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Abstract Background Acute-phase reactions (APRs) are common among people treated for the first time with zoledronate (ZOL). The current view is that both the APRs caused by ZOL and its efficacy are related to the mevalonic acid pathway. However, the relationship between APRs and ZOL efficacy remains unclear. Methods This was a prospective observational cohort study involving postmenopausal women with osteoporosis in Shanghai, China, for 1 year. A total of 108 patients with an average age of 67.4 ± 5.8 years were treated with 5 mg intravenous ZOL for the first time. Data on demographic characteristics, APRs, blood counts, bone turnover markers, including C-telopeptide collagen crosslinks (CTX) and N-terminal propeptide of type 1 collagen (PINP), and bone mineral density (BMD) were collected. Results (1) The results did not reveal a relationship between APRs and changes in bone turnover markers and BMD but showed that changes in body temperature (T) within 3 days after administration were positively correlated with changes in the BMD of the LS at Month 12 (β = 0.279 P = 0.034). (2) This effect was mediated mainly by changes in serum CTX (b = 0.046, 95% CI [0.0010–0.0091]). (3) The ROC curve revealed that when T increased by 1.95 °C, the sensitivity and specificity of identifying clinically important changes in LS BMD after 1 year were optimized. Conclusions In this study, we tested the hypothesis that people with elevated body T after initial ZOL treatment had greater improvements in BMD and better outcomes. Trial registration NCT, NCT03158246. Registered 18/05/2017.

Abstract Purpose Good sleep is one of the necessary conditions to ensure the normal performance of the physiological and psychological functions of college students. This study aimed to explore the relationship between mobile phone addiction and bedtime procrastination among Chinese college students and the mediating mechanisms of physical exercise and anxiety between the two, with a view to seek ways to prevent and intervene in college students’ sleep procrastination and improve their sleep quality. Methods Using SPSS 29.0 analysis with Bootstrap’s method, 3,800 first-year students, sophomores, and juniors were given the Mobile Phone Addiction Tendency Scale, Bedtime Procrastination Scale, Physical Activity Scale, and Anxiety Scale. The results of the analyses included mediation tests and effect analyses of anxiety and physical activity. Results The correlation analysis revealed significant positive correlations between mobile phone addiction and bedtime procrastination (r = 0.149, p

Abstract Efficiently fabricating a cavity that can achieve strong interactions between terahertz waves and matter would allow researchers to exploit the intrinsic properties due to the long wavelength in the terahertz waveband. Here we show a terahertz detector embedded in a Tamm cavity with a record Q value of 1017 and a bandwidth of only 469 MHz for direct detection. The Tamm-cavity detector is formed by embedding a substrate with an Nb5N6 microbolometer detector between an Si/air distributed Bragg reflector (DBR) and a metal reflector. The resonant frequency can be controlled by adjusting the thickness of the substrate layer. The detector and DBR are fabricated separately, and a large pixel-array detector can be realized by a very simple assembly process. This versatile cavity structure can be used as a platform for preparing high-performance terahertz devices and opening up the study of the strong interactions between terahertz waves and matter.

Aluminum (Al), the most abundant metallic element on the earth crust, has been reckoned as a promising battery material for its the highest theoretical volume capacity (8046 mAh cm−3). Being rechargeable in ionic liquid electrolytes, however, the Al anode and battery case suffer from corrosion. On the other hand, Al is irreversible in aqueous electrolyte with severe hydrogen evolution reaction. Here, we demonstrate a water-in-salt aluminum ion electrolyte (WISE) based on Al and lithium salts to tackle the above challenges. In the WISE system, water molecules can be confined within the Li+ solvation structures. This diminished Al3+-H2O interaction essentially eliminates the hydrolysis effect, effectively protecting Al anode from corrosion. Therefore, long-term Al plating/stripping can be realized. Furthermore, two types of high-performance full batteries have been demonstrated using copper hexacyanoferrate (CuHCF, a Prussian Blue Analogues) and LiNi0.8Co0.1Mn0.1O2 (NCM) as cathodes. The reversibility of Al anode laid the foundation for low cost rechargeable batteries suffering for large-scale energy storage.Broader context: Al batteries are expected to become a safe and sustainable alternative to lithium batteries. For decades, chase for a feasible Al secondary battery has not been successful. The key challenge is to find suitable cathode and electrolyte materials, together with which Al anode battery can function reversibly. Currently, fatal drawbacks have impeded the practical application of Al metal batteries (AMBs), such as sustained corrosion of Al anode and battery case in ionic liquid electrolytes, irreversibility issues as well as severe hydrogen evolution reaction during cycling in aqueous electrolyte. Therefore, electrolyte and their electrochemical kinetics play a vital role in the performance and environmental operating limitations of high-energy Al metal batteries. In this work, we demonstrate a nearly neutral Al ion water-in-salt electrolyte (WISE) to tackle the above challenges. The WISE shows excellent stability in the open atmosphere. The distinct solvation-sheath structure of Al3+ in the WISE system would protect Al metal anodes from corrosion and eliminate hydrogen evolution reaction effectively, further promoting the reversibility of Al metal anodes with dendrite-free morphology. Moreover, such a WISE exhibits superior compatibility with LiNi0.3Co0.3Mn0.3O2 (NCM) and copper hexacyanoferrate (CuHCF) cathodes and long-term stabilities with high coulombic efficiency (CE) can be attained for full batteries with the WISE. The approach in this study can furnish an opportunity to develop reversible AMBs and lay the foundation for other potential multivalent-metal-based secondary batteries suffering from interface passivation and poor reversibility, which suggest the promise of multivalent metal batteries and their applications in large-scale energy storage.

Objectives To appraise the quality of clinical practice guidelines (CPGs) and expert consensus statements on rehabilitation for patients with COVID-19, summarise recommendations of rehabilitation assessments and interventions and evaluate the heterogeneity of the recommendations.Design Systematic review.Data sources PubMed and Embase databases and five online guideline repositories: The National Guideline Clearinghouse, Guidelines International Network, Scottish Intercollegiate Guidelines Network, National Institute for Health and Clinical Excellence and WHO were searched from their inception to August 2024. In addition, we reviewed reference lists of eligible citations and searched the grey literature on the relevant websites.Eligibility criteria for selecting studies We included CPGs and expert consensus statements which provided information about rehabilitation of patients with COVID-19. To be eligible, the CPGs and expert consensus statements were issued in English by a nationally or internationally recognised government authority, medical/academic society or organisation. If there were multiple versions of the guidelines, we included the latest one. The translations, interpretations and abstracts of guidelines were excluded.Data extraction and synthesis All recommendations on rehabilitation assessments and interventions for COVID-19 were extracted and summarised. Two reviewers independently evaluated the methodological quality with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, and two other reviewers assessed the reporting quality using the Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement of included CPGs and expert consensus statements. We used the Measurement Scale of Rate of Agreement to evaluate the heterogeneity of the recommendations in different CPGs and expert consensus statements.Results A total of 31 CPGs and expert consensus statements were included. 14 guidelines provided recommendations for rehabilitation assessments. At the early, development, critical and recovery stages of COVID-19, the most frequently recommended were exercise therapy (25.8%, 35.5%, 25.8% and 58.1%, respectively). According to AGREE II, 17 included guidelines were assessed as low methodological quality (35%–56%), 10 guidelines were rated as moderate quality (46%– 62%) and four had high quality (69%–79%). Among 31 eligible guidelines, the reporting rate of 22 items in the RIGHT checklist ranged from 10% to 100%. The included guidelines were consistent with the reference guidelines (80%–100%). Only one guideline existed minor (60%–80%) disagreements in respiratory muscle training relative to the reference guideline.Conclusions Rehabilitation assessments and interventions should be implemented consistently throughout the entire process of COVID-19. The recommendations should be tailored to each stage of COVID-19. The methodological and reporting qualities of several guidelines remain suboptimal. Therefore, developers should adhere strictly to the AGREE II standard and RIGHT checklist to formulate and publish CPGs and expert consensus statements with high quality.PROSPERO registration number CRD42020190761.

Abstract Background Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. Methods The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. Results The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. Conclusions Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

Abstract Background Macrophage activation may play a crucial role in the increased susceptibility of obese individuals to acute lung injury (ALI). Dysregulation of miRNA, which is involved in various inflammatory diseases, is often observed in obesity. This study aimed to investigate the role of miR-192 in lipopolysaccharide (LPS)-induced ALI in obese mice and its mechanism of dysregulation in obesity. Methods Human lung tissues were obtained from obese patients (BMI ≥ 30.0 kg/m2) and control patients (BMI 18.5–24.9 kg/m2). An obese mouse model was established by feeding a high-fat diet (HFD), followed by intratracheal instillation of LPS to induce ALI. Pulmonary macrophages of obese mice were depleted through intratracheal instillation of clodronate liposomes. The expression of miR-192 was examined in lung tissues, primary alveolar macrophages (AMs), and the mouse alveolar macrophage cell line (MH-S) using RT-qPCR. m6A quantification and RIP assays helped determine the cause of miR-192 dysregulation. miR-192 agomir and antagomir were used to investigate its function in mice and MH-S cells. Bioinformatics and dual-luciferase reporter gene assays were used to explore the downstream targets of miR-192. Results In obese mice, depletion of macrophages significantly alleviated lung tissue inflammation and injury, regardless of LPS challenge. miR-192 expression in lung tissues and alveolar macrophages was diminished during obesity and further decreased with LPS stimulation. Obesity-induced overexpression of FTO decreased the m6A modification of pri-miR-192, inhibiting the generation of miR-192. In vitro, inhibition of miR-192 enhanced LPS-induced polarization of M1 macrophages and activation of the AKT/ NF-κB inflammatory pathway, while overexpression of miR-192 suppressed these reactions. BIG1 was confirmed as a target gene of miR-192, and its overexpression offset the protective effects of miR-192. In vivo, when miR-192 was overexpressed in obese mice, the activation of pulmonary macrophages and the extent of lung injury were significantly improved upon LPS challenge. Conclusions Our study indicates that obesity-induced downregulation of miR-192 expression exacerbates LPS-induced ALI by promoting macrophage activation. Targeting macrophages and miR-192 may provide new therapeutic avenues for obesity-associated ALI. Graphical Abstract

Abstract Background Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. Methods Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. Results Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. Conclusions AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.

Abstract Background Both epidemiological and clinical studies have indicated that headache and sleep disturbances share a complex relationship. Although headache and sleep share common neurophysiological and anatomical foundations, the mechanism underlying their interaction remains poorly understood. The structures of the diencephalon and brainstem, particularly the locus coeruleus (LC), are the primary sites where the sleep and headache pathways intersect. To better understand the intricate nature of the relationship between headache and sleep, our study focused on investigating the role and function of noradrenergic neurons in the LC during acute headache and acute sleep disturbance. Method To explore the relationship between acute headache and acute sleep disturbance, we primarily employed nitroglycerin (NTG)-induced migraine-like headache and acute sleep deprivation (ASD) models. Initially, we conducted experiments to confirm that ASD enhances headache and that acute headache can lead to acute sleep disturbance. Subsequently, we examined the separate roles of the LC in sleep and headache. We observed the effects of drug-induced activation and inhibition and chemogenetic manipulation of LC noradrenergic neurons on ASD-induced headache facilitation and acute headache-related sleep disturbance. This approach enabled us to demonstrate the bidirectional function of LC noradrenergic neurons. Results Our findings indicate that ASD facilitated the development of NTG-induced migraine-like headache, while acute headache affected sleep quality. Furthermore, activating the LC reduced the headache threshold and increased sleep latency, whereas inhibiting the LC had the opposite effect. Additional investigations demonstrated that activating LC noradrenergic neurons further intensified pain facilitation from ASD, while inhibiting these neurons reduced this pain facilitation. Moreover, activating LC noradrenergic neurons exacerbated the impact of acute headache on sleep quality, while inhibiting them alleviated this influence. Conclusion The LC serves as a significant anatomical and functional region in the interaction between acute sleep disturbance and acute headache. The involvement of LC noradrenergic neurons is pivotal in facilitating headache triggered by ASD and influencing the effects of headache on sleep quality.

Background Targeting kinases presents a potential strategy for treating solid tumors; however, the therapeutic potential of vaccines targeting kinases remains uncertain.Methods Adenovirus (Ad) vaccines encoding Aurora kinase A (AURKA) or cyclin-dependent kinase 7 (CDK7) were developed, and their therapeutic potentials were investigated by various methods including western blot, flow cytometry, cytotoxic T lymphocyte assay, and enzyme-linked immunospot (ELISpot), in mouse and humanized solid tumor models.Results Co-immunization with Ad-AURKA/CDK7 effectively prevented subcutaneous tumor growth in the Renca, RM-1, MC38, and Hepa1-6 tumor models. In therapeutic tumor models, Ad-AURKA/CDK7 treatment impeded tumor growth and increased immune cell infiltration. Administration of Ad-AURKA/CDK7 promoted the induction and maturation of dendritic cell subsets and augmented multifunctional CD8+ T-cell antitumor immunity. Furthermore, the vaccine induced a long-lasting antitumor effect by promoting the generation of memory CD8+ T cells. Tumor recovery on CD8+ T-cell depletion underscored the indispensable role of these cells in the observed therapeutic effects. The potent efficacy of the Ad-AURKA/CDK7 vaccine was consistently demonstrated in lung metastasis, orthotopic, and humanized tumor models by inducing multifunctional CD8+ T-cell antitumor immune responses.Conclusions Our findings illustrate that the Ad-AURKA/CDK7 vaccine targeting dual kinases AURKA and CDK7 emerges as a promising and effective therapeutic approach for the treatment of solid tumors.

Sepsis is a syndrome that causes dysfunction of multiple organs due to the host's uncontrolled response to infection and is a significant contributor to morbidity and mortality in intensive care units worldwide. Surviving patients are often left with acute brain injury and long-term cognitive impairment, known as sepsis-associated encephalopathy (SAE). In recent years, researchers have directed their focus towards the pathogenesis of SAE. However, due to the complexity of its development, there remains a lack of effective treatment measures that arise as a serious issue affecting the prognosis of sepsis patients. Further research on the possible causes of SAE aims to provide clinicians with potential therapeutic targets and help develop targeted prevention strategies. This paper aims to review recent research on the pathogenesis of SAE, in order to enhance our understanding of this syndrome.

Abstract We investigated the effect of eldecalcitol on disuse muscle atrophy. C57BL/6J male mice aged 6 weeks were randomly assigned to control, tail suspension (TS), and TS-eldecalcitol–treated groups and were injected intraperitoneally twice a week with either vehicle (control and TS) or eldecalcitol at 3.5 or 5 ng for 3 weeks. Grip strength and muscle weights of the gastrocnemius (GAS), tibialis anterior (TA), and soleus (SOL) were determined. Oxidative stress was evaluated by malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase. Bone microarchitecture was analyzed using microcomputed tomography. The effect of eldecalcitol on C2C12 myoblasts was analyzed by measuring myofibrillar protein MHC and the atrophy markers Atrogin-1 and MuRF-1 using immunofluorescence. The influence of eldecalcitol on NF-κB signaling pathway and vitamin D receptor (VDR) was assessed through immunofluorescence, (co)-immunoprecipitation, and VDR knockdown studies. Eldecalcitol increased grip strength (P < 0.01) and restored muscle loss in GAS, TA, and SOL (P < 0.05 to P < 0.001) induced by TS. An improvement was noted in bone mineral density and bone architecture in the eldecalcitol group. The impaired oxidative defense system was restored by eldecalcitol (P < 0.05 to P < 0.01 vs. TS). Eldecalcitol (10 nM) significantly inhibited the expression of MuRF-1 (P < 0.001) and Atrogin-1 (P < 0.01), increased the diameter of myotubes (P < 0.05), inhibited the expression of P65 and P52 components of NF-κB and P65 nuclear location, thereby inhibiting NF-κB signaling. Eldecalcitol promoted VDR binding to P65 and P52. VDR signaling is required for eldecalcitol-mediated anti-atrophy effects. In conclusion, eldecalcitol exerted its beneficial effects on disuse-induced muscle atrophy via NF-κB inhibition.

Acute liver failure is an uncommon presentation in the clinic. Common causes for acute liver failure include viral hepatitis and drug-related hepatotoxicity. However, acute liver failure due to Budd-Chiari syndrome is rare. This case highlights the importance of necessary constrast-enhanced imaging studies to rule out vascular etiologies of acute liver failure, in addition to common causes like viral or drug-induced hepatic failure. We present a case of a male Chinese patient who presented with nausea, vomiting, fatigue, and fever after eating a large amount of fatty food. Six days after hospitalization, the patient developed acute liver failure and hepatic encephalopathy. Contrast-enhanced computerized tomography and ultrasound examinations revealed thromboses in the hepatic veins and inferior vena cava. Further testing also showed decreased protein C activity. Therefore, a diagnosis of Budd-Chiari syndrome secondary to protein C deficiency was made. He received supportive care and a transjugular intrahepatic portal shunt. Hepatic function, coagulation panel results, and clinical presentations gradually returned to normal. Budd-Chiari syndrome from protein C deficiency could be a rare but valid cause of acute liver failure in Chinese patients.

Corona Virus Disease 2019 (COVID-19) is a global pandemic epidemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which poses a serious threat to human health worldwide and results in significant economic losses. With the continuous emergence of new virus strains, small molecule drugs remain the most effective treatment for COVID-19. The traditional drug development process usually requires several years; however, the development of computer-aided drug design (CADD) offers the opportunity to develop innovative drugs quickly and efficiently. The literature review describes the general process of CADD, the viral proteins that play essential roles in the life cycle of SARS-CoV-2 and can serve as therapeutic targets, and examples of drug screening of viral target proteins by applying CADD methods. Finally, the potential of CADD in COVID-19 therapy, the deficiency, and the possible future development direction are discussed.

Abstract Background Henan is the province with the greatest wheat production in China. Although more than 100 cultivars are used for production, many cultivars are still insufficient in quality, disease resistance, adaptability and yield potential. To overcome these limitations, it is necessary to constantly breed new cultivars to maintain the continuous and stable growth of wheat yield and quality. To improve breeding efficiency, it is important to evaluate the genetic diversity and population genetic structure of its cultivars. However, there are no such reports from Henan Province. Therefore, in this study, single nucleotide polymorphism (SNP) markers were used to study the population genetic structure and genetic diversity of 243 wheat cultivars included in a comparative test of wheat varieties in Henan Province, aiming to provide a reference for the utilization of backbone parents and the selection of hybrid combinations in the genetic improvement of wheat cultivars. Results In this study, 243 wheat cultivars from Henan Province of China were genotyped by the Affymetrix Axiom Wheat660K SNP chip, and 21 characteristics were investigated. The cultivars were divided into ten subgroups; each subgroup had distinct characteristics and unique utilization value. Furthermore, based on principal component analysis, Zhoumai cultivars were the main hybrid parents, followed by Aikang 58, high-quality cultivars, and Shandong cultivars. Genetic diversity analysis showed that 61.3% of SNPs had a high degree of genetic differentiation, whereas 33.4% showed a moderate degree. The nucleotide diversity of subgenome B was relatively high, with an average π value of 3.91E-5; the nucleotide diversity of subgenome D was the lowest, with an average π value of 2.44E-5. Conclusion The parents used in wheat cross-breeding in Henan Province are similar, with a relatively homogeneous genetic background and low genetic diversity. These results will not only contribute to the objective evaluation and utilization of the tested cultivars but also provide insights into the current conditions and existing challenges of wheat cultivar breeding in Henan Province, thereby facilitating the scientific formulation of breeding objectives and strategies to improve breeding efficiency.

Abstract Background Migraine, a complex brain disorder, is regarded as a possible clinical manifestation of brain energy dysfunction. The trigeminovascular system is considered the basis for the pathogenesis of migraine, hence we depicted the proteomics profiling of key regions in this system, then focusing on protein alterations related to mitochondrial function. The aim of this study is to illustrate the role of mitochondria in migraine. Methods A mouse model of chronic migraine (CM) was established by repeated nitroglycerin (NTG) stimulation and evaluated by von-Frey filaments, a hot plate and a light-dark box. Differentially expressed proteins (DEPs) in some subcortical brain regions of the trigeminovascular system were screened through liquid chromatography-tandem mass spectrometry (LC‒MS/MS) to analyse the specificity of key signaling pathways in different brain regions. And then mitochondrial function, structure and dynamics were determined by qPCR, ELISA, and transmission electron microscope (TEM). Finally, the effect of mitochondrial intervention-Urolithin A (UA) on CM was investigated. Results Repeated NTG injection triggered photophobia, periorbital and hind paw allodynia in mice. The proteomics profiling of CM model showed that 529, 109, 163, 152 and 419 DEPs were identified in the thalamus, hypothalamus, periaqueductal grey (PAG), trigeminal ganglion (TG) and trigeminocervical complex (TCC), respectively. The most significant changes in the brain region-specific pathways pointed to thalamic mitochondrial impairment. NTG induced mitochondrial structural disruption, dysfunction and homeostatic dysregulation, which could be partially attenuated by UA intervention. Conclusion Our findings highlight the involvement of mitochondrial damage in the thalamus in central sensitization of CM, which provides evidence of possible metabolic mechanisms in migraine pathophysiology.

Abstract Stable picosecond dissipative soliton pulses were observed in an ytterbium-doped fiber laser employing a high-quality mixture of BP/SnSe2-PVA saturable absorber (SA). The modulation depth, saturation intensity, and non-saturable loss of the mixture of BP/SnSe2-PVA SA were measured with values of 5.98%, 18.37 MW/cm2, and 33%, respectively. Within the pump power range of 150–270 mW, stable dissipative soliton pulses were obtained with an output power of 1.68–4 mW. When the minimum pulse duration is 1.28 ps, a repetition rate of 0.903 MHz, center wavelength of 1064.38 nm and 3 dB bandwidth of 2 nm were obtained. The maximum pulse energy of 4.43 nJ and the signal-to-noise ratio up to 72 dB were achieved at pump power of 270 mW. The results suggest that the BP/SnSe2-PVA mixture SA has outstanding nonlinear saturable absorption characteristics and broad ultrafast laser applications. Graphical Abstract

Abstract As a member of Xenes family, germanene has excellent nonlinear saturable absorption characteristics. In this work, we prepared germanene nanosheets by liquid phase exfoliation and measured their saturation intensity as 0.6 GW/cm2 with a modulation depth of 8%. Then, conventional solitons with a pulse width of 946 fs and high-energy noise-like pulses with a pulse width of 784 fs were obtained by using germanene nanosheet as a saturable absorber for a mode-locked Erbium-doped fiber laser. The characteristics of the two types of pulses were investigated experimentally. The results reveal that germanene has great potential for modulation devices in ultrafast lasers and can be used as a material for creation of excellent nonlinear optical devices to explore richer applications in ultrafast photonics. Graphical Abstract

Membranes with precise ion-ion separation are critical for sustainable water treatment. Here, authors demonstrated controlled construction of a nanofiltration membrane with fast permeation and high Cl-/SO4 2- selectivity by simultaneous spatial and temporal control of interfacial polymerization.

Highlights 1. We established an optogenetic mouse CSD model without irritation dura, which could mimic the behaviors of headache and photophobia. 2. It was the first time to depict a broad, unbiased neuronal activity map throughout the mouse brain after CSD. 3. Results of whole brain image and immunofluorescence staining showed that optogenetic CSD could activate multiple sensory-related networks without activating thalamus or TNC to induce cortical pain.

Abstract Background Mesenchymal stem cells (MSCs) have shown immense therapeutic potential for various brain diseases. Intrathecal administration of MSCs may enhance their recruitment to lesions in the central nervous system, but any impact on cerebrospinal fluid (CSF) flow remains unclear. Methods Rats with or without middle cerebral artery occlusion (MCAO) received intrathecal injections of 2D cultured MSCs, 3D cultured MSCs or an equal volume of artificial cerebrospinal fluid (ACSF). Ventricle volume was assessed by MRI on Days 2 and 14 post-MCAO surgery. A beam walking test was used to assess fine motor coordination and balance. Aggregation of MSCs was evaluated in CSF and frozen brain tissue. Differential expression of cell adhesion molecules was evaluated by RNA-Seq, flow cytometry and immunofluorescence analyses. The influence of VCAM-1 blockade in mediating the aggregation of 2D MSCs was investigated in vitro by counting cells that passed through a strainer and in vivo by evaluating ventricular dilation. Results MSC expanded in 2D culture formed aggregates in the CSF and caused ventricular enlargement in both MCAO and normal rats. Aggregates were associated with impaired motor function. 2D MSCs expressed higher levels of integrin α4 and VCAM-1 than 3D MSCs. Blockade of VCAM-1 in 2D MSCs reduced their aggregation in vitro and reduced lateral ventricular enlargement after intrathecal infusion. 3D MSCs exhibited lower cell aggregation and reduced cerebral ventricular dilation after intrathecal transplantation Conclusions The aggregation of 2D MSCs, mediated by the interaction of integrin α4 and VCAM-1, is a potential risk for obstruction of CSF flow after intrathecal transplantation.

Anthocyanins exist widely in various plant tissues and organs, and they play an important role in plant reproduction, disease resistance, stress resistance, and protection of human vision. Most fruit anthocyanins can be induced to accumulate by light. Here, we shaded the “Hong Deng” sweet cherry and performed an integrated analysis of its transcriptome and metabolome to explore the role of light in anthocyanin accumulation. The total anthocyanin content of the fruit and two of its anthocyanin components were significantly reduced after the shading. Transcriptome and metabolomics analysis revealed that PAL, 4CL, HCT, ANS and other structural genes of the anthocyanin pathway and cyanidin 3-O-glucoside, cyanidin 3-O-rutinoside, and other metabolites were significantly affected by shading. Weighted total gene network analysis and correlation analysis showed that the upstream and middle structural genes 4CL2, 4CL3, and HCT2 of anthocyanin biosynthesis may be the key genes affecting the anthocyanin content variations in fruits after light shading. Their expression levels may be regulated by transcription factors such as LBD, ERF4, NAC2, NAC3, FKF1, LHY, RVE1, and RVE2. This study revealed for the first time the possible role of LBD, FKF1, and other transcription factors in the light-induced anthocyanin accumulation of sweet cherry, thereby laying a preliminary foundation for further research on the role of light in anthocyanin accumulation of deep red fruit varieties and the genetic breeding of sweet cherry.

Background and purposeBlood markers have important value in the diagnosis of depressive disorders. Serum alkaline phosphatase (ALP) not only predicts stroke recurrence and poor functional prognosis in cerebrovascular disease (CVD) patients but also increases significantly in middle-aged women with depression. Thus, it has not been reported whether serum ALP is associated with the development of depression and/or vascular depression (VDe) in CVD patients.MethodsThis was a cross-sectional study of 353 CVD patients (stroke patients, n = 291; cerebral small vessel disease (CSVD) patients, n = 62). Baseline demographic information, fasting blood markers (such as blood counts, liver function, kidney function and lipids), and brain CT/MRI scans were collected. CVD patients were divided into non-depression, suspected vascular depression (SVD), and positive vascular depression (PVD) groups according to their Hamilton Rating Scale for Depression (HAMD) scores. Univariate analysis of baseline data, blood markers, and the prevalence of lesions (> 1.5 cm) was performed. Subsequently, the diagnostic performance of the univariate and combined variables for SVD and PVD was analyzed using binary logistic regression. The diagnostic value of the multivariate model for VDe was analyzed by ordinal logistic regression.Results(1) Serum ALP (p = 0.003) and hypersensitive C-reactive protein (hs-CRP, p = 0.001) concentrations increased as HAMD scores increased, and the prevalence of brain atrophy (p = 0.016) and lesions in the basal ganglia (p = 0.001) and parietal (p = 0.001), temporal (p = 0.002), and frontal lobes (p = 0.003) also increased, whereas the concentrations of hemoglobin (Hb, p = 0.003), cholinesterase (ChE, p = 0.001), and high-density lipoprotein cholesterol (HDL-C, p = 0.005) declined. Among these variables, hs-CRP (r = 0.218, p

PtSe _2 has high carrier mobility, excellent electrical and optical properties, and high potential in the field of optoelectronic devices. In this paper, the conventional selenization method is optimized and a single-temperature zone preparation is used to prepare large-area and homogeneous PtSe _2 thin-film materials on sapphire substrates in a shorter time and at a lower temperature. The prepared sample is characterized by optical microscopy, atomic force microscopy, Raman spectroscopy and Z-scan method. The saturable absorption properties of layered PtSe _2 as a passive Q-switched are investigated in a solid-state laser. The results show that the PtSe _2 thin film material is synthesized at 400 °C for 1 h to cover the entire one-inch sapphire wafer with a thickness of about 25 nm and the surface roughness is 13.1 nm. The modulation at 1064 nm yielded an output pulse with a maximum repetition frequency of 688.47 kHz, corresponding to a pulse width of 202.5 ns, a peak power of 7.35 W, a single-pulse energy of 1.51 μJ, and a stable pulse train.

Growth differentiation factor-15 (GDF-15) is proposed to be strongly associated with several cardiovascular diseases, such as heart failure and atherosclerosis. Moreover, some recent studies have reported an association between GDF-15 and platelet activation. In this study, we isolated peripheral blood platelets from healthy volunteers and evaluated the effect of GDF-15 on adenosine diphosphate (ADP)-induced platelet activation using the platelet aggregation assay. Subsequently, we detected the expression of GDF-15-related receptors on platelets, including the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), transforming growth factor-beta receptor I (TGF-βRI), transforming growth factor-beta receptor II (TGF-βRII), glial-cell-line-derived neurotrophic factor family receptor α-like (GFRAL), and those rearranged during transfection (RET). Then, we screened for GDF-15 receptors using the GDF-15-related receptor microarray comprising these recombinant proteins. We also performed the immunoprecipitation assay to investigate the interaction between GDF-15 and the receptors on platelets. For the further exploration of signaling pathways, we investigated the effects of GDF-15 on the extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and Janus kinase 2 (JAK2) pathways. We also investigated the effects of GDF-15 on the ERK and AKT pathways and platelet aggregation in the presence or absence of RET agonists or inhibition. Our study revealed that GDF-15 can dose-independently inhibit ADP-induced human platelet aggregation and that the binding partner of GDF-15 on platelets is GFRAL. We also found that GDF-15 inhibits ADP-induced AKT and ERK activation in platelets. Meanwhile, our results revealed that the inhibitory effects of GDF-15 can be mediated by the GFRAL/RET complex. These findings reveal the novel inhibitory mechanism of ADP-induced platelet activation by GDF-15.

Abstract Background Gut microbial dysbiosis and gut-brain axis dysfunction have been implicated in the pathophysiology of migraine. However, it is unclear whether migraine-related cephalic allodynia could induce the alteration of gut microbial composition. Methods A classic migraine rat model was established by repeated dural infusions of inflammatory soup (IS). Periorbital mechanical threshold and nociception-related behaviors were used to evaluate IS-induced cephalic allodynia and the preventive effect of topiramate. The alterations in gut microbial composition and potential metabolic pathways were investigated based on the results of 16 S rRNA gene sequencing. Microbiota-related short-chain fatty acids and tryptophan metabolites were detected and quantified by mass spectrometry analysis. Results Repeated dural IS infusions induced cephalic allodynia (decreased mechanical threshold), migraine-like behaviors (increased immobility time and reduced moving distance), and microbial composition alteration, which were ameliorated by the treatment of topiramate. Decreased Lactobacillus was the most prominent biomarker genus in the IS-induced alteration of microbial composition. Additionally, IS infusions also enhanced metabolic pathways of the gut microbiota in butanoate, propanoate, and tryptophan, while the increased tryptophan-related metabolites indole-3-acetamide and tryptophol in feces could be the indicators. Conclusions Inflammatory dural stimulation-induced cephalic allodynia causes the alterations of gut microbiota profile and microbial metabolic pathways.

Abstract Background Astrocytic activation might play a significant role in the central sensitization of chronic migraine (CM). However, the temporal characteristics of the astrocytic activation in the trigeminal nucleus caudalis (TNC) and the molecular mechanism under the process remain not fully understood. Therefore, this study aims to investigate the duration and levels change of astrocytic activation and to explore the correlation between astrocytic activation and the levels change of cytokines release. Methods We used a mice model induced by recurrent dural infusion of inflammatory soup (IS). The variation with time of IS-induced mechanical thresholds in the periorbital and hind paw plantar regions were evaluated using the von Frey filaments test. We detected the expression profile of glial fibrillary acidic protein (GFAP) in the TNC through immunofluorescence staining and western blot assay. We also investigated the variation with time of the transcriptional levels of GFAP and ionized calcium binding adapter molecule 1 (Iba1) through RNAscope in situ hybridization analysis. Then, we detected the variation with time of cytokines levels in the TNC tissue extraction and serum, including c-c motif chemokine ligand 2 (CCL2), c-c motif chemokine ligand 5 (CCL5), c-c motif chemokine ligand 7 (CCL7), c-c motif chemokine ligand 12 (CCL12), c-x-c motif chemokine ligand 1 (CXCL1), c-x-c motif chemokine ligand 13 (CXCL13), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), macrophage colony-stimulating factor (M-CSF), interleukin 1beta (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 17A (IL-17A). Results Recurrent IS infusion resulted in cutaneous allodynia in both the periorbital region and hind paw plantar, ranging from 5 d (after the second IS infusion) to 47 d (28 d after the last infusion) and 5 d to 26 d (7 d after the last infusion), respectively. The protein levels of GFAP and messenger ribonucleic acid (mRNA) levels of GFAP and Iba1 significantly increased and sustained from 20 d to 47 d (1 d to 28 d after the last infusion), which was associated with the temporal characteristics of astrocytic activation in the TNC. The CCL7 levels in the TNC decreased from 20 d to 47 d. But the CCL7 levels in serum only decreased on 20 d (1 d after the last infusion). The CCL12 levels in the TNC decreased on 22 d (3 d after the last infusion) and 33 d (14 d after the last infusion). In serum, the CCL12 levels only decreased on 22 d. The IL-10 levels in the TNC increased on 20 d. Conclusions Our results indicate that the astrocytic activation generated and sustained in the IS-induced mice model from 1 d to 28 d after the last infusion and may contribute to the pathology through modulating CCL7, CCL12, and IL-10 release.

The recalcitrant structure of raw poplar limited the production of fermentable sugars when applied as the material in the pretreatment of biochemical conversions. Phosphoric acid pretreatment is an efficient method to destroy the compact lignocellulose matrix presence in the poplar. In this study, phosphoric acid pretreatment of poplar was optimised by an orthogonal experimental design [L9(33)] to improve enzymatic digestibility through investigating the effects of reaction temperature, time duration, and phosphoric acid concentration. The optimal conditions were selected based on the variance of chemical compositions, hemicellulose removal ratio, and delignification of the woody material after pretreatment. The optimum enzymatic hydrolysis yield of up to 73.44% was obtained when the phosphoric acid pretreatment performed at 190°C for 150 min under 1.5% of v/v phosphoric acid concentration.

Activated phosphoinositide 3-kinase δ syndrome 1 (APDS1) is a primary immunodeficiency disease caused by gain-of-function mutations in PIK3CD. Clinical features of autoimmune disease have been reported in patients with APDS1. In this study, we reported three patients with APDS1 presenting with systemic lupus erythematosus (SLE) phenotype. The clinical manifestations included recurrent respiratory tract infection, lymphoproliferation, Coombs-positive hemolytic anemia, decreased complement fractions, positive antinuclear antibodies, renal complications related to SLE associated diseases, which met the clinical spectrum of APDS1 and the classification criteria of SLE. The immunological phenotype included an inversion in the CD4:CD8 ratio, an increase in both non-circulating Tfh CD4+ memory T and circulating Tfh populations, a low level of recent thymic emigrant T cells, overexpression of CD57 on T cells, and a decrease in B cells with fewer antibody class switch recombination. These phenotypes detected in patients with APDS1 presenting with SLE were resemble that in patients with APDS1 presenting without SLE. Meanwhile, we described the effect of glucocorticoids and rapamycin therapy on patients with APDS1. The phosphorylation of S6 at Ser235/236 was inhibited in patients with APDS1 who underwent glucocorticoids therapy, including two who presented with SLE phenotype. The phosphorylation of AKT at Ser473 and phosphorylation of S6 at Ser235/236 were inhibited in other patients with APDS1 who underwent rapamycin therapy. Here, we showed the coexistence of immunodeficiency and SLE phenotype in APDS1, and the inhibition of rapamycin in activated Akt-mTOR signaling pathway.

Abstract Background Osteoporosis and sarcopenia are major health issues in postmenopausal women due to their high prevalence and association with several adverse outcomes. However, no biomarkers may be used for screening and diagnosis. The current study investigated potential biomarkers for osteoporosis and/or sarcopenia in postmenopausal women. Methods A cross-sectional study on 478 healthy community-dwelling postmenopausal women aged 50–90 years was performed. Osteoporosis and sarcopenia were defined according to the World Health Organization (WHO) and Asian Working Group for Sarcopenia (AWGS). Results Dehydroepiandrosterone (DHEA) was related to muscle strength (β = 0.19, p = 0.041) and function (β = 0.58, p = 0.004). Follistatin (β = − 0.27, p = 0.01) was related to muscle mass. Oxytocin (β = 0.59, p = 0.044) and DHEA (β = 0.51, p = 0.017) were related to bone mass. After adjusting for age, oxytocin (odds ratio (OR) 0.75; 95% confidence intervals (CI) 0.63–0.98; p = 0.019) was associated with osteoporosis, and DHEA (OR 0.73; 95% CI 0.51–0.96; p = 0.032) and follistatin (OR 1.66; 95% CI 1.19–3.57; p = 0.022) were associated with sarcopenia. Conclusions Postmenopausal women with sarcopenia were more likely to have lower DHEA levels and higher follistatin levels, and postmenopausal women with osteoporosis were more likely to have lower oxytocin levels.

ObjectiveMigraine is frequently reported in patients with irritable bowel syndrome (IBS), and emerging evidence suggests that gut microbiota plays a role in migraine and IBS. However, alterations in the gut microbiome in migraine patients with IBS remain unknown. This study aimed to explore the compositions of gut microbiota in migraine patients with IBS in a Chinese Han population.MethodsSixteen migraine patients with IBS and thirteen age- and gender-matched IBS patients with similar dietary and lifestyle habits were enrolled in this pilot study. Demographic data, clinical data, eating habits, lifestyle habits, comorbidities, and medications were recorded using a unified case registration form. Questionnaires for the Migraine Disability Assessment (MIDAS), Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD) were completed. Fecal samples were collected, and microbial DNA was extracted. Gut microbiota 16S ribosomal RNA (16S rRNA) gene sequencing targeting the V4 region was performed using the Illumina HiSeq 2500 high-throughput sequencing platform. The relationships between gut microbiota and clinical characteristics of migraine were analyzed.ResultsThe structure of gut microbiota differed between migraine patients with IBS and patients with IBS, while the richness and diversity of gut microbiota in migraine patients with IBS showed no significant difference from that of patients with IBS. We found a higher relative abundance of the genus Parabacteroides and a lower relative abundance of the genera Paraprevotella, Lachnospiraceae_UCG-010, Lactococcus, Collinsella, and Comamonas in migraine patients with IBS than in patients with IBS. According to random forest predictive models, the phylum Bacteroidota shows the most important role in migraine patients with IBS. Furthermore, no statistical correlation was found between significantly different taxa at the genus level and migraine clinical data.ConclusionThis study identified that altered gut microbiota occurred in Chinese Han migraine patients with IBS, but no correlation was found between gut microbiota and the clinical characteristics of migraine. Further study is needed to better understand the role of gut microbiota in the pathogenesis of migraine in IBS.

Flesh color is an important target trait in peach [Prunus persica (L.) Batsch] breeding. In this study, two white-fleshed peach cultivars were crossed [Changsong Whitepeach (WP-1) × ‘Xiacui’], and their hybrid F1 generation showed color segregation of white flesh (BF1) and yellow flesh (HF1). Metabolome analysis revealed that the flesh color segregation in the hybrid F1 generation was related to the carotenoid content. The decrease in β-carotene and β-cryptoxanthin in BF1 flesh and increase in β-cryptoxanthin oleate, rubixanthin caprate, rubixanthin laurate and zeaxanthin dipalmitate in HF1 flesh contributed to their difference in carotenoid accumulation. Transcriptome analysis demonstrated that compared with BF1, HF1 showed significant up-regulation and down-regulation of ZEP and CCD8 at the core-hardening stage, respectively, while significant down-regulation of NCED in the whole fruit development stage. The down-regulation of NCED might inhibit the breakdown of the violaxanthin and its upstream substances and further promote the accumulation of carotenoids, resulting in yellow flesh. Therefore, NCED may be a key gene controlling the fruit color traits of peach. In this study, targeted metabolomics and transcriptomics were used to jointly explore the mechanism controlling the fruit color of peach, which may help to identify the key genes for the differences in carotenoid accumulation and provide a reference for the breeding of yellow-fleshed peach.

Gibberellin (GA) is an important phytohormone that can participate in various developmental processes of plants. The study found that application of GA3 can induce parthenocarpy fruit and improve fruit set. However, the use of GA3 affects endogenous hormones in fruits, thereby affecting fruit quality. This study mainly investigates the effect of exogenous GA3 on endogenous hormones in sweet cherries. The anabolic pathways of each hormone were analyzed by metabolome and transcriptome to identify key metabolites and genes that affect endogenous hormones in response to exogenous GA3 application. Results showed that exogenous GA3 led to a significant increase in the content of abscisic acid (ABA) and GA and affected jasmonic acid (JA) and auxin (IAA). At the same time, the key structural genes affecting the synthesis of various hormones were preliminarily determined. Combined with transcription factor family analysis, WRKY genes were found to be more sensitive to the use of exogenous GA3, especially the genes belonging to Group III (PaWRKY16, PaWRKY21, PaWRKY38, PaWRKY52, and PaWRKY53). These transcription factors can combine with the promoters of NCED, YUCCA, and other genes to regulate the content of endogenous hormones. These findings lay the foundation for the preliminary determination of the mechanism of GA3’s effect on endogenous hormones in sweet cherry and the biological function of WRKY transcription factors.

Elderly male patients are susceptible to develop osteoporosis and sarcopenia, especially those with fragility fractures, hypogonadism, and prostate cancer with androgen deprivation therapy. However, at present, very few treatments are available for men with sarcopenia. Previous preclinical studies in ovariectomized rats have shown the promising effects of eldecalcitol in ameliorating the bone strength and muscle atrophy. We thus investigated the effects of eldecalcitol on androgen-deficient male mice. Six-week-old male mice underwent orchiectomy (ORX) or sham surgery. Mice were randomly divided into 4 groups (n = 12/per group), including 1) sham mice, 2) ORX group, 3) ORX eldecalcitol 30 ng/kg, and 4) ORX eldecalcitol 50 ng/kg. Eldecalcitol increased bone mass and strength of femur in ORX mice. Eldecalcitol 30 ng/kg dose completely rescued ORX-induced muscle weakness. The RT-qPCR showed that eldecalcitol enhanced the mRNA levels of type I and IIa fibers. The expression levels of MuRF1 and Atrogin-1 of gastrocnemius in the eldecalcitol groups were much lower than that of the ORX group. It is assumed that eldecalcitol potentially acts via PI3K/AKT/FOXOs signaling pathway. These findings provide evidence for evaluating eldecalcitol as an investigational treatment for male patients with sarcopenia and osteoporosis.

In the production process of sweet cherry, there are unreasonable planting densities and tree shape selections. With increasing tree age, the crown of the tree continues to expand and the tree body is prone to canopy closure, which leads to the inability to efficiently use space and light energy. Low-light has become a major limiting factor in the quality of sweet cherry. Therefore, we analyzed the changes of various physiological indicators and the transcriptome of ‘Hongdeng’ sweet cherry under shading treatment in this study to investigate the effects of low-light stress on the photosynthetic characteristics of sweet cherry leaves and fruit physiology and biochemistry. The results showed that shading significantly reduces the light capture capacity of leaves, damages the photosystem, reduces carbon assimilation capacity, and consumes the majority of the captured light energy as photochemical energy, thereby restricting the growth and development of leaves and reducing the accumulation of nutrients in fruits. Shading significantly reduced fruit weight, sugar content, and vitamin C content at maturity and significantly increased acid content. Transcriptomic data demonstrated that low-light stress produces a large number of differential genes related to carbon metabolism, organic acid metabolism, and stress resistance, thereby suggesting that low-light stress may affect the expression of these related genes and inclusions in the fruit. The results of this study will provide theoretical and technical support for the physiological response mechanism of low-light tolerance in sweet cherry, the selection and breeding of low-light tolerant sweet cherry varieties, and the cultivation of sweet cherry in facilities.

Abstract Background Mutations in ATP1A2, the gene encoding the α2 subunit of Na+/K+-ATPase, are the main cause of familial hemiplegic migraine type 2 (FHM2). The clinical presentation of FHM2 with mutations in the same gene varies from pure FHM to severe forms with epilepsy and intellectual disability, but the correlation of these symptoms with different ATP1A2 mutations is still unclear. Methods Ten ATP1A2 missense mutations were selected according to different phenotypes of FHM patients. They caused pure FHM (FHM: R65W, R202Q, R593W, G762S), FHM with epilepsy (FHME: R548C, E825K, R938P), or FHM with epilepsy and intellectual disability (FHMEI: T378N, G615R, D718N). After ouabain resistance and fluorescence modification, plasmids carrying those mutations were transiently transfected into HEK293T and HeLa cells. The biochemical functions were studied including cell survival assays, membrane protein extraction, western blotting, and Na+/K+-ATPase activity tests. The electrophysiological functions of G762S, R938P, and G615R mutations were investigated in HEK293T cells using whole-cell patch-clamp. Homology modeling was performed to determine the locational distribution of ATP1A2 mutations. Results Compared with wild-type pumps, all mutations showed a similar level of protein expression and decreased cell viability in the presence of 1 µM ouabain, and there was no significant difference among the mutant groups. The changes in Na+/K+-ATPase activity were correlated with the severity of FHM phenotypes. In the presence of 100 µM ouabain, the Na+/K+-ATPase activity was FHM > FHME > FHMEI. The ouabain-sensitive Na+/K+-ATPase activity of each mutant was significantly lower than that of the wild-type protein, and there was no significant difference among all mutant groups. Whole-cell voltage-clamp recordings in HEK293T cells showed that the ouabain-sensitive pump currents of G615R were significantly reduced, while those of G762S and R938P were comparable to those of the wild-type strain. Conclusions ATP1A2 mutations cause phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability presented with severe impairment of Na+/K+-ATPase. Whether epilepsy is accompanied, or the type of epilepsy did not seem to affect the degree of impairment of pump function.

ObjectiveThis systematic review and meta-analysis aimed to comprehensively evaluate the effectiveness and safety of acupuncture for post-stroke spasticity.MethodsNine electronic databases were searched from their inception to 6 June 2022, to identify randomized-controlled trials (RCTs) that investigated the effectiveness and safety of acupuncture for post-stroke spasticity. Two reviewers independently screened the studies, extracted the data, assessed the risk of bias. The reporting quality of interventions in controlled trials of acupuncture was evaluated using Revised Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA). The RevMan 5.4 and R 4.2.0 software were used for statistical analysis.ResultsA total of 88 eligible studies were included, involving 6,431 individuals. The pooled data demonstrated that acupuncture combined with conventional rehabilitation (CR) was superior to CR in reducing the Modified Ashworth Scale (MAS) score (standardized mean difference [SMD] = −0.73; 95% CI = −0.83 to −0.63; I2 = 65%; low certainty of evidence). The favorable results were also observed in comparisons of acupuncture vs. CR (SMD = −0.22, 95% CI = −0.36 to −0.07; I2 = 49%; moderate certainty of evidence). Subgroup analysis showed that acupuncture treatment with a frequency of once or twice a day was more effective than CR. In addition, the antispasmodic effect of acupuncture treatment increased with more sessions. Four studies explicitly reported slight acupuncture-related adverse events.ConclusionAcupuncture could be recommended as adjuvant therapy for spasticity after stroke. However, due to the high risk of bias and heterogeneity of the included studies, the effectiveness of acupuncture for post-stroke spasticity remains to be confirmed.

Background: Resveratrol (RES) has a protective effect on acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Our purpose was to conduct a meta−analysis to investigate the efficacy of RES for ALI/ARDS in animal models.Methods: PubMed, EMBASE and Web of Science were searched to screen relevant preclinical trials. The standardized mean difference (SMD) was used to compare the lung injury score, lung wet−dry weight ratio (W/D ratio), tumor necrosis factor−α (TNF−α), interleukin−1β (IL−1β), IL−6, IL−10, the number of neutrophils in bronchoalveolar lavage fluid (BALF) and the total protein in BALF between the treatment and control groups. SYRCLE’s risk of bias tool was used for quality assessment.Results: A total of 17 studies published from 2005 to 2021 were included in our study to calculate the SMD with corresponding confidence interval (CI). As compared with controls, RES significantly decreased the lung injury score (SMD −2.06; 95% CI −2.77, −1.35; p < 0.00001) and W/D ratio (SMD −1.92; 95% CI −2.62, −1.22; p < 0.00001). RES also reduced the number of neutrophils in BALF (SMD −3.03; 95% CI −3.83, −2.24; p < 0.00001) and the total protein in BALF (SMD −5.59; 95% CI −10.10, −1.08; p = 0.02). Furthermore, RES was found to downregulate proinflammatory mediators such as TNF−α (SMD −2.02; 95% CI −3.09, −0.95; p = 0.0002), IL−1β (SMD −2.51; 95% CI −4.00, −1.02; p = 0.001) and IL−6 (SMD −2.26; 95% CI −3.49, −1.04; p = 0.0003). But RES had little effect on the anti−inflammatory mediators such as IL−10 (SMD 2.80; 95% CI −0.04, 5.63; p = 0.05). Sensitivity analysis and stratified analysis were performed for the outcome indicators with heterogeneity.Conclusion: RES treatment is effective on reducing the severity of ALI. However, more animal studies and human trials are needed for further investigation. Our study may provide a reference for preclinical and clinical studies in the future to some extent.

Excellent Q-switching operations modulated by new two-dimensional (2D) saturable absorber (SA) materials with stable performance is a hot topic in all-solid-state pulsed laser research. In this work, the watt-level high-stability passive Q-switching operation in a solid-state Nd:YVO4 laser utilizing the 2D germanene nanosheets as SA was first realized. The nonlinear optical properties of the germanene nanosheets (Ge-Ns) were characterized by experimental means. The stable Q-switched pulse sequence was acquired with a 60.6 ns narrowest pulse width and a 528.6 kHz maximal repetition rate. The average output power of 0.965 W and the corresponding pulse peak power of 30.12 W are obtained under the pump power of 7 W. The findings of the experiments demonstrate that germanene material has remarkable nonlinear optical properties and can be used as an excellent saturable absorber in the field of optical pulse modulation.

Objective: Exercise is reported to be beneficial for breast cancer. However, the results seem inconsistent. We conducted this systematic review and meta-analysis of animal experimental studies to fully understand the effect of exercise on breast cancer in animal model.Methods: We searched databases from inception to April 2022 and manually searched related references to retrieve eligible studies. We screened eligible studies and extracted related data. We assessed the risk of bias and reporting quality using the SYstematic Review Centre for Laboratory animal Experimentation Risk of Bias tool and the Animal Research: Reporting of In Vivo Experiments guidelines 2.0, respectively. We summarized the study characteristics and findings of included studies and conducted meta-analysis with RevMan software. Subgroup analysis and sensitivity analysis were also performed.Results: We identified 537 potential literatures and included 47 articles for analysis. According to the results of risk of bias assessment, only selective outcome reporting was in low risk of bias. Items of sequence generation, random outcome assessment, and incomplete outcome data were rated as high risk of bias. Most of other items were rated unclear risk of bias. In reporting quality assessment, all included articles reported grouping method and experimental procedures. However, no study provided information of the study protocol registration. Meta-analysis showed that, compared with sedentary lifestyle, exercise reduced more tumor weight (MD = −0.76, 95%CI −0.88 to −0.63, p = 0.85, I2 = 0%) and tumor number per animal (MD = −0.61, 95%CI −0.91 to −0.31, p = 0.34, I2 = 8%). Exercise decreased more tumor incidence than sedentary lifestyle both in motorized wheel/high-intensity (OR = 0.22, 95%CI 0.11 to 0.46, p = 0.09, I2 = 41%) and free wheel/low-intensity treadmill running (OR = 0.45, 95%CI 0.14 to 1.44, p = 0.04, I2 = 60%). Sensitivity analysis showed that the results were robust.Conclusion: Exercise could reduce tumor weight, number of tumors per animal, and incidence of tumor in breast cancer model of mice and rats. However, the risk of bias items and reporting guidelines in preclinical studies should be concerned. Future research should consider standards of conducting and reporting preclinical studies and choose suitable exercise protocol for higher quality evidence of exercise for breast cancer.

The pumping of Tm-doped crystal or fiber by a 792 nm semiconductor laser is an important way to generate a mid-infrared laser, which is widely used in various fields. In this paper, a high–power 792 nm fiber–coupled semiconductor laser module was successfully fabricated with the output power of 232 W at a 10 A continuous current and the electro-optic conversion efficiency of 48.6%. The laser module is coupled with 24 chips into a fiber by spatial multiplexing and polarization combination technology. For a single emitting laser chip, the continuous wave (CW) output power and threshold current are 10.45 W at 10 A and 1.55 A, respectively. A polarization as high as 94% can also be realized, which is more suitable for laser spatial beam combining. The laser module was aged for more than 4000 h at 12 A and 25 °C without obvious power degradation.

Traditional laser diodes operating at 650 nm are more prone to high-order mode excitation, resulting in poorer beam quality. In this paper, we designed GaInP–AlGaInP laser diodes (LD) with a 650 nm range and a trench mode-modulation structure based on the structure of edge-emitting laser (EEL) diodes. The effect of the three-trench structure was investigated theoretically and experimentally. The right trench structure laser chips demonstrated good beam quality while maintaining a high power output. An electro-optical conversion efficiency of 56% was demonstrated with a slope efficiency of 1.32 W/A at a 40 mA current. The maximum optical output power reached 40.8 mW.

Peripheral blood mononuclear cells (PBMC) were donated by a healthy 25-year-old Han Chinese man and reprogrammed with human transcription factors (Oct4, Sox2, Klf4, and c-Myc) using CytoTune™-iPS 2.0 Sendai Reprogramming Kit. The pluripotency was confirmed by pluripotency markers. The iPSC lines could be differentiated into three germ layers and be used as a control in drug development and studies on pathological mechanisms.

Background and Purpose: Hemoglobin is one of the main proteins in erythrocytes. There are significant correlations between low hemoglobin and white matter hyperintensities (WMH) and cognitive impairment. This study explored whether erythrocytopenia has predictive value for vascular cognitive impairment (VCI) in patients with WMH.Method: We conducted a cross-sectional study of 302 patients, including 62 with cerebral small vessel disease and 240 with stroke. Basic demographic data and fasting blood were collected. First, all patients were divided into normal cognition (NC), mild VCI (mVCI), and severe VCI (sVCI) groups (subgroups later) based on cognitive behavior scores. Second, all patients were divided into mild WMH (mWMH) and severe WMH (sWMH) groups based on Fazekas scores. The differences in blood markers between different groups or subgroups with different cognitive levels were analyzed by univariate analysis. Then, binary logistic regression was used to analyze the diagnostic value of erythrocyte counts for VCI in the sWMH group, and ordinal logistic regression was used to analyze the predictive value of multiple variables for different cognitive levels.Results: Univariate analysis showed that erythrocytes, hemoglobin, high-sensitivity C-reactive protein, retinol binding protein and prealbumin were potential blood markers for different cognitive levels in sWMH patients. Among them, erythrocytopenia has good predictive value for the diagnosis of mVCI (AUC = 0.685, P = 0.008) or sVCI (AUC = 0.699, P = 0.003) in patients with sWMH. Multivariate joint analysis showed that erythrocytes were an independent protective factor reducing the occurrence of VCI in patients with sWMH (OR = 0.633, P = 0.045). Even after adjusting for age, there was still a significant difference (P = 0.047).Conclusion: Erythrocytes are an independent protective factor for VCI in patients with sWMH. Promoting hematopoietic function may have potential value for prevention of cognitive decline in patients with cerebrovascular disease.

Objective. Obesity-induced endoplasmic reticulum (ER) stress plays a role in increased susceptibility to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The activation of peroxisome proliferator-activated receptor-γ (PPARγ) is associated with lung protection and is effective in ameliorating ER stress and mitochondrial dysfunction. The aim of this study was to investigate the expression of PPARγ in the lung tissues of obese mice and explore whether the PPARγ-dependent pathway could mediate decreased ALI/ARDS by regulating ER stress and mitochondrial biogenesis. Methods. We determined PPARγ expression in the lung tissues of normal and obese mice. ALI models of alveolar epithelial cells and of obese mice were used and treated with either PPARγ activator rosiglitazone (RSG) or PPARγ inhibitor GW9662. Lung tissue and cell samples were collected to assess lung inflammation and apoptosis, and ER stress and mitochondrial biogenesis were detected. Results. PPARγ expression was significantly decreased in the lung tissue of obese mice compared with that in normal mice. Both in vivo and in vitro studies have shown that activation of PPARγ leads to reduced expression of the ER stress marker proteins 78-kDa glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP), and Caspase12. Conversely, expression of the mitochondrial biogenesis-related proteins peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α), nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) increased. Furthermore, activation of PPARγ is associated with decreased levels of lung inflammation and epithelial apoptosis and increased expression of adiponectin (APN) and mitofusin2 (MFN2). GW9662 bound to PPARγ and blocked its transcriptional activity and then diminished the protective effect of PPARγ on lung tissues. Conclusions. PPARγ activation exerts anti-inflammation effects in alveolar epithelia by alleviating ER stress and promoting mitochondrial biogenesis. Therefore, lower levels of PPARγ in the lung tissues of obese mice may lead to an increased susceptibility to ALI.

Abstract Background Tianshu capsule (TSC), a formula of traditional Chinese medicine, has been widely used in clinical practice for prophylactic treatment of headaches in China. However, former clinical trials of TSC were small, and lack of a standard set of diagnostic criteria to enroll patients. The study was conducted to re-evaluate the efficacy and safety of TSC post-marketing in an extending number of migraineurs who have diagnosed migraine with the International Classification of Headache Disorders, 3rd edition (beta version, ICHD-3β). Methods The study was a double-blind, randomized, placebo-controlled clinical trial that conducted at 20 clinical centers in China. At enrollment, patients between 18 and 65 years of age diagnosed with migraine were assigned to receive either TSC (4.08 g, three times daily) or a matched placebo according to a randomization protocol. The primary endpoint was a relative reduction of 50% or more in the frequency of headache attacks. The secondary outcomes included a reduction in the incidence of headache, the visual analogue scale of headache attacks, days of acute analgesic usage, and percentage of patients with a decrease of 50% or more in headache severity. Accompanying symptoms were also assessed. Results One thousand migraine patients were initially enrolled in the study, and 919 of them completed the trial. Following the 12-week treatment, significant improvement was observed in the TSC group concerning both primary and secondary outcomes. After therapy discontinuation, the gap between the TSC group and the placebo group in efficacy outcomes continued to increase. There were no severe adverse effects. Conclusions TSC is an effective, well-tolerated medicine for prophylactic treatment of migraine, and still have prophylactic effect after medicine discontinuation. Trial registration ClinicalTrials.gov Identifier: NCT02035111; Data of registration: 2014-01-10.

Objective: We performed a single-center retrospective study to determine the different efficacy of tocilizumab (TCZ) in the early and late stages and in three phenotypic subgroups (monocyclic, polycyclic, and persistent) of systemic juvenile idiopathic arthritis (sJIA).Methods: Clinical and serological parameters of 77 sJIA patients treated by TCZ were collected from November 1, 2013 to May 1, 2019. Patients were grouped based on the duration group A < 6 months (n = 41) and group B > 6 months (n = 36) and divided into three phenotypes: monocyclic (n = 12), polycyclic (n = 14), and persistent (n = 51) course.Results: At baseline, group A had pronounced ESR, fever less active arthritis than group B (p < 0.05). After 12 weeks of therapy, TCZ alleviated fever, ESR, CRP, and systemic-onset juvenile arthritis disease activity score-27 (sJADAS27) in both group A and group B (p>0.05), while the efficacy of TCZ in relieving active arthritis in group A was better than that in group B (p

DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by mutations in LIG4. Patients suffer from a broad spectrum of clinical problems, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and a predisposition to autoimmune diseases and malignancy. In this study, the clinical, molecular, and immunological characteristics of 15 Chinese patients with LIG4 deficiency are summarized in detail. p.R278L (c.833G>T) is a unique mutation site present in the majority of Chinese cases. We conducted pedigree and haplotype analyses to examine the founder effect of this mutation site in China. This suggests that implementation of protocols for genetic diagnosis and for genetic counseling of affected pedigrees is essential. Also, the search might help determine the migration pathways of populations with Asian ancestry.

BackgroundInfections are the major cause of morbidity and mortality in patients with primary immunodeficiency disease (PID). Timely and accurate microbiological diagnosis is particularly important in these patients. Metagenomic next-generation sequencing (mNGS) has been used for pathogen detection recently. However, few reports describe the use of mNGS for pathogen identification in patients with PID.ObjectiveTo evaluate the utility of mNGS for detecting pathogens in patients with PID, and to compare it with conventional microbiological tests (CMT).MethodsThis single center retrospective study investigated the diagnostic performance of mNGS for pathogens detection in PID patients and compared it with CMT. Sixteen PID patients with suspected infection were enrolled, and medical records were analyzed to extract detailed clinical characteristics such as gene variation, immune status, microbial distribution, time-consuming of mNGS and CMT, treatment, and outcomes.ResultsmNGS identified pathogenic microbe in 93.75% samples, compared to 31.25% for culture and 68.75% for conventional methods, and detected an extra 18 pathogenic microorganisms including rare opportunistic pathogens and Mycobacterium tuberculosis. Pathogen identification by mNGS required 48 hours, compared with bacterial culture for 3-7 days and even longer for fungus and Mycobacterium tuberculosis culture.ConclusionsmNGS has marked advantages over conventional methods for pathogenic diagnosis, particularly opportunistic pathogens and mixed infections, in patients with PID. This method might enable clinicians to make more timely and targeted therapeutic decisions, thereby improving the prognosis of these patients.