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Abstract: Graft-versus-host disease (GvHD), including the acute and chronic types (aGvHD, cGvHD), arise as the dominating secondary disease in patients with unsatisfying consequences of allogeneic hematopoietic stem cell transplantation (HSCT). Approximately half of GvHD patients were steroid-resistant, with a two-year overall survival rate lower than 20%. Worse still, there are no standardized criteria for an optimal second-line therapy for steroid-resistant aGVHD patients. Notably, pioneering investigators have highlighted the ameliorative or therapeutic effects of human umbilical cord-derived mesenchymal stem/stromal cells (hUC-MSCs) upon GvHD largely attributed to their unique hematopoietic-supporting and immunomodulatory properties. Of note, quality control (QC) is the prerequisite to assure the safety and quality of hUC-MSCs before investigational new drug (IND) applications and large-scale clinical applications. Herein, we summarize the state-of-the-art updates upon IND-associated QC and clinical trials of hUC-MSCs during allogeneic HSCT in China. Meanwhile, the supervisory policy and medical ethics of current licensed MSC products for GvHD administration and the concomitant opportunities and challenges have also been discussed.

The community coupler (C-Coupler) for Earth system modelling is a coupler family that was developed in China in 2010. C-Coupler3.0, the latest version, is fully compatible with the previous version, C-Coupler2, and is an integrated infrastructure with new features, i.e. a series of parallel-optimization technologies for accelerating coupling initialization and reducing memory usage, a common halo-exchange library for developing a parallel version of a model, a common module-integration framework for integrating a software module (e.g. a flux algorithm, a parameterization scheme, and a data assimilation method), a common framework for conveniently developing a weakly coupled ensemble data assimilation system, and a common framework for flexibly inputting and outputting fields in parallel. Specifically, C-Coupler3.0 is able to handle coupling under much finer resolutions (e.g. more than 100 million horizontal grid cells) with fast coupling initialization and successful generation of remapping-weight files.

Background: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. Methods: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan ( Bgn ), Tlr3 , and IFN-α/β receptor alpha chain ( Ifnar1 )–deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. Results: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn −/− , Tlr3 −/− , and Ifnar1 −/− mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1–BGN–TLR3–interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. Conclusions: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

BACKGROUND: Few studies have compared the clinical efficacy of unilateral and bilateral pedicle screw fixation and fusion in treating atlantoaxial fracture-dislocation. OBJECTIVE: To compare the efficacy of unilateral and bilateral fixation and fusion for atlantoaxial fracture-dislocation and to explore the feasibility of the unilateral surgical procedure. METHODS: Twenty-eight consecutive patients with atlantoaxial fracture-dislocation were included in the study from June 2013 to May 2018. They were divided into a unilateral fixation group and a bilateral fixation group (14 patients in each group with an average age of 43.6 ± 16.3 years and 51.8 ± 15.4 years, respectively). The unilateral group had a unilateral anatomical variation of the pedicle or vertebral artery, or traumatic pedicle destruction. All patients underwent atlantoaxial unilateral or bilateral pedicle screw fixation and fusion. Intraoperative blood loss and operation time were recorded. The visual analog scale (VAS) and Japanese Orthopedic Association (JOA) scoring systems were used to evaluate pre- and postoperative occipital-neck pain and neurological function. X-ray and computerized tomography (CT) were used to assess atlantoaxial stability, the implants’ position, and bone graft fusion. RESULTS: All patients were followed up for 39–71 months postoperatively. Intraoperatively, no spinal cord or vertebral artery injury was observed. At the last follow-up, occipital-neck pain and neurological function in the two groups were significantly improved (P< 0.05). The X-ray films and CT showed satisfactory atlantoaxial stability, implant position, and osseous fusion in all the patients at 6 months postoperatively. CONCLUSION: Unilateral and bilateral pedicle screw fixation and fusion can restore atlantoaxial stability and improve occipital-neck pain and neurological function in patients with atlantoaxial fracture-dislocation. The unilateral surgical procedure can be a supplementary option for patients with unilateral abnormal atlantoaxial lesions.

Using a large ensemble of simulations from the Polar Amplification Model Intercomparison Project (PAMIP) and Coupled Model Intercomparison Project Phase 6 (CMIP6), we compare the response of winter-mean precipitation and daily extremes across the North Hemisphere in response to future Arctic sea-ice loss and global ocean warming. North Atlantic is simulated to become drier in response to future Arctic sea-ice loss, with reduced precipitation intensity and more dry days. A wetting response to sea-ice loss is simulated over the midlatitude Atlantic Ocean. These responses are robust across the eight models analysed, albeit with differences in their magnitude and spatial pattern. The precipitation response to global ocean warming is broadly opposite in sign, but larger in magnitude, compared to the response to sea-ice loss, over these regions. The precipitation responses to both sea-ice loss and ocean warming are strongly related to coincident changes in storm density and intensity. More specifically, there is an equatorward shift of the North Atlantic storm track in response to sea-ice loss, and northeastern extension of the North Atlantic storm track and weakening of Mediterranean storm track in response to ocean warming. The linear combination of the responses of future Arctic sea-ice loss and global ocean warming explain well the spatial pattern of the precipitation change at 2 °C global warming projected in CMIP6. Our results suggest that projected future precipitation change over North Atlantic reflects a ‘tug-of-war’ between Arctic sea-ice loss and global ocean warming, but the latter dominates over the former.

Childhood maltreatment has been suggested to have an adverse impact on neurodevelopment, including microstructural brain abnormalities. Existing neuroimaging findings remain inconsistent and heterogeneous. We aim to explore the most prominent and robust cortical thickness (CTh) and gray matter volume (GMV) alterations associated with childhood maltreatment. A systematic search on relevant studies was conducted through September 2022. The whole-brain coordinate-based meta-analysis (CBMA) on CTh and GMV studies were conducted using the seed-based d mapping (SDM) software. Meta-regression analysis was subsequently applied to investigate potential associations between clinical variables and structural changes. A total of 45 studies were eligible for inclusion, including 11 datasets on CTh and 39 datasets on GMV, consisting of 2550 participants exposed to childhood maltreatment and 3739 unexposed comparison subjects. Individuals with childhood maltreatment exhibited overlapped deficits in the median cingulate/paracingulate gyri simultaneously revealed by both CTh and GM studies. Regional cortical thinning in the right anterior cingulate/paracingulate gyri and the left middle frontal gyrus, as well as GMV reductions in the left supplementary motor area (SMA) was also identified. No greater regions were found for either CTh or GMV. In addition, several neural morphology changes were associated with the average age of the maltreated individuals. The median cingulate/paracingulate gyri morphology might serve as the most robust neuroimaging feature of childhood maltreatment. The effects of early-life trauma on the human brain predominantly involved in cognitive functions, socio-affective functioning and stress regulation. This current meta-analysis enhanced the understanding of neuropathological changes induced by childhood maltreatment.

Objectives Fluoxetine has been used as the first line for the therapy of depression. However, lack of therapeutic efficacy and time lag still limit the application of fluoxetine. Gap junction dysfunction is a potentially novel pathogenic mechanism for depression. To clarify the mechanism underlying these limitations, we investigated whether gap junction was related to the antidepressant effects of fluoxetine. Methods and key findings After chronic unpredictable stress (CUS), animals showed decreases in gap junction intracellular communication (GJIC). Treatment with fluoxetine 10 mg/kg significantly improved GJIC and anhedonia of rats until six days. These results indicated that fluoxetine improved gap junction indirectly. Furthermore, to test the role of gap junction on antidepressant effects of fluoxetine, we blocked gap junction using carbenoxolone (CBX) infusion in the prefrontal cortex. CBX dampened fluoxetine-induced decrease in immobility time of mice in tail suspension test (TST). Conclusions Our study suggested that gap junction dysfunction blocks antidepressant effects of fluoxetine, contributing to understanding the mechanism underlying the time lag of fluoxetine.

Due to ultra-high theoretical capacity (4200 mAh g

The highly penetrated distributed generators (DGs) aggravate the voltage violations in active distribution networks (ADNs). The coordination of various regulation devices such as on-load tap changers (OLTCs) and DG inverters can effectively address the voltage issues. Considering the problems of inaccurate network parameters and rapid DG fluctuation in practical operation, multi-source data can be utilized to establish the data-driven control model. In this paper, a data-driven coordinated voltage control method with the coordination of OLTC and DG inverters on multiple time-scales is proposed without relying on the accurate physical model. First, based on the multi-source data, a data-driven voltage control model is established. Multiple regulation devices such as OLTC and DG are coordinated on multiple time-scales to maintain voltages within the desired range. Then, a critical measurement selection method is proposed to guarantee the voltage control performance under the partial measurements in practical ADNs. Finally, the proposed method is validated on the modified IEEE 33-node and IEEE 123-node test cases. Case studies illustrate the effectiveness of the proposed method, as well as the adaptability to DG uncertainties.

Ning-Ping Foo,1,2 Yang Chien Tun,3 Che Chao Chang,4,5 Hung-Lin Lin,3 Cheng-Hsin Cheng,2,4,&ast; Hao-Yu Chuang4,6,&ast; 1Department of Emergency, An Nan Hospital, China Medical University, Tainan, 70965 Taiwan; 2Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, 71101 Taiwan; 3Department of Neurosurgery, China Medical University Hospital, Taichung, 40447 Taiwan; 4Department of Neurosurgery, An Nan Hospital, China Medical University, Tainan, 70965 Taiwan; 5Neurophysiology Laboratory, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan, 70101 Taiwan; 6Department of Neurosurgery, China Medical University Beigang Hospital, Beigang, Yunlin County, 65152 Taiwan&ast;These authors contributed equally to this workCorrespondence: Cheng-Hsin Cheng; Hao-Yu Chuang, Department of Neurosurgery, An-Nan Hospital, China Medical University, No. 66, Sec. 2, Changhe Road, Annan District, Tainan City, Taiwan, Tel +886-6-3553111, Email u701018.tw@yahoo.com.tw; sn232099@gmail.comObjective: This study aimed to evaluate the functional outcomes of lumboperitoneal (LP) shunt for the treatment of non-obstructive hydrocephalus.Methods: We retrospectively studied the clinical surgical results of 172 adult patients with hydrocephalus who underwent LP shunt surgery between June 2014 and June 2019. Data regarding the following were collected: pre- and postoperative symptom status, third ventricle width changes, Evans index, and postoperative complications. Additionally, the baseline and follow-up Glasgow Coma Scale (GCS) score, Glasgow Outcome Scale (GOS), and Modified Rankin Scale (mRS) scores were investigated. All patients were followed up for ≥ 12 months using clinical interview and braining imaging using computed tomography (CT) scan or magnetic resonance imaging (MRI).Results: Majority of patients presented with normal pressure hydrocephalus as the etiology of their disease (48.8%), followed by cardiovascular accident (28.5%), trauma (19.7%), and brain tumor (3%). The mean GCS, GOS, and mRS improved postoperatively. The average period from symptomatic onset to surgery was 402 days. The average width of the third ventricle on CT scan or MRI was 11.43 mm preoperatively and 10.8 mm postoperatively (P< 0.001). The Evans index improved from 0.258 to 0.222 after operation. The symptomatic improvement score was 7.0, with a complication rate of 7%.Conclusion: Significant improvement was observed in the functional score and brain image after LP shunt placement. Moreover, the satisfaction with symptomatic improvement after surgery remains high. LP shunt operation is a viable alternative in the treatment of non-obstructive hydrocephalus due to the low complication rate, fast recovery, and high satisfaction.Keywords: clinical outcome, complication, lumboperitoneal shunt, non-obstructive hydrocephalus