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Abnormal posttranslational modifications of tau play important roles in mediating neurodegeneration in tauopathies including Alzheimer's disease. Both phosphorylation and truncation are implicated in the pathogenesis of tauopathies. However, whether phosphorylation aggravates truncated tau-induced pathology and neurodegeneration remains elusive. Here, we construct different tau fragments cleaved by delta secretase, with either phosphorylation or non-phosphorylation mimic mutations, and evaluate the contributions of phosphorylation to truncated tau-induced pathological and behavioral alterations in vitro and in vivo through biochemical methods including detergent insoluble tau extraction, western blot, immunofluorescence, flow cytometry, and behavior tests. Our results show that the self-aggregation of phospho-truncated tau is significantly influenced by the domain it contains. N-terminal inhibits, proline-rich domain promotes, and C-terminus have no impact on phospho-truncated tau aggregation. Phosphorylation of truncated tau1-368, which contains the microtubule-binding repeat domain and the proline-rich domain, induces endogenous tau phosphorylation and aggregation. In vivo, phospho-tau1-368 but not non-phospho-tau1-368 leads to a decrease in body weight of C57BL/6 J mice. Intriguingly, although tau1-368-induced anxiety behavior in C57BL/6 J mice is phosphorylation-independent, the recognition memory of mice is impaired by phospho-tau1-368, but not by non-phospho-tau1-368. Immunofluorescence staining shows that overexpressing phospho-tau1-368 results in neuronal loss and gliosis in the hippocampus, while the transmission of tau1-368 is phosphorylation-independent as revealed by the flow cytometry results in vitro and immunofluorescence staining in vivo. Our findings indicate that phosphorylation of truncated tau significantly fosters endogenous tau pathology and neurodegeneration.

Background We investigated the clinical and immunological features in a Chinese cohort of activated phosphatidylinositol 3-kinase δ syndrome 2 (APDS2) and assessed the efficacy of Rapamycin therapy and the underlying mechanism.Results The shared clinical manifestation of patients included recurrent respiratory tract infection, lymphadenopathy, persistent or recurrent splenomegaly, and hepatomegaly. Three patients carry PIK3R1 c.1425 + 1G > A mutation, and one patient has the mutation c.1425 + 2T > G. Patients have defective humoral immunity with decreased B lymphocytes, especially memory B cells, and suffered from decreased naïve T cells and elevated senescent CD8+ T cells. Two patients after rapamycin therapy showed improved clinical symptoms. They also have decreased CD8+ effector memory T cells and terminal effector memory cytotoxic T cells. TCF1 was downregulated in CD8+ T cells of PIK3R1 patients but upregulated after Rapamycin treatment, which was correlated with decreased senescent CD8+ T cells.Conclusions mTOR inhibitor rapamycin improved clinical symptoms in APDS2 patients and reversed CD8+ T cell senescence through TCF1-dependent signal pathway.

Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS-based risk prediction, particularly assessment of calibration (comparing predicted to observed risks).To evaluate PRS-based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry.We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case-cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single-nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta-analysis (PRS68), 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment.Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62-0·68] and MCCS (E/O = 0·63, 95% CI 0·56-0·72). For UKB, calibration was improved by PRS adjustment, with PRS50-adjusted risks E/O = 0·91, 95% CI 0·87-0·95. The discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07-0·10, P 0·0001), and higher than for PRS45-adjusted risks (Δ area under the curve 0·02-0·04, P 0·001).A PRS derived from a larger, more diverse meta-analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations.

Alzheimer’s disease (AD) is the most common neurodegenerative disease with limited therapeutic strategies. Cell cycle checkpoint protein kinase 1 (Chk1) is a Ser/Thr protein kinase which is activated in response to DNA damage, the latter which is an early event in AD. However, whether DNA damage-induced Chk1 activation participates in the development of AD and Chk1 inhibition ameliorates AD-like pathogenesis remain unclarified. Here, we demonstrate that Chk1 activity and the levels of protein phosphatase 2A (PP2A) inhibitory protein CIP2A are elevated in AD human brains, APP/PS1 transgenic mice, and primary neurons with Aβ treatment. Chk1 overexpression induces CIP2A upregulation, PP2A inhibition, tau and APP hyperphosphorylation, synaptic impairments, and cognitive memory deficit in mice. Moreover, Chk1 inhibitor (GDC0575) effectively increases PP2A activity, decreases tau phosphorylation, and inhibits Aβ overproduction in AD cell models. GDC0575 also reverses AD-like cognitive deficits and prevents neuron loss and synaptic impairments in APP/PS1 mice. In conclusion, our study uncovers a mechanism by which DNA damage-induced Chk1 activation promotes CIP2A-mediated tau and APP hyperphosphorylation and cognitive dysfunction in Alzheimer’s disease and highlights the therapeutic potential of Chk1 inhibitors in AD.

In the implementation of management error proofing, enterprises need to carry out risk evaluation and ranking of management activities error, to determine error proofing improvement order. We note that management function failure is different from industrial failure, and the management activity error as its cause is also different from operational or device error, so the method generally used in industry is not suitable for the risk assessment of management activity error. To address this issue, this study integrates the FMEA (failure modes and effect analysis) with the ISO9001 standardized management system framework describing multilevel and multi-attribute management activities, and the human errors that may lead to functional failure of quality management activities are identified at each level and each category. The three factors (severity (S), occurrence (O), and detection (D)) of errors in each management activity are evaluated and integrated into the risk priority number for each quality management activity error. The two major defects of the traditional FMEA in the practical application process are as follows: (1) the evaluation of error attributes of various management activities is basically qualitative language description, which cannot be quantified; (2) the other one disadvantage is that it ignores the fact that three factors have the different weights in the system rather than equality, and not considering the relative importance of between them. In this article, the fuzzy set theory and the grey relational decision theory are, respectively, applied to improve the two defects and to improve the accuracy of the decision. Finally, a numerical example of a coal mine is given to verify the effectiveness of the proposed method. This study provides a basis for managers and practitioners to quantitatively evaluate and prevent errors in management activities.

Rapid testing, generally refers to the paper-based diagnostic platform known as “lateral flow assay” (LFA), has emerged as a critical asset to the containment of coronavirus disease 2019 (COVID-19) around the world. LFA technology stands out amongst peer platforms due to its cost-effective design, user-friendly interface, and low sample-to-readout times. This article aims to introduce its design, use, and practicality for the purpose of diagnosing SARS-CoV-2 infection. A connection is made from the normal COVID-19 immune response to the design and efficacy of rapid testing. Interference in test results is a challenge shared by most diagnostic platforms and can be rooted in various underlying issues. The current knowledge and situation about interference in rapid COVID-19 tests due to variant strains as well as vaccination are discussed. The cost and societal impact are reviewed as they play important roles in determining how to properly implement public testing practices. Perspectives on improving the performance, especially detection sensitivity, of LFA for COVID-19 are provided. Graphical abstract

Background and ObjectivesSuicide has become a major public health concern worldwide and in the United States. Rates of suicide increase during the life course and are highest among middle- to old-age adults. Help-seeking represents a crucial coping mechanism that can mitigate suicide risk. Yet, less is known about suicide risk help-seeking, especially among these age groups. To address this knowledge gap, a systematic review of existing literature was performed to obtain a refined understanding of help-seeking for suicide risk among middle- to old-age adults.Research Design and MethodsUsing Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, electronic databases and key journals with suicide and/or gerontology focuses were searched to identify peer-reviewed publications in English between 2010 and 2020. A total of 4 732 unduplicated publications were screened for relevance based on titles and abstracts, of which 52 were reviewed in full text.ResultsTwenty-four articles met inclusion criteria and were included in the qualitative synthesis. These articles discussed a range of topics, including the prevalence of service utilization, service use prior to a suicide death, and correlates of help-seeking. In general, the prevalence of service utilization was low and varied by suicidal history (eg, higher prevalence among individuals with a history of suicide attempts than those with suicide ideation only). Key facilitators (eg, current or history of suicidal thoughts, plans, or attempts) and barriers (eg, stigma) for service use and help-seeking were also identified.Discussion and ImplicationsFindings highlight the need for future studies and tailored services to improve age-appropriate and culturally responsive suicide prevention and intervention strategies for middle- to old-age adults.

Objectives To assess outcomes of bilateral single-session percutaneous nephrolithotomy (PCNL) with minimally invasive technique in pediatric population. Patients and methods Children who were treated with minimally invasive bilateral single-session PCNL from August 2015 to July 2021 were analyzed. Minimally invasive PCNL in this study included miniPCNL (12-16-Fr) and Microperc (4.8-Fr). Patient demographics, stone and operative characteristics, stone-free rate (SFR) and complication rate (CR) were detailed and compared. Independent predictors for operation time, irrigated fluid volume, postoperative hospital stay and postoperative complication were determined. Results Forty-five children (including 12 infants) with mean stone burden of 3.2 cm were enrolled, among whom the male-to-female ratio was nearly 1.5:1. SFR was 93.3% and overall CR was 53.3% (Clavien grade 1 + 2, 46.7%). SFR were favourable with different sizes of PCNL. Self-limiting hematuria represented the most common complication (33.3%), especially with miniPCNL. Stone burden was the only independent predictor for operation time (p

3D segmentation has been a hot spot in numerical geometry processing. But the accuracy of the segmentation methods can be easily affected by the types of models because their sensitivity to different models is uneven. To address this problem, we propose a semi-automatic 3D mesh segmentation algorithm based on harmonic field. Firstly, our algorithm utilizes the strokes of users as constraints on the harmonic field of the mesh surface. Secondly, a smooth harmonic field based on Laplacian operator and Poisson equation is introduced. Through the generated harmonic field, the correct weights are selected to further fit the geometric characteristics of the grid. Afterwards, we find a set of most suitable isolines on the harmonic field as the segmentation path. Finally, a mesh density enhancement method is designed, which optimizes sub-graphs after segmentation. Experimental results demonstrate that the effectiveness of our proposed algorithm. Moreover, the semi-automatic 3D mesh segmentation algorithm can better understand the intention of users.

Background Macular corneal dystrophy (MCD) is a rare corneal stromal dystrophy with bilateral progressive vision loss. The pathogenic gene of MCD is carbohydrate sulfotransferase 6 (CHST6). Herein, we report a novel missense mutation and a rare exon deletion mutation in the CHST6 gene in a Chinese family with MCD. Methods Genomic DNA was extracted from the peripheral blood, and next generation sequencing was used to analyse the gene sequence. The pathogenic mutations were identified in all affected family members. The proband successively received binocular penetrating keratoplasty (PKP), and the corneas were examined by histopathology and colloidal iron staining to prove the diagnosis. A long-term follow-up was made to observe the changes after PKP. Results Genetic analysis demonstrated hemizygous mutations in the proband, including a novel c.520A>C (p.K174Q) missense mutation and a rarely reported exon 3 deletion mutation, which were co-segregated with the MCD phenotypes in the pedigree. The positive colloidal iron staining confirmed the diagnosis of MCD in the proband. However, the clinical phenotype and pathological manifestation of both eyes were different from each other because of complicated keratitis in the left eye. During the nine years of follow-up, visual acuity was improved significantly, and the cornea was transparent without rejection and postoperative recurrence in both eyes. Conclusions The novel hemizygous mutations were thought to contribute to the loss of CHST6 function, which induced typical clinical and pathological features of MCD. PKP was an effective treatment for MCD.

The Coronavirus disease 2019 (COVID-19) disproportionately affects nursing home residents, resulting in an elevated risk for COVID-19 morbidity and mortality for this frail population. It is critical to understand whether nursing home quality is related to COVID-19 cases and deaths. Using publicly available data obtained from Centers for Medicare & Medicaid Services COVID-19 Nursing Home Dataset, Nursing Home Compare and Long-Term Care Focus, this study compares key nursing home characteristics, infection prevention and control deficiencies, and five-star ratings among Florida nursing homes with and without resident COVID-19 cases and deaths. The study further examines the association between facility and resident characteristics, quality indicators, and COVID-19 cases and deaths. Findings from our study indicate that through late October 2020, over 90% of Florida nursing homes have at least one resident case and 65% have at least one resident death. The likelihood of having COVID-19 cases is more related to ownership status, facility size and average occupancy rate, rather than quality indicators. Associations between infection prevention and control deficiencies, overall quality ratings, and presence of COVID-19 resident deaths varied across different phases of the pandemic (e.g., overall five-star rating was found related to the odds of having resident deaths after, but not during, the surging stage). Training, uptake, and adherence to infection control procedures are needed to better protect the vulnerable nursing home resident population.

Open Source Software (OSS) community has attracted a large number of distributed developers to work together, e.g. reporting and discussing issues as well as submitting and reviewing code. OSS developers create links among development units (e.g. issues and pull requests in GitHub), share their opinions and promote the resolution of development units. Although previous work has examined the role of links in recommending high-priority tasks and reducing resource waste, the understanding of the actual usage of links in practice is still limited. To address the research gap, we conduct an empirical study based on the 5W1H model and data mining from five popular OSS projects on GitHub. We find that links originating from a PR are more common than the other three types of links, and links are more frequently created in Documentation. We also find that average duration between development units’ create time in a link is half a year. We observed that link behaviors are very complex and the duration of link increases with the complexity of link structure. We also observe that the reasons of link are very different, especially in P–P and I–I. Finally, future works are discussed in conclusion.

Background: As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer’s disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. Objective: To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. Methods: We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. Results: All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3β-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAβPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAβPPβ, thereby reduced Aβ production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10μM. Conclusion: Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aβ production and inhibiting AChE in AD.

Purpose Summarize the characteristics of the largest cohort of BCG disease and compare differences in clinical characteristics and outcomes among different genotypes and between primary immunodeficiency disease (PID) and non-PID patients. Methods We collected information on patients with BCG disease in our center from January 2015 to December 2020 and divided them into four groups: chronic granulomatous disease (CGD), Mendelian susceptibility to mycobacterial disease (MSMD), severe combined immunodeficiency disease (SCID) and unspecified pathogenic group. Results A total of 134 patients were reviewed, and most of them had PID. A total of 112 (83.6%) patients had 19 different types of pathogenic gene mutations, most of whom (91.1%) were classified with CGD, MSMD and SCID. CYBB was the most common gene mutation (53/112). BCG disease behaves differently in individuals with different PIDs. Significant differences in sex (P P = 0.019), frequency of recurrent fever (P = 0.003) and infection severity (P = 0.038) were noted among the four groups. The CGD group had the highest rate of males and the oldest age at diagnosis. The MSMD group had the highest probability of disseminated infection (46.4%). The course of anti-tuberculosis treatment and the survival time between PID and non-PID patients were similar. Conclusion Greater than 80% of BCG patients have PID; accordingly, gene sequencing should be performed in patients with BCG disease for early diagnosis. BCG disease behaves differently in patients with different types of PID. Non-PID patients had similar outcomes to PID patients, which hints that they may have pathogenic gene mutations that need to be discovered.

Objective This study aimed to investigate the prevalence and clinical characteristics of monogenic disease in paediatric patients with a predominant respiratory phenotype. Methods Exome sequencing was performed in a cohort of 971 children with a predominant respiratory phenotype and suspected genetic aetiology. A total of 140 positive cases were divided into subgroups based on recruitment age and the primary biological system(s) involved. Results There were 140 (14.4%) patients with a positive molecular diagnosis, and their primary clinical manifestations were respiratory distress (12.9%, 18 of 140), respiratory failure (12.9%, 18 of 140) and recurrent/persistent lower respiratory infections (66.4%, 93 of 140). Primary immunodeficiency (49.3%), multisystem malformations/syndromes (17.9%), and genetic lung disease (16.4%) were the three most common genetic causes in the cohort, and they varied among the age subgroups. A total of 72 (51.4%) patients had changes in medical management strategies after genetic diagnosis, and the rate in those with genetic lung disease (82.6%, 19 of 23) was far higher than that in patients with genetic disease with lung involvement (45.3%, 53 of 117) (p=0.001). Conclusion Our findings demonstrate that exome sequencing is a valuable diagnostic tool for monogenic diseases in children with a predominant respiratory phenotype, and the genetic spectrum varies with age. Taken together, genetic diagnoses provide invaluable clinical and prognostic information that may also facilitate the development of precision medicine for paediatric patients., This manuscript reports on the prevalence and clinical characteristics of monogenic disease in paediatric patients with a predominant respiratory phenotype. And that exam sequencing is a valuable tool for this with 140 positive cases in a cohort of 971.

Objectives: Depression has become one major mental health concern among Asian older adults. Yet, less is known about the role of social support on depression help-seeking among this population. This study examined the association between positive (i.e., open up to, rely on) and negative (i.e., too many demands, criticism) social support and depression help-seeking among U.S. Chinese older adults. Methods: Data were derived from the Population Study of Chinese Elderly in Chicago (PINE). Study sample consisted of 994 U.S. Chinese older adults with depressive symptoms. Results: Stepwise logistic regression results indicated that greater positive social support was associated with increased likelihood of both formal and informal help-seeking behaviors, whereas negative support was not a significant predictor. Discussion: Findings highlight the key role of positive social support in influencing U.S. Chinese older adults’ depression help-seeking behaviors. Tailored strategies are recommended to better meet the mental health needs of this vulnerable population.

Background We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation. Results The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved. Conclusions Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.

Variations in the NBAS gene is known to cause a spectrum of phenotypes ranging from isolated recurrent acute liver failure (RALF) to a multisystemic presentation known as SOPH syndrome. Patients with SOPH present with optic atrophy, acute liver failure, short stature, and Pelger-Huet anomaly. We report the presence of a novel pair of biallelic heterozygous mutations c.5139-5T>G and c.2203-2A>G in the NBAS gene of a patient with SOPH syndrome. A 9-year-old patient was clinically diagnosed with SOPH following clinical laboratory analyses. Current interventions for managing the disease encompass IVIG, methylprednisolone, calcium, and vitamin D administration. Whole-exome sequencing (WES) results showed two mutations: c.2203-2A>G and c.5139-5T>G, in the NBAS gene, which had not been previously reported. Notably, we hypothesize that NBAS mutations could potentially contribute to the development of Fanconi syndrome, a clinical diagnosis reported in our patient. Our study also supports the renaming of SOPH to SOPHIA to allow early detection and effective treatment.

Multispectral stealth technology including terahertz (THz) band will play an increasingly important role in modern military and civil applications. Here, based on the concept of modularization design, two kinds of flexible and transparent metadevices were fabricated for multispectral stealth, covering the visible, infrared (IR), THz, and microwave bands. First, three basic functional blocks for IR, THz, and microwave stealth are designed and fabricated by using flexible and transparent films. And then, via modular assembling, that is, by adding or removing some stealth functional blocks or constituent layers, two multispectral stealth metadevices are readily achieved. Metadevice 1 exhibits THz-microwave dual-band broadband absorption, with average measured absorptivity of 85% in 0.3-1.2 THz and higher than 90% in 9.1-25.1 GHz, suitable for THz-microwave bi-stealth. Metadevice 2 is for IR and microwave bi-stealth, with measured absorptivity higher than 90% in 9.7-27.3 GHz and low emissivity around 0.31 in 8-14 µm. Both metadevices are optically transparent and able to maintain good stealth ability under curved and conformal conditions. Our work offers an alternative approach for designing and fabricating flexible transparent metadevices for multispectral stealth, especially for applications in nonplanar surfaces.

This study provides an exploration of foster child stress and behavioral health during and after Hurricane Irma. Results from a survey of 50 foster parents indicated that foster child stress was si...

Context: COVID-19 has a high case fatality rate in high-risk populations and can cause severe morbidity and high healthcare resource use. Nursing home residents are a high-risk population; they live in congregate settings, often with shared rooms, and require hands-on care.Objectives: To assess state responses to the coronavirus pandemic related to nursing homes in the first half of 2020.Methods: An in-depth examination of 12 states’ responses to the COVID-19 pandemic in nursing homes through June 2020, using publicly reported information such as government decrees, health department guidance, and news reports.Findings: No state emerged as a model of care. All states faced difficulty with limited availability of testing and Personal Protective Equipment (PPE). State-level efforts to increase pay and benefits as a strategy to enable infected staff to quickly physically separate from residents were minimal, and other separation strategies depended on the ability to obtain test results rapidly and on state rules regarding accepting discharged COVID-19 patients into nursing homes. Visitor restrictions to reduce risk were ubiquitous, though based on a slim evidence-base.Limitations: The information used was limited to that which was publicly available.Implications: Overall, the results suggest that the states that handle the ongoing pandemic in nursing homes best will be those that find ways to make sure nursing homes have the resources to follow best practices for testing, PPE, separation, and staffing. Evidence is needed on visitor restrictions and transmission, as states and their citizens would benefit from finding safe ways to relax visitor restrictions.

The apolipoprotein E ε4 (APOE4) allele is a major genetic risk factor for Alzheimer’s disease (AD), and its protein product, ApoE4, exerts its deleterious effects mainly by influencing amyloid-β (Aβ) and Tau (neurofibrillary tangles, NFTs) deposition in the brain. However, the molecular mechanism dictating its expression during ageing and in AD remains incompletely clear. Here we show that C/EBPβ acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPβ binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPβ in AD mouse models diminishes ApoE expression and Aβ pathologies, whereas overexpression of C/EBPβ accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPβ selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPβ in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPβ is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4’s role in AD pathogenesis.

Drawing on data from the National Latino and Asian American Study, this article examines the influence of family relational factors, independently and jointly with immigration generation status, on past-year mental health service utilization among Asian Americans ( N = 1,599). Findings revealed the important role of family relation in influencing the likelihood and type of Asian Americans’ mental health service use. Lower level of family cohesion and higher level of family conflict were associated with increased likelihood of service use. Results from multiple logistic regressions further indicated that generation status interacts with family relation in affecting service use. Specifically, effect of family cohesion on general health service use was modified by generation status among third- or later-generation Asian Americans. Practice implications and future research directions are discussed to better understand and address the mental health needs of this population.

Hyperphosphorylation of the microtubule associated protein tau is associated with several neurodegenerative diseases including Alzheimer's Disease (AD), collectively referred to as tauopathies. However, the mechanisms by which tau is linked to synaptic dysfunction and memory impairment remain unclear. To address this question, we constructed a mouse model with brain-specific deficiency of SIRT1 (SIRT1 flox/Cre + ). Here, we show that increase of site-specific phosphorylation of tau is coupled with the strengthened O-GlcNAcylation of tau triggered by reduced O-GlcNAcase (OGA) and increased O-GlcNAc transferase (OGT) protein level in the brain of SIRT1 flox/Cre+ mice. SIRT1 deletion in mice brain changes the synaptosomal distribution of site-specific phospho-tau. Learning and memory deficiency induced by dendritic spine deficits and synaptic dysfunction are revealed via SIRT1 flox/Cre+ mice. Our results provide evidence for SIRT1 as a potential therapeutic target in clinical tauopathies.

Background: Obesity is a worldwide health problem that has been implicated in many diseases, including Alzheimer’s disease (AD). AD is one of the most common neurodegenerative disorders and is characterized by two pathologies, including extracellular senior plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau. According to current research, a high-fat diet (HFD) could exacerbate Aβ accumulation, oxidative damage, and cognitive defects in AD mice. However, the accurate role of HFD in the pathogenesis of AD is far more unclear. Objective: To explore the accurate role of HFD in the pathogenesis of AD. Methods: Open Field, Barns Maze, Elevated zero-maze, Contextual fear condition, Tail suspension test, western blotting, immunofluorescence, Fluoro-Jade C Labeling, Perls’ Prussian blue staining, and ELISA were used. Results: HFD caused nonheme iron overload in the brains of APPswe/PS1dE9 (APP/PS1) mice. Furthermore, the administration of M30 (0.5 mg/kg) for iron chelation once every 2 days per os (p.o.) for 1 month remitted memory deficits caused by HFD in APP/PS1 mice. Notably, a variety of hematological parameters in whole blood had no difference after iron chelation. In addition, iron chelation effectively reduced synaptic impairment in hippocampus and neuronal degeneration in cortex in the HFD-fed APP/PS1 mice. Meanwhile, iron chelation decreased Aβ1–40 and Aβ1–42 level as well as neuroinflammation in HFD-fed APP/PS1 mice. Conclusion: These data enhance our understanding of how HFD aggravates AD pathology and cognitive impairments and might shed light on future preclinical studies.

Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is upregulated and causes reactive astrogliosis, synaptic degeneration, and cognitive deficits in Alzheimer's disease (AD). However, the mechanism underlying the increased CIP2A expression in AD brains remains unclear. We here demonstrated that the DNA damage-related Checkpoint kinase 1 (ChK1) is activated in AD human brains and 3xTg-AD mice. ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induces reactive astrogliosis, degeneration of neurons, and exacerbation of AD through the CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 may be a potential therapeutic approach for AD treatment.

Purpose: Chronic granulomatous disease(CGD) is mainly caused by defects in genes encoding subunits of NADPH oxidase complex (CYBB, CYBA, NCF1, NCF2, NCF4), and its chaperone (CYBC1). Next generation sequencing has successfully identified pathogenic variants in 131 clinically confirmed CGD patients in the single center, left 4 cases negative. This study sought to explore new technology to resolve these diagnostic dilemmas at whole genome level. Methods: The clinical data were collected. Optical genome mapping (OGM) was performed to investigate clinically-relevant structural variants greater than 500 bp in size. Targeted long-range PCR followed by next generation sequencing and Sanger sequencing were utilized for confirming breakpoints junctions.Results: OGM find a novel pathogenic copy number variant in NCF2 (1506 bp ~ 1526 bp in length) in P3. The exact downstream breakpoints of this deletion located in a thymine (T) rich region (18 T in reference and 58 T in P3), which remain difficult to detect with current short-read and long-read sequencing. Together with a second pathogenic variant in NCF2 in trans (c.1130_1135del) detected by exome sequencing, P3 was genetically diagnosed. Conclusion: OGM improves genetic diagnostic yield (1/3) in challenging CGD patients. Structural variants in NCF2 and other genes should be considered in undiagnosed CGD disease. Further research in undiagnosed population with OGM is warranted.

Polyphyllin I (PPI) is a natural phytochemical drug isolated from plants which can inhibit the proliferation of cancer cells. One of the PPI tumor-inhibitory effects is through downregulating the expression of Cancerous Inhibitor of PP2A (CIP2A), the latter, is found upregulated in Alzheimer's disease (AD) brains and participates in the development of AD. In this study, we explored the application of PPI in experimental AD treatment in CIP2A-overexpressed cells and 3XTg-AD mice. In CIP2A-overexpressed HEK293 cells or primary neurons, PPI effectively reduced CIP2A level, activated PP2A, and decreased the phosphorylation of tau/APP and the level of Aβ. Furthermore, synaptic protein levels were restored by PPI in primary neurons overexpressing CIP2A. Animal experiments in 3XTg-AD mice revealed that PPI treatment resulted in decreased CIP2A expression and PP2A re-activation. With the modification of CIP2A-PP2A signaling, the hyperphosphorylation of tau/APP and Aβ overproduction were prevented, and the cognitive impairments of 3XTg-AD mice were rescued. In summary, PPI ameliorated AD-like pathology and cognitive impairment through modulating CIP2A-PP2A signaling pathway. It may be a potential drug candidate for the treatment of AD.

Traumatic brain injury (TBI) is regarded as a high-risk factor for Alzheimer's disease (AD). Asparaginyl endopeptidase (AEP), a lysosomal cysteine protease involved in AD pathogenesis, is normally activated under acidic conditions and also in TBI. However, both the molecular mechanism underlying AEP activation-mediated TBI-related AD pathologies, and the role of AEP as an AD therapeutic target, still remain unclear. Here, we report that TBI induces hippocampus dependent cognitive deficit and synaptic dysfunction, accompanied with AEP activation, I2PP2A (inhibitor 2 of PP2A, also called SET) mis-translocation from neuronal nucleus to cytoplasm, an obvious increase in AEP interaction with SET, and tau hyperphosphorylation in hippocampus of rats. Oxygen-glucose deprivation (OGD), mimicking an acidic condition, also leads to AEP activation, SET mis-translocation, PP2A inhibition, tau hyperphosphorylation, and a decrease in synaptic proteins, all of which are abrogated by AEP inhibitor AENK in primary neurons. Interestingly, AENK restores SET back to the nucleus, mitigates tau pathologies, rescuing TBI-induced cognitive deficit in rats. These findings highlight a novel etiopathogenic mechanism of TBI-related AD, which is initiated by AEP activation, accumulating SET in cytoplasm, and favoring tau pathology and cognitive impairments. Lowering AEP activity by AEP inhibitor would be beneficial to AD patients with TBI.