RAD51 paralogs synergize with RAD51 to protect reversed forks from cellular nucleases.

Fork reversal is a conserved mechanism to prevent stalled replication forks from collapsing. Formation and protection of reversed forks are two crucial steps in ensuring fork integrity and stability. Five RAD51 paralogs, namely, RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, which share sequence and structural similarity to the recombinase RAD51, play poorly defined mechanistic roles in these processes. Here, using purified BCDX2 (RAD51BCD-XRCC2) and CX3 (RAD51C-XRCC3) complexes and in vitro reconstituted biochemical systems, we mechanistically dissect their functions in forming and protecting reversed forks. We show that both RAD51 paralog complexes lack fork reversal activities. Whereas CX3 exhibits modest fork protection activity, BCDX2 significantly synergizes with RAD51 to protect DNA against attack by the nucleases MRE11 and EXO1. DNA protection is contingent upon the ability of RAD51 to form a functional nucleoprotein filament on DNA. Collectively, our results provide evidence for a hitherto unknown function of RAD51 paralogs in synergizing with RAD51 nucleoprotein filament to prevent degradation of stressed replication forks.

The HSP40 family chaperone isoform DNAJB6b prevents neuronal cells from tau aggregation.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder with clinical presentations of progressive cognitive and memory deterioration. The pathologic hallmarks of AD include tau neurofibrillary tangles and amyloid plaque depositions in the hippocampus and associated neocortex. The neuronal aggregated tau observed in AD cells suggests that the protein folding problem is a major cause of AD. J-domain-containing proteins (JDPs) are the largest family of cochaperones, which play a vital role in specifying and directing HSP70 chaperone functions. JDPs bind substrates and deliver them to HSP70. The association of JDP and HSP70 opens the substrate-binding domain of HSP70 to help the loading of the clients. However, in the initial HSP70 cycle, which JDP delivers tau to the HSP70 system in neuronal cells remains unclear. RESULTS: We screened the requirement of a diverse panel of JDPs for preventing tau aggregation in the human neuroblastoma cell line SH-SY5Y by a filter retardation method. Interestingly, knockdown of DNAJB6, one of the JDPs, displayed tau aggregation and overexpression of DNAJB6b, one of the isoforms generated from the DNAJB6 gene by alternative splicing, reduced tau aggregation. Further, the tau bimolecular fluorescence complementation assay confirmed the DNAJB6b-dependent tau clearance. The co-immunoprecipitation and the proximity ligation assay demonstrated the protein-protein interaction between tau and the chaperone-cochaperone complex. The J-domain of DNAJB6b was critical for preventing tau aggregation. Moreover, reduced DNAJB6 expression and increased tau aggregation were detected in an age-dependent manner in immunohistochemical analysis of the hippocampus tissues of a mouse model of tau pathology. CONCLUSIONS: In summary, downregulation of DNAJB6b increases the insoluble form of tau, while overexpression of DNAJB6b reduces tau aggregation. Moreover, DNAJB6b associates with tau. Therefore, this study reveals that DNAJB6b is a direct sensor for its client tau in the HSP70 folding system in neuronal cells, thus helping to prevent AD.

TargetMine 2022: a new vision into drug target analysis.

SUMMARY: We introduce the newest version of TargetMine, which includes the addition of new visualization options; integration of previously disaggregated functionality; and the migration of the front-end to the newly available Bluegenes service. AVAILABILITY AND IMPLEMENTATION: TargeteMine is accessible online at https://targetmine.mizuguchilab.org/bluegenes. Users do not need to register to use the software. Source code for the different components listed in the article is available from TargetMine's organizational account at http://github.com/targetmine. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Essential Role of Social Context and Self-Efficacy in Daily Paretic Arm/Hand Use After Stroke: An Ecological Momentary Assessment Study With Accelerometry.

OBJECTIVE: To determine the momentary effect of social-cognitive factors, in addition to motor capability, on post-stroke paretic arm/hand use in the natural environment. DESIGN: A 5-day observational study in which participants were sent 6 Ecological Momentary Assessment (EMA) prompts/day. SETTING: Participants' daily environment. PARTICIPANTS: Community-dwelling, chronic stroke survivors with right-dominant, mild-moderate upper extremity paresis (N=30). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Time duration of bimanual and unimanual paretic arm/hand use indexed by accelerometry; social-cognitive factors (social context, self-efficacy, mood) captured by EMA; motor capability of the paretic limb measured by Fugl-Meyer Upper Extremity Motor Assessment (FM). RESULTS: After accounting for participants' motor capability, we found that momentary social context (alone or not) and self-efficacy significantly predicted post-stroke paretic arm/hand use behavior in the natural environment. When participants were not alone, paretic arm/hand movement increased both with and without the less-paretic limb (bimanual and unimanual movements, P=.018 and P<.001, respectively). Importantly, participants were more likely to use their paretic arm/hand (unimanually) if they had greater self-efficacy for limb use (P=.042). EMA repeated-measures provide a real-time approach that captures the natural dynamic ebb and flow of social-cognitive factors and their effect on daily arm/hand use. We also observed that people with greater motor impairments (FM<50.6) increase unimanual paretic arm/hand movements when they are not alone, regardless of motor capability. CONCLUSIONS: In addition to motor capability, stroke survivors' momentary social context and self-efficacy play a role in paretic arm/hand use behavior. Our findings suggest the development of personalized rehabilitative interventions which target these factors to promote daily paretic arm/hand use. This study highlights the benefits of EMA to provide real-time information to unravel the complexities of the biopsychosocial (ie, motor capability and social-cognitive factors) interface in post-stroke upper extremity recovery.

Efficient thermal treatment of radish (Raphanus sativus) for enhancing its bioactive compounds.

Old preserved radish (OPR), a traditional pickled-food of Asia, contains the healthy bioactive compounds, such as phenols and flavonoids. To preserve the phenols levels in radish by thermal treatment, which are decreased due to the polyphenol oxidase activity during long storage. Range of thermal processing evaluated to retain the maximum phenols level in the radish while processed at temperatures of 70 °C, 80 °C and 90 °C for 30 days. In this study, the bioactive compounds and antioxidant activity of thermal processing radish (TPR) were evaluated and compared with commercial products of OPR. Results showed the best condition of thermal processing, 80°C for 30 days, could increase the values of phenols, flavonoids and antioxidant activity that were 2.27, 2.74 and 2.89 times, respectively. When comparing the thermally processed radish or TPR with OPR, TPR has a higher content of phenols and flavonoids, indicating that the thermal processing was effective to increase the content of functional compounds in radish and significantly improved its nutritional values.

Mitochondrial DNA Copy Number Is Associated With Treatment Response and Cognitive Function in Euthymic Bipolar Patients Receiving Valproate.

BACKGROUND: Bipolar disorder (BD) is associated with cognitive impairment and mitochondrial dysfunction. However, the associations among mitochondrial DNA copy number (MCN), treatment response, and cognitive function remain elusive in BD patients. METHODS: Sixty euthymic BD patients receiving valproate (VPA) and 66 healthy controls from the community were recruited. The indices of metabolic syndrome (MetS) were measured. Quantitative polymerase chain reaction analysis of blood leukocytes was used to measure the MCN. Cognitive function was measured by calculating perseverative errors and completed categories on the Wisconsin Card Sorting Test (WCST). The VPA treatment response was measured using the Alda scale. RESULTS: BD patients had significantly higher MCN, triglyceride, and C-reactive protein (CRP) levels, waist circumference, and worse performance on the WCST than the controls. Regression models showed that BD itself and the VPA concentration exerted significant effects on increased MCN levels. Moreover, the receiver operating characteristic curve analysis showed that an MCN of 2.05 distinguished VPA responders from nonresponders, with an area under the curve of 0.705 and a sensitivity and specificity of 0.529 and 0.816, respectively. An MCN level ≥2.05 was associated with 5.39 higher odds of being a VPA responder (P = .006). BD patients who were stratified into the high-MCN group had a higher VPA response rate, better WCST performance, lower CRP level, and less MetS. CONCLUSIONS: The study suggests a link between the peripheral MCN and cognitive function in BD patients. As an inflammatory status, MetS might modulate this association.

Comprehensive analysis of gut microbiota of a healthy population and covariates affecting microbial variation in two large Japanese cohorts.

BACKGROUND: Inter-individual variations in gut microbiota composition are observed even among healthy populations. The gut microbiota may exhibit a unique composition depending on the country of origin and race of individuals. To comprehensively understand the link between healthy gut microbiota and host state, it is beneficial to conduct large-scale cohort studies. The aim of the present study was to elucidate the integrated and non-redundant factors associated with gut microbiota composition within the Japanese population by 16S rRNA sequencing of fecal samples and questionnaire-based covariate analysis. RESULTS: A total of 1596 healthy Japanese individuals participated in this study via two independent cohorts, NIBIOHN cohort (n = 954) and MORINAGA cohort (n = 642). Gut microbiota composition was described and the interaction of these microorganisms with metadata parameters such as anthropometric measurements, bowel habits, medical history, and lifestyle were obtained. Thirteen genera, including Alistipes, Anaerostipes, Bacteroides, Bifidobacterium, Blautia, Eubacterium halli group, Faecalibacterium, Fusicatenibacter, Lachnoclostridium, Parabacteroides, Prevotella_9, Roseburia, and Subdoligranulum were predominant among the two cohorts. On the basis of univariate analysis for overall microbiome variation, 18 matching variables exhibited significant association in both cohorts. A stepwise redundancy analysis revealed that there were four common covariates, Bristol Stool Scale (BSS) scores, gender, age, and defecation frequency, displaying non-redundant association with gut microbial variance. CONCLUSIONS: We conducted a comprehensive analysis of gut microbiota in healthy Japanese individuals, based on two independent cohorts, and obtained reliable evidence that questionnaire-based covariates such as frequency of bowel movement and specific dietary habit affects the microbial composition of the gut. To our knowledge, this was the first study to investigate integrated and non-redundant factors associated with gut microbiota among Japanese populations.

Unusual Cerebral Aneurysm after Stereotactic Radiosurgery to Treat Trigeminal Neuralgia.

Stereotactic radiosurgery is a treatment option for trigeminal neuralgia. This procedure is minimally invasive, but tumor development and facial numbness have been reported. Here, we report an unusual presentation after stereotactic radiosurgery to treat trigeminal neuralgia. A 60-year-old man demonstrated typical signs for type 1 trigeminal nerve neuralgia and was treated with medication for 5 years. Owing to an intolerance to that medication, he received stereotactic radiosurgery with 66 Gy. During a 9-year follow-up exam, dizziness with a spinning sensation was reported and a right superior cerebellar thrombosed aneurysm was diagnosed. He received transarterial embolization with coiling of aneurysm and subsequently reported no complications on follow-up exams. Although stereotactic radiosurgery is a promising treatment for trigeminal neuralgia, aneurysm development may be considered a possible complication. Long-term follow-up care of these patients should be considered. To understand the relationship between radiosurgery and the potential development of a cerebral aneurysm, further research is needed.

Cerebral air embolism after percutaneous kyphoplasty: a rare case report.

Cerebral air embolism (CAE) is considered as a rare complication during the routine medical procedures in the literature review. We reported a very rare complication of CAE after the percutaneous kyphoplasty (PKP) for the treatment of acute vertebral compression fracture.

Mesenchymal Stem Cell-Derived Extracellular Vesicle: A Promising Alternative Therapy for Osteoporosis.

Osteoporosis is the chronic metabolic bone disease caused by the disturbance of bone remodeling due to the imbalance of osteogenesis and osteoclastogenesis. A large population suffers from osteoporosis, and most of them are postmenopausal women or older people. To date, bisphosphonates are the main therapeutic agents in the treatment of osteoporosis. However, limited therapeutic effects with diverse side effects caused by bisphosphonates hindered the therapeutic applications and decreased the quality of life. Therefore, an alternative therapy for osteoporosis is still needed. Stem cells, especially mesenchymal stem cells, have been shown as a promising medication for numerous human diseases including many refractory diseases. Recently, researchers found that the extracellular vesicles derived from these stem cells possessed the similar therapeutic potential to that of parental cells. To date, a number of studies demonstrated the therapeutic applications of exogenous MSC-EVs for the treatment of osteoporosis. In this article, we reviewed the basic back ground of EVs, the cargo and therapeutic potential of MSC-EVs, and strategies of engineering of MSC-EVs for osteoporosis treatment.

Evaluation of Class IIa Histone Deacetylases Expression and In Vivo Epigenetic Imaging in a Transgenic Mouse Model of Alzheimer's Disease.

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.

Effect of Cerenkov Radiation-Induced Photodynamic Therapy with 18F-FDG in an Intraperitoneal Xenograft Mouse Model of Ovarian Cancer.

Ovarian cancer (OC) metastases frequently occur through peritoneal dissemination, and they contribute to difficulties in treatment. While photodynamic therapy (PDT) has the potential to treat OC, its use is often limited by tissue penetration depth and tumor selectivity. Herein, we combined Cerenkov radiation (CR) emitted by 18F-FDG accumulated in tumors as an internal light source and several photosensitizer (PS) candidates with matched absorption bands, including Verteporfin (VP), Chlorin e6 (Ce6) and 5'-Aminolevulinic acid (5'-ALA), to evaluate the anti-tumor efficacy. The in vitro effect of CR-induced PDT (CR-PDT) was evaluated using a cell viability assay, and the efficiency of PS was assessed by measuring the singlet oxygen production. An intraperitoneal ES2 OC mouse model was used for in vivo evaluation of CR-PDT. Positron emission tomography (PET) imaging and bioluminescence-based imaging were performed to monitor the biologic uptake of 18F-FDG and the therapeutic effect. The in vitro studies demonstrated Ce6 and VP to be more effective PSs for CR-PDT. Moreover, VP was more efficient in the generation of singlet oxygen and continued for a long time when exposed to fluoro-18 (18F). Combining CR emitted by 18F-FDG and VP treatment not only significantly suppressed tumor growth, but also prolonged median survival times compared to either monotherapy.

Reduction of 3-Deoxyglucosone by Epigallocatechin Gallate Results Partially from an Addition Reaction: The Possible Mechanism of Decreased 5-Hydroxymethylfurfural in Epigallocatechin Gallate-Treated Black Garlic.

5-Hydroxymethylfurfural (5-HMF) is a harmful substance generated during the processing of black garlic. Our previous research demonstrated that impregnation of black garlic with epigallocatechin gallate (EGCG) could reduce the formation of 5-HMF. However, there is still a lack of relevant research on the mechanism and structural identification of EGCG inhibiting the production of 5-HMF. In this study, an intermediate product of 5-HMF, 3-deoxyglucosone (3-DG), was found to be decreased in black garlic during the aging process, and impregnation with EGCG for 24 h further reduced the formation of 3-DG by approximately 60% in black garlic compared with that in the untreated control. The aging-mimicking reaction system of 3-DG + EGCG was employed to determine whether the reduction of 3-DG was the underlying mechanism of decreased 5-HMF formation in EGCG-treated black garlic. The results showed that EGCG accelerated the decrease of 3-DG and further attenuated 5-HMF formation, which may be caused by an additional reaction with 3-DG, as evidenced by LC-MS/MS analysis. In conclusion, this study provides new insights regarding the role of EGCG in blocking 5-HMF formation.

Quantitative comparison of endoscopically assisted endonasal, sublabial and transorbital transmaxillary approaches to the anterolateral skull base.

OBJECTIVES: The aim of this anatomical study is to make quantitative comparison among three endoscopic approaches, encompassing contralateral endonasal transseptal transmaxillary transpterygoid approach (contralateral EEA), endoscopic sublabial transmaxillary transalisphenoid (Caldwell-Luc) approach and endoscopic transorbital transmaxillary approach through inferior orbital fissure (ETOA), to the anterolateral skull base for assisting preoperative planning. DESIGN & PARTICIPANTS: Anatomical dissections were performed in four adult cadaveric heads bilaterally using three endoscopic transmaxillary approaches described above. SETTING: Skull Base Laboratory at the National Defense Medical Center. MAIN OUTCOME MEASURES: The area of exposure, angles of attack and depth of surgical corridor of each approach were measured and obtained for statistical comparison. RESULTS: The ETOA had significantly larger exposure over middle cranial fossa (731.40 ± 80.08 mm2 ) than contralateral EEA (266.60 ± 46.74 mm2 ) and Caldwell-Luc approach (468.40 ± 59.67 mm2 ). In comparison with contralateral EEA and Caldwell-Luc approach, the ETOA offered significantly greater angles of attack and shorter depth of surgical corridor (P < .05 for all comparisons). CONCLUSIONS: The ETOA is the superior choice for target lesion occupying multiple compartments with its epicentre located in the middle cranial fossa or superior portion of infratemporal fossa.

Extrahepatic pseudocyst in an adult.

Ventriculoperitoneal (VP) shunts are commonly used in neurosurgical procedures to treat hydrocephalus. Although shunt-associated abdominal complications are well documented, extrahepatic pseudocysts are a rare shunt complication in adult patients. Therefore, we herein report the case of a 54-year-old male patient who presented with a bulging mass around the previous surgical site at the right upper quadrant of the abdomen. He had a 4-year history of VP shunt surgery for posthemorrhagic hydrocephalus. A computed tomographic scan revealed a large extrahepatic pseudocsyt. Our case represented a rare entity of extrahepatic pseudocyst in adult patients underwent VP shunt surgery. The clinical presentation, diagnostic tools, and treatment methods were discussed.

Recovering cavity effects in corrugated organic light emitting diodes.

Cavity effects play an important role in determining the out-coupling efficiency of an OLED. By fabricating OLEDs on corrugated substrates, the waveguide and SPP modes can be extracted by diffraction. However, corrugation does not always lead to an enhancement in out-coupling efficiency due to the reduction of the electrode reflectance and hence the cavity effects. Based on the results of our rigorous couple-wave analysis (RCWA) simulation, we found that the cavity effects can be partially recovered using a low index Teflon layer inserted between the ITO anode and the substrate due to the enhancement of the reflectance of the corrugated electrodes. To verify the simulation results, we fabricated corrugated OLEDs having a low-index Teflon interlayer with an EQE of 36%, which is 29% higher than an optimized planar OLED. By experimentally measuring the OLED air mode dispersion, we confirm the cavity emission of a corrugated OLED is enhanced by the low index layer.

Integrating sequence and gene expression information predicts genome-wide DNA-binding proteins and suggests a cooperative mechanism.

DNA-binding proteins (DBPs) perform diverse biological functions ranging from transcription to pathogen sensing. Machine learning methods can not only identify DBPs de novo but also provide insights into their DNA-recognition dynamics. However, it remains unclear whether available methods that can accurately predict DNA-binding sites in known DBPs can also identify novel DBPs. Moreover, sequence information is blind to the cellular- and disease-specific contexts of DBP activities, whereas the under-utilized knowledge from public gene expression data offers great promise. To address these issues, we have developed novel methods for predicting DBPs by integrating sequence and gene expression-derived features and applied them to explore human, mouse and Arabidopsis proteomes. While our sequence-based models outperformed the gene expression-based ones, some proteins with weaker DBP-like sequence features were correctly predicted by gene expression-based features, suggesting that these proteins acquire a tangible DBP functionality in a conducive gene expression environment. Analysis of motif enrichment among the co-expressed genes of top 100 candidates DBPs from hitherto unannotated genes provides further avenues to explore their functional associations.

Impact of quality trimming on the efficiency of reads joining and diversity analysis of Illumina paired-end reads in the context of QIIME1 and QIIME2 microbiome analysis frameworks.

BACKGROUND: To increase the accuracy of microbiome data analysis, solving the technical limitations of the existing sequencing machines is required. Quality trimming is suggested to reduce the effect of the progressive decrease in sequencing quality with the increased length of the sequenced library. In this study, we examined the effect of the trimming thresholds (0-20 for QIIME1 and 0-30 for QIIME2) on the number of reads that remained after the quality control and chimera removal (the good reads). We also examined the distance of the analysis results to the gold standard using simulated samples. RESULTS: Quality trimming increased the number of good reads and abundance measurement accuracy in Illumina paired-end reads of the V3-V4 hypervariable region. CONCLUSIONS: Our results suggest that the pre-analysis trimming step should be included before the application of QIIME1 or QIIME2.

Combined treatment of sodium ferulate, n-butylidenephthalide, and ADSCs rehabilitates neurovascular unit in rats after photothrombotic stroke.

The remodelling of structural and functional neurovascular unit (NVU) becomes a central therapeutic strategy after cerebral ischaemic stroke. In the present study, we investigated the effect of combined therapy of sodium ferulate (SF), n-butylidenephthalide (BP) and adipose-derived stromal cells (ADSCs) to ameliorate the injured NVU in the photochemically induced thrombotic stroke in rats. After solely or combined treatment, the neovascularization, activation of astrocytes, neurogenesis, expressions of vascular endothelial growth factor (VEGF) and claudin-5 were assessed by immunohistochemical or immunofluorescence staining. In order to uncover the underlying mechanism of therapeutic effect, signalling of protein kinase B/mammalian target of rapamycin (AKT/mTOR), extracellular signal-regulated kinase 1/2 (ERK1/2), and Notch1 in infarct zone were analysed by western blot. 18 F-2-deoxy-glucose/positron emission tomography, magnetic resonance imaging, Evans blue staining were employed to evaluate the glucose metabolism, cerebral blood flow (CBF), and brain-blood barrier (BBB) permeability, respectively. The results showed that combined treatment increased the neovascularization, neurogenesis, and VEGF secretion, modulated the astrocyte activation, enhanced the regional CBF, and glucose metabolism, as well as reduced BBB permeability and promoted claudin-5 expression, indicating the restoration of structure and function of NVU. The activation of ERK1/2 and Notch1 pathways and inhibition of AKT/mTOR pathway might be involved in the therapeutic mechanism. In summary, we have demonstrated that combined ADSCs with SF and BP, targeting the NVU remodelling, is a potential treatment for ischaemic stroke. These results may provide valuable information for developing future combined cellular and pharmacological therapeutic strategy for ischaemic stroke.

Mono-Heteroatom Substitution for Harnessing Excited-State Structural Planarization of Dihydrodibenzo[a,c]phenazines.

With the aim of generalizing the structure-properties relationship of bending heterocyclic molecules that undergo prominent photoinduced structural planarization (PISP), a series of new dihydrodibenzo[ac]phenazine derivatives in which one nitrogen atom is replaced by oxygen (PNO), sulfur (PNS), selenium (PNSe), or dimethylmethanediyl (PNC) was strategically designed and synthesized. Compounds PNO, PNS, and PNSe have significantly nonplanar geometries in the ground state, which undergo PISP to give a planarlike conformer and hence a large emission Stokes shift. A combination of femtosecond early relaxation dynamics and computational approaches established an R*→I* (intermediate)→P* sequential kinetic pattern for PNS and PNSe, whereas PNO undergoes R*→P* one-step kinetics. The polarization ability of the substituted heteroatoms, which is in the order O