data of discharged patients was barely described.
Aim
To investigate clinical outcomes, distribution of ...quarantine locations and the infection status of the contacts of COVID-19 patients after discharge.
Design
A prospective cohort study.
Methods
Demographics, baseline characteristics of 131 COVID-19 patients discharged from 3 February 2020 to 21 February 2020 in Wuhan, China were collected and analyzed by reviewing the medical records retrospectively. Post-hospitalization data related to clinical outcomes, quarantine locations and close contact history were obtained by following up the patients every week up to 4 weeks.
Results
Fifty-three (40.05%) patients on discharge had cough (29.01%), fatigue (7.63%), expectoration (6.11%), chest tightness (6.11%), dyspnea (3.82%), chest pain (3.05%) and palpitation (1.53%). These symptoms constantly declined in 4 weeks post-discharge. Transient fever recurred in 11 (8.4%) patients. Among the discharged patients, 78 (59.5%) underwent chest CT and 2 (1.53%) showed deterioration. A total of 94 (71.8%) patients received SARS-CoV-2 retest and 8 (6.10%) reported positive. Seven (2.29%) patients were readmitted because of fever or positive SARS-CoV-2 retest. After discharge, 121 (92.37%) and 4 (3.05%) patients were self-quarantined at home or community spots, respectively, after a close contact with 167 persons in total who were free of COVID-19 at the endpoint of study.
Conclusion
The majority of COVID-19 patients after discharge were in the course of recovery. Readmission was required in rare cases due to suspected recurrence of COVID-19. Although no contacted infection observed, appropriate self-quarantine and regular re-examination are necessary, particularly for those who have recurred symptoms.
The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the ...SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.
Background
The aim of this study was to assess the immune profile within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), and to investigate the prognostic value of intratumoral ...infiltrating immune/inflammatory cells (IICs) in patients after surgery.
Methods
Eighteen phenotypic markers representing 11 types of IIC and the protein products of genes TP53, CDKN2A/p16 and SMAD4/DPC4 were assessed by immunohistochemistry of specimens from patients with pancreatic cancer. The expression of IICs and the mutational status of the genes were correlated with tumour recurrence and survival, and results were validated in an independent cohort.
Results
CD15+ neutrophils, CD20+ B cells and CD206+ tumour‐associated macrophages were seen frequently in tumours, and their presence was associated with reduced survival in a cohort of 79 patients. Expression of CD4+ T helper cells, CD8+ cytotoxic T lymphocytes and CD117+ mast cells was associated with a favourable prognosis. A weighted Cox regression recurrence‐predictive model was constructed that showed good correlation of IICs and gene mutations. A combination of CD15, CD206, CD117 and Smad4 expression was independently associated with overall (hazard ratio (HR) 3·63, 95 per cent c.i. 2·18 to 6·04; P < 0·001) and recurrence‐free (HR 2·93, 1·81 to 4·75; P < 0·001) survival. These findings were validated in an independent cohort (151 patients) and in 54 tissue samples obtained by preoperative endoscopic ultrasound‐guided fine‐needle aspiration.
Conclusion
PDAC has a unique immunosuppressive phenotype that is associated with characteristic gene mutations, disease recurrence and survival after pancreatectomy.
Surgical relevance
The immune microenvironment plays a critical role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is associated with mutations in major driver genes, including KRAS, TP53, CDKN2A/p16 and SMAD4/DPC4.
This study shows that the microenvironment of PDAC has a unique immunosuppressive phenotype, which may be driven by oncogene mutations. Patients with PDAC with a highly immunosuppressive profile tended to have poor postoperative survival. A model including three intratumoral infiltrating immune markers (CD15+, CD206+ and CD117+) and a SMAD4 mutation can be used to predict recurrence and survival in patients after surgery for PDAC.
Immunosuppressive phenotype has poor prognosis
Abstract
Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory ...diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.
This systematic review and meta-analysis estimated the global, regional prevalence, and risk factors of osteoporosis. Prevalence varied greatly according to countries (from 4.1% in Netherlands to ...52.0% in Turkey) and continents (from 8.0% in Oceania to 26.9% in Africa). Osteoporosis is a common metabolic bone disorder in the elderly, usually resulting in bone pain and an increased risk of fragility fracture, but few summarized studies have guided global strategies for the disease. Therefore, we pooled the epidemiologic data to estimate the global, regional prevalence, and potential risk factors of osteoporosis. We conducted a comprehensive literature search through PubMed, EMBASE, Web of Science, and Scopus, to identify population-based studies that reported the prevalence of osteoporosis based on the World Health Organization (WHO) criteria. Meta-regression and subgroup analyses were used to explore the sources of heterogeneity. The study was registered in the PROSPERO database (CRD42021285555). Of the 57,933 citations evaluated, 108 individual studies containing 343,704 subjects were included. The global prevalence of osteoporosis and osteopenia was 19.7% (95%CI, 18.0%–21.4%) and 40.4% (95%CI, 36.9%–43.8%). Prevalence varied greatly according to countries (from 4.1% in Netherlands to 52.0% in Turkey) and continents (from Oceania 8.0% to 26.9% in Africa). The prevalence was higher in developing countries (22.1%, 95%CI, 20.1%–24.1%) than in developed countries (14.5%, 95%CI, 11.5%–17.7%). Our study indicates a considerable prevalence of osteoporosis among the general population based on WHO criteria, and the prevalence varies substantially between countries and regions. Future studies with robust evidence are required to explore risk factors to provide effective preventive strategies for the disease.
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