Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery.

JOURNAL/nrgr/04.03/01300535-202501000-00030/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery. Our previous in vitro study demonstrated that exosomes/small extracellular vesicles (sEVs) isolated from cerebral endothelial cells (CEC-sEVs) of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a (miR-27a) is an elevated miRNA in ischemic CEC-sEVs. In the present study, we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a (27a-sEVs) further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs. 27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector. Small EVs isolated from CECs transfected with a scramble vector (Scra-sEVs) were used as a control. Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs. An array of behavior assays was used to measure neurological function. Compared with treatment of ischemic stroke with Scra-sEVs, treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side, and significantly improved neurological outcomes. In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth. Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone, while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a, and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone. Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs. Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes. Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.

The impact of mold exposure on anxiety symptoms in the older adults: A moderated mediation model based on CLHLS.

BACKGROUND: Mold exposure is a common environmental issue that can adversely affect health, particularly among older adults. The impact of mold exposure on anxiety symptoms in this population has not been extensively studied. OBJECTIVE: This study aims to examine the relationship between mold exposure and anxiety symptoms in older adults, considering the mediating role of cognitive function and the moderating effects of open window ventilation and multivitamin supplementation. METHODS: Data from the eighth wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) was utilized, including 11,021 participants aged 65 and older. Logistic regression models and moderated mediation analysis were employed to explore these relationships. RESULTS: Mold exposure was significantly associated with increased anxiety symptoms (OR=1.831, 95 % CI=1.588-2.110). Cognitive impairment partially mediated this relationship. Open window ventilation (B=-0.040, P<0.001) and multivitamin supplementation (B=-0.197, P<0.001) served as protective factors. Subgroup analysis indicated higher vulnerability among females (OR=1.72, P<0.001), those aged 65-79 (OR=1.86, P<0.001), urban residents (OR=2.50, P<0.001), individuals not living with family members (OR=1.89, P<0.001), those with higher education (OR=2.01, P<0.001), married individuals (OR=1.80, P<0.001), and those in very good health (OR=2.11, P=0.026). CONCLUSION: Mold exposure contributes to anxiety symptoms in older adults, with cognitive decline playing a mediating role. Effective interventions, including improved ventilation and multivitamin supplementation, can mitigate these effects. These findings highlight the need for targeted public health strategies to enhance the well-being of older adults.

Structural basis for the evolution and antibody evasion of SARS-CoV-2 BA.2.86 and JN.1 subvariants.

The Omicron subvariants of SARS-CoV-2, especially for BA.2.86 and JN.1, have rapidly spread across multiple countries, posing a significant threat in the ongoing COVID-19 pandemic. Distinguished by 34 additional mutations on the Spike (S) protein compared to its BA.2 predecessor, the implications of BA.2.86 and its evolved descendant, JN.1 with additional L455S mutation in receptor-binding domains (RBDs), are of paramount concern. In this work, we systematically examine the neutralization susceptibilities of SARS-CoV-2 Omicron subvariants and reveal the enhanced antibody evasion of BA.2.86 and JN.1. We also determine the cryo-EM structures of the trimeric S proteins from BA.2.86 and JN.1 in complex with the host receptor ACE2, respectively. The mutations within the RBDs of BA.2.86 and JN.1 induce a remodeling of the interaction network between the RBD and ACE2. The L455S mutation of JN.1 further induces a notable shift of the RBD-ACE2 interface, suggesting the notably reduced binding affinity of JN.1 than BA.2.86. An analysis of the broadly neutralizing antibodies possessing core neutralizing epitopes reveals the antibody evasion mechanism underlying the evolution of Omicron BA.2.86 subvariant. In general, we construct a landscape of evolution in virus-receptor of the circulating Omicron subvariants.

Structural and Physical Properties of Two Distinct 2D Lead Halides with Intercalated Cu(II).

Transition metal cation intercalation between the layers of two-dimensional (2D) metal halides is an underexplored research area. In this work we focus on the synthesis and physical property characterizations of two layered hybrid lead halides: a new compound [Cu(O2C-CH2-NH2)2]Pb2Br4 and the previously reported [Cu(O2C-(CH2)3-NH3)2]PbBr4. These compounds exhibit 2D layered crystal structures with incorporated Cu2+ between the metal halide layers, which is achieved by combining Cu(II) and lead bromide with suitable amino acid precursors. The resultant [Cu(O2C-(CH2)3-NH3)2]PbBr4 adopts a 2D layered perovskite structure, whereas the new compound [Cu(O2C-CH2-NH2)2]Pb2Br4 crystallizes with a new structure type based on edge-sharing dodecahedral PbBr5O3 building blocks. [Cu(O2C-CH2-NH2)2]Pb2Br4 is a semiconductor with a bandgap of 3.25 eV. It shows anisotropic charge transport properties with a semiconductor resistivity of 1.44×1010 Ω·cm (measured along the a-axis) and 2.17×1010 Ω·cm (along the bc-plane), respectively. The fabricated prototype detector based on this material showed response to soft low-energy X-rays at 8 keV with a detector sensitivity of 1462.7 µCGy-1cm-2, indicating its potential application for ionizing radiation detection. These encouraging results are discussed together with the results from density functional theory calculations, optical, magnetic, and thermal property characterization experiments.

Comparative study on the incidence of non-COVID-19 viral pneumonia before and after the COVID-19 pandemic: A retrospective analysis based on respiratory non-COVID viral nucleic acid results.

Background: The impact of the coronavirus disease 2019 (COVID-19) pandemic on the etiology of non-COVID-19 viral pneumonia remains to be identified. We investigated the evolution of non-COVID-19 viral pneumonia in hospitalized patients before and after the COVID-19 pandemic. Methods: This is a single-center retrospective study. Patients who came to West China Hospital of Sichuan University diagnosed with non-COVID-19 viral pneumonia from January 1, 2016 to December 31, 2021, were included and divided into pre- and post-COVID-19 groups according to the date of the COVID-19 outbreak in China. The results of 13 viral nucleic acid tests were compared between the two groups. Results: A total of 5937 patients (3954 in the pre-COVID-19 group and 1983 in the post-COVID-19 group) were analyzed. Compared with the pre-COVID-19 group, the proportion of patients tested for respiratory non-COVID-19 viral nucleic acid was significantly increased in the post-COVID-19 group (14.78% vs. 22.79%, P <0.05). However, the non-COVID-19 virus-positive rates decreased from 37.9% to 14.6% after the COVID-19 outbreak (P < 0.001). Notably, non-COVID-19 viral pneumonia caused by the influenza A virus H1N1 (InfAH1N1) (2009) dropped to 0% after the pandemic. The top three viruses were InfAH1N1 (2009) (13.9%), human rhinovirus (7.4%), and human adenovirus (3.4%) in the pre-COVID-19 group, and human rhinovirus (3.8%), human respiratory syncytial virus (2.0%), human parainfluenza virus (1.1%) and InfAH3N2 (1.1%) in the post-COVID-19 group. Conclusions: The proportion of non-COVID-19 viral pneumonia decreased significantly after the COVID-19 outbreak, among which InfAH1N1 (2009) pneumonia decreased the most dramatically.

Realizing the Rapid Release of Drag Reducers via pH-Induced Oil Phase Transition of Inverse Emulsion.

As a key component of slickwater fracturing fluids, emulsion drag reducers play a vital role. The dissolving capacity of traditional emulsion drag reducers is improved by adding hydrophilic surfactants, which leads to poor stability of the emulsion drag reducer. In order to eliminate the contradiction between stability and release of the emulsion drag reducer, here, pH-responsive polymer emulsion was fabricated using the switching solvent (HA) and white oil as the continuous phase. Monomer emulsions exhibit obvious pH-responsive behavior. This is because the deprotonation of HA by pH stimulation leads to a change in the oil-water ratio of the emulsion, thereby facilitating the demulsification of emulsion. The remarkable stability of the monomer emulsion benefits the preparation of inverse emulsion polymers (P(AM-AA-AMPS)). The obtained P(AM-AA-AMPS) polymer emulsion features remarkable stability even after 15 days of storage. Importantly, the P(AM-AA-AMPS) polymer was released from the emulsion efficiently by pH stimulation instead of introducing an extra hydrophilic surfactant, which confirmed the improvement of polymer release by pH stimulation. The viscosity of the P(AM-AA-AMPS) polymer aqueous solution reaches a maximum value of 96 mPa s within 80 s at a pH value of 9.2. The release efficiency of P(AA-AM-AMPS) polymer emulsion is increased by 33% in comparison with that of traditional polymer emulsion (2 min). The P(AM-AA-AMPS) emulsion demonstrated remarkable drag-reduction performance by achieving a drag-reduction rate of 73% at a concentration of 0.05 wt %. P(AM-AA-AMPS) polymer emulsion with pH responsiveness eliminates the contradiction between the stability and release of emulsion drag reducers. Research based on pH-responsive P(AM-AA-AMPS) polymer emulsion provides other ideas for the development of quickly dissolving and long-term storage drag reducers, which is helpful for the development of low-permeability oil and gas resources.

Efficacy and safety of various corticosteroids in the treatment of children with allergic rhinitis: A systematic review and network meta-analysis.

BACKGROUND: Intranasal corticosteroids were recommended as first-line drugs for the treatment of allergic rhinitis (AR) children. A variety of corticosteroids were available for clinical choice; however, which could relieve the clinical symptoms of patients to the greatest extent was currently unknown. Thus, we performed a network meta-analysis (NMA) to systematically evaluate the effectiveness and safety of different corticosteroids in treating children with AR, which might provide a basis for more rational clinical treatment decisions. METHODS: Seven electronic databases were searched, and the retrieval time range was the time from their inception to November 2023. The literature screening, data extraction, and assessment of the risk of bias of included studies were completed independently by two reviewers. A frequentist NMA was performed with Stata17.0 software. RESULTS: A total of 43 RCTs covering 10,897 participants were included. In the improvement of reflective total nasal symptom score (rTNSS) and instantaneous total nasal symptom score (iTNSS), fluticasone furoate nasal spray (FFNS) and beclomethasone dipropionate (BDP) nasal aerosol presented the best efficacy. Regarding the incidence of adverse reactions, mometasone furoate aqueous nasal spray (MFANS) and BDP showed a good safety profile. In terms of the influence of cortisol (urinary free cortisol, plasma cortisol) and growth, no significant difference was observed between the different groups. CONCLUSION: The results showed that BDP nasal aerosol and FFNS had best efficacy; MFANS and BDP had the best safety profile. However, this conclusion was less convincing because of the limited numbers of patients/controls and study quality.

An epigenetically mediated double negative cascade from EFD to HB21 regulates anther development.

Epigenetic modifications are crucial for plant development. EFD (Exine Formation Defect) encodes a SAM-dependent methyltransferase that is essential for the pollen wall pattern formation and male fertility in Arabidopsis. In this study, we find that the expression of DRM2, a de novo DNA methyltransferase in plants, complements for the defects in efd, suggesting its potential de novo DNA methyltransferase activity. Genetic analysis indicates that EFD functions through HB21, as the knockout of HB21 fully restores fertility in efd mutants. DNA methylation and histone modification analyses reveal that EFD represses the transcription of HB21 through epigenetic mechanisms. Additionally, we demonstrate that HB21 directly represses the expression of genes crucial for pollen formation and anther dehiscence, including CalS5, RPG1/SWEET8, CYP703A2 and NST2. Collectively, our findings unveil a double negative regulatory cascade mediated by epigenetic modifications that coordinates anther development, offering insights into the epigenetic regulation of this process.

Blocking antibodies against integrin-α3, -αM, and -αMß2 de-differentiate myofibroblasts, and improve lung fibrosis and kidney fibrosis.

Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of lung or kidney fibrosis. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMß2 de-differentiate myofibroblasts in vitro, lower the pro-fibrotic secretome of myofibroblasts, and treat lung fibrosis and inhibit kidney fibrosis in vivo. Decorin's collagen-binding peptide can be used to direct functionalized blocking antibodies (against integrins-α3, -αM, -αMß2) to both fibrotic lungs and fibrotic kidneys, reducing the dose of antibody necessary to treat fibrosis. This targeted immunotherapy blocking key integrins may be an effective therapeutic for the treatment of fibrosis.

The correlation between traditional Chinese medicine constitution and primary osteoporosis: A systematic review and meta-analysis.

BACKGROUND: In recent years, as societal awareness of the risks associated with primary osteoporosis (POP) has deepened, numerous studies have explored the relationship between POP and Traditional Chinese Medicine (TCM) constitution types. To further clarify the TCM constitution types closely associated with POP and provide evidence-based medical support for the prevention and treatment of osteoporosis from a TCM perspective, we have employed evidence-based methods to investigate the relationship between POP and TCM constitution types. METHODS: We conducted a comprehensive search of observational studies on the relationship between POP and TCM constitutional types in databases, including PubMed, Embase, MEDLINE, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Scientific Journal Database (VIP), up to October 2023. RESULTS: After literature selection, data extraction, and bias assessment, 29 studies were included in the meta-analysis, comprising 20 cross-sectional studies and 9 case-control studies. Using R software (version 4.2.3), we analyzed the distribution of TCM constitutional types in POP patients and compared the TCM constitutional types between POP patients and healthy individuals. The meta-analysis results revealed that in POP patients, Yang-deficiency constitution accounted for 22.7% (95% CI: 19.8-25.8%), Yin-deficiency constitution accounted for 15.8% (95% CI: 13.0-18.6%), and Qi-deficiency constitution accounted for 14.1% (95% CI: 12.2-16.0%). The proportions of the three mentioned TCM constitutions all exceed that of the Balanced constitution, with the balanced constitution accounting for 12.3% (95% CI: 7.4-18.1%). The proportions of Yang-deficiency, Yin-deficiency, and Qi-deficiency constitutions were higher in POP patients compared to healthy individuals, with odds ratios (OR) of 2.36 (95% CI: 1.43-3.89), 1.69 (95% CI: 1.36-2.04), and 1.80 (95% CI: 1.23-2.64), respectively, while the Balanced type was lower in POP patients with an OR of 0.16 (95% CI: 0.11-0.23) compared to healthy individuals. CONCLUSION: The evidence suggests that the Yang-deficiency constitution, Yin-deficiency constitution, and Qi-deficiency constitution are the predominant TCM constitutional types in POP patients. Furthermore, Yang-deficiency constitution, Yin-deficiency constitution, and Qi-deficiency constitution may serve as potential risk factors for POP, while the Balanced constitution may act as a protective factor.

A 2D Optoelectronic Logic Device with Ultralow Supply Voltage.

Optoelectronic logic devices (OELDs) provide a cure for many visually impaired individuals. However, traditional OELDs have limitations, such as excessive channel resistance and complex structure, leading to high supply voltage and decreased efficiency of signal transmission. We report ultralow-voltage OELDs by seriating two 2D MoTe2 transistors with sub-10 nm channel lengths. The short channel length and atomically flat interface result in a low-resistance light-sensing unit that can operate with a low supply voltage and function well in weak-light conditions. The devices achieve an on state without light signal input and an off state with light signal input at an ultralow supply voltage of 50 mV, lower than the retinal bearing voltage of 70 mV. Additionally, MoTe2's excellent optoelectronic properties allow the device to perceive light from visible to near-infrared wavelengths with high sensitivity to weak light signals. The specific perception of visible light intensity is 0.03 mW·mm-2, and the near-infrared light intensity is 0.1 mW mm-2. The device also has a response time of 8 ms, meeting human needs. Our findings provide a promising solution for developing low-voltage artificial retinas.

Cytosolic Hmgb1 accumulation in mesangial cells aggravates diabetic kidney disease progression via NFκB signaling pathway.

Diabetic kidney disease (DKD) is the predominant type of end-stage renal disease. Increasing evidence suggests thatglomerular mesangial cell (MC) inflammation is pivotal for cell proliferation and DKD progression. However, the exactmechanism of MC inflammation remains largely unknown. This study aims to elucidate the role of inflammatoryfactor high-mobility group box 1 (Hmgb1) in DKD. Inflammatory factors related to DKD progression are screened viaRNA sequencing (RNA-seq). In vivo and in vitro experiments, including db/db diabetic mice model, CCK-8 assay, EdUassay, flow cytometric analysis, Co-IP, FISH, qRT-PCR, western blot, single cell nuclear RNA sequencing (snRNA-seq),are performed to investigate the effects of Hmgb1 on the inflammatory behavior of MCs in DKD. Here, wedemonstrate that Hmgb1 is significantly upregulated in renal tissues of DKD mice and mesangial cells cultured withhigh glucose, and Hmgb1 cytopasmic accumulation promotes MC inflammation and proliferation. Mechanistically,Hmgb1 cytopasmic accumulation is two-way regulated by MC-specific cyto-lncRNA E130307A14Rik interaction andlactate-mediated acetylated and lactylated Hmgb1 nucleocytoplasmic translocation, and accelerates NFκB signalingpathway activation via directly binding to IκBα. Together, this work reveals the promoting role of Hmgb1 on MCinflammation and proliferation in DKD and helps expound the regulation of Hmgb1 cytopasmic accumulation in twoways. In particular, Hmgb1 may be a promising therapeutic target for DKD.

Lung-Targeted Lipid Nanoparticle-Delivered siUSP33 Attenuates SARS-CoV-2 Replication and Virulence by Promoting Envelope Degradation.

As a structural protein of SARS-CoV-2, the envelope (E) protein not only plays a key role in the formation of viral particles, but also forms ion channels and has pathogenic functions, including triggering cell death and inflammatory responses. The stability of E proteins is controlled by the host ubiquitin-proteasome system. By screening human deubiquitinases, it is found that ubiquitin-specific protease 33 (USP33) can enhance the stability of E proteins depending on its deubiquitinase activity, thereby promoting viral replication. In the absence of USP33, E proteins are rapidly degraded, leading to a reduced viral load and inflammation. Using lipid nanoparticle (LNP) encapsulation of siUSP33 by adjusting the lipid components (ionizable cationic lipids), siUSP33 is successfully delivered to mouse lung tissues, rapidly reducing USP33 expression in the lungs and maintaining knockdown for at least 14 days, effectively suppressing viral replication and virulence. This method of delivery allows efficient targeting of the lungs and a response to acute infections without long-term USP33 deficiency. This research, based on the deubiquitination mechanism of USP33 on the E protein, demonstrates that LNP-mediated siRNA delivery targeting USP33 plays a role in antiviral and anti-inflammatory responses, offering a novel strategy for the prevention and treatment of SARS-CoV-2.

Assessment of the impact of low-density lipoprotein cholesterol on retinal vessels using optical coherence tomography angiography.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is acknowledged as an independent risk factor (IRF) for atherosclerotic cardiovascular disease. Nevertheless, studies on the impact of LDL-C on microvasculature are still scarce. The retina, abundant in microvasculature, can now be examined for microvascular alterations through the novel, non-invasive, and quantitative optical coherence tomography angiography (OCTA) technique. METHODS: In this cross-sectional study, 243 patients from the geriatric department were recruited (between December 2022 and December 2023). Individuals were classified into four groups based on their LDL-C levels: Group 1 (≤ 1.8 mmol/L), Group 2 (> 1.8 mmol/L to ≤ 2.6 mmol/L), Group 3 (> 2.6 mmol/L to ≤ 3.4 mmol/L), and Group 4 (> 3.4 mmol/L). The OCTA results including retinal vessel density (VD), foveal avascular zone (FAZ) area, macula thickness, and retinal nerve fiber layer (RNFL) thickness were contrasted across these groups. T-tests, analysis of variance, Welch's tests, or rank-sum tests were employed for statistical comparisons. In cases where significant differences between groups were found, post-hoc multiple comparisons or rank-sum tests were performed for pairwise group comparisons. Spearman's correlation coefficient was employed to perform bivariate correlation analysis to evaluate the relationship between LDL-C levels and various OCTA measurements. Multivariable regression analysis was used to evaluate the association between LDL-C levels and various OCTA measurements. Linear regression analysis or mixed-effects linear models were applied. RESULTS: It was discovered that individuals with LDL-C levels exceeding 2.6 mmol/L (Groups 3 and 4) exhibited reduced VD in the retina, encompassing both the optic disc and macular regions, compared to those with LDL-C levels at or below 2.6 mmol/L (Groups 1 and 2). A negative correlation among LDL-C levels and retinal VD was identified, with r values spanning from - 0.228 to -0.385. Further regression analysis presented ß values between - 0.954 and - 2.378. Additionally, no notable disparities were detected among the groups regarding FAZ area, macular thickness, and RNFL thickness. CONCLUSIONS: The outcomes of this study suggest that elevated LDL-C levels constitute an IRF for decreased VD across the entire retina. TRIAL REGISTRATION: NCT05644548, December 1, 2022.

Vitamin B12-catalyzed coupling reaction of nitroalkanes and diazo compounds.

Vitamin B12 is a natural and environmentally friendly catalyst. When exposed to light or heat, central Co(i) can react with electrophiles to obtain alkyl radicals, which can subsequently be used in complex processes. Herein, the vitamin B12-catalyzed coupling reaction of nitroalkanes and diazo compounds is reported leading to substituted tertiary nitroalkanes in moderate yields. The reaction conditions were optimized, and the scope and limitations of the reaction were also investigated.

Schwann cell-derived exosomes ameliorate peripheral neuropathy induced by ablation of dicer in Schwann cells.

Background: MicroRNAs (miRNAs) in Schwann cells (SCs) mediate peripheral nerve function. Ablating Dicer, a key gene in miRNA biogenesis, in SCs causes peripheral neuropathy. Exosomes from healthy SCs (SC-Exo) ameliorate diabetic peripheral neuropathy in part via miRNAs. Thus, using transgenic mice with conditional and inducible ablation of Dicer in proteolipid protein (PLP) expressing SCs (PLP-cKO), we examined whether SC-Exo could reduce peripheral neuropathy in PLP-cKO mice. Methods: PLP-cKO mice at the age of 16 weeks (8 week post-Tamoxifen) were randomly treated with SC-Exo or saline weekly for 8 weeks. Age-and sex-matched wild-type (WT) littermates were used as controls. Peripheral neurological functions, sciatic nerve integrity, and myelination were analyzed. Quantitative RT-PCR and Western blot analyses were performed to examine miRNA and protein expression in sciatic nerve tissues, respectively. Results: Compared to the WT mice, PLP-cKO mice exhibited a significant decrease in motor and sensory conduction velocities, thermal sensitivity, and motor coordination. PLP-cKO mice exhibited substantial demyelination and axonal damage of the sciatic nerve. Treatment of PLP-cKO mice with SC-Exo significantly ameliorated the peripheral neuropathy and sciatic nerve damage. PLP-cKO mice showed a substantial reduction in a set of Dicer-related miRNAs known to regulate myelination, axonal integrity, and inflammation such as miR-138, -146a and - 338 in the sciatic nerve. In addition, PLP-cKO mice exhibited significant reduction of myelin forming proteins, early growth response 2 (EGR2) and sex determining region Y-box10 (Sox10), but significantly increased myelination inhibitors, Notch1, c-Jun, and Sox2 and the axonal growth inhibitor phosphatase and tens in homolog (PTEN). However, SC-Exo treatment reversed the PLP-cKO altered miRNAs and proteins. Conclusion: This study demonstrates that exogenous SC-Exo ameliorate peripheral neuropathy induced by Dicer ablation in PLP expressing SCs. The therapeutic benefit may be mediated by the SC-Exo altered miRNAs and their targeted genes.

Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota.

The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8+ T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8+ T cell recruitment through the CXCL10-CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8+ T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy.

Specific persistent symptoms of COVID-19 and associations with reinfection: a community-based survey study in southern China.

Background: Surveillance remains fundamental to understanding the changes in epidemiological patterns regarding post-COVID conditions and reinfections. Persistent symptoms and reinfection in previously infected individuals are increasing being reported in many countries, but their associations among general populations were seldomly reported. Understanding the association with persistent symptoms of COVID-19 reinfection is essential to develop strategies to mitigate the long-term health and socio-economic impacts of the post-COVID conditions. This study aimed to investigate the incidence of COVID-19 persistent symptoms among previously infected Chinese community residents and explore associations of specific COVID-19 persistent symptoms with reinfection and other factors. Methods: A community-based survey was conducted in a southern city of China with about 20 million residents from August 3 to 24, 2023. Face-to-face questionnaires were distributed to a total of 1,485 residents to collect their information about COVID-19 infection, reinfection, specific ongoing persistent symptoms, and other COVID-19 related information. Multivariable logistic regression analysis was used to examine the association between specific persistent symptoms and reinfection of COVID-19, along with age, gender, and educational level. Results: Of the 1,485 participants, 1,089 (73.3%) reported they had been infected with COVID-19. Among them, 89.1% reported having ongoing persistent symptoms and 14.2% reported had two or more times of infection. About 20% participants were infected 1 year or more since their initial infection. Fatigue, cough, and headaches were the top 3 symptoms being reported. Participants with reinfection were associated with a higher probability of reporting headaches (OR: 1.54, 95% CI: 1.06-2.25), loss of or change in smell and/or taste (OR: 1.90, 95% CI: 1.27-2.83), impaired sleep (OR: 1.55, 95% CI: 1.02-2.35), and brain fog (OR: 1.76, 95% CI: 1.12-2.76). Participants aged 45 and above and who had a bachelor's or higher degree were more likely to report chest tightness or shortness of breath, impaired sleep, and brain fog. Discussion: During the post-emergency period of COVID-19 pandemic, the incidence of ongoing persistent symptoms among Chinese residents remains high. Individuals whose initial infection was longer than 1 year have the highest probability of reporting having multiple symptoms. Reinfection may increase the risk of reporting headaches, loss of or change in smell and/or taste, impaired sleep, and brain fog. It is important to maintain routine syndromic surveillance among previously infected people and provide recommendations for clinical management of individuals with multiple ongoing symptoms.

Distinct mutation features and its clinical significance in myelodysplastic syndromes with normal karyotype.

Myelodysplastic syndromes (MDS) is a highly heterogeneous myeloid neoplastic disease, which needs personalized evaluation and therapy. To analyze the features and significance of gene mutations for MDS patients with normal karyotype (NK) at diagnosis, targeted sequencing was conducted on 616 MDS patients with NK, alongside 457 MDS cases with abnormal karyotype (AK). The results showed that the incidence of somatic mutation reached 70.3% and 83.8% in the NK and AK group, respectively. Initial mutation including ASXL1, DNMT3A and TET2 were common in NK group, which is the same as AK group. Some karyotype-associated gene mutations, such as TP53 and U2AF1, were relatively rare in NK group. Moreover, 34 out of 91 samples who progressed to acute myeloid leukemia (AML) underwent repeat sequencing during follow-up. 25 cases were checked out with newly emerged mutations. The AML-associated genetic alterations mainly involved with active signaling and transcription factors. In patients with NK, serial targeted sequencing was employed for minimal residual disease (MRD) monitoring, indicating the efficacy and relapse of the patients. In summary, MDS with NK showed distinct mutation features from those with AK. High-frequency gene mutations together with the mutational evolution suggested the diagnostic and monitoring significance of next generation sequencing for NK-MDS.