IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of ß cells.

Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in ß cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in ß cells, named IER3IP1-ßKO and IER3IP1-ißKO, respectively. We found that IER3IP1-ßKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated ß-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with ß-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-ßKO impaired ß-cell maturation and proliferation, along with increased condensation of ß-cell nuclear chromatin. Inducible ß-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after ß-cell early development. Importantly, IER3IP1 was decreased in ß cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with ß-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in ß cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.

Integrated full-length transcriptome and metabolome analysis reveals the defence response of melon to gummy stem blight.

Gummy stem blight (GSB), a widespread disease causing great loss to cucurbit production, has become a major threat to melon cultivation. However, the melon-GSB interaction remains largely unknown. Here, full-length transcriptome and widely targeted metabolome were used to investigate the defence responses of resistant (PI511089) and susceptible (Payzawat) melon accessions to GSB pathogen infection at 24 h. The biosynthesis of secondary metabolites and MAPK signalling pathway were specifically enriched for differentially expressed genes in PI511890, while carbohydrate metabolism and amino acid metabolism were specifically enriched in Payzawat. More than 1000 novel genes were identified and MAPK signalling pathway was specifically enriched for them in PI511890. There were 11 793 alternative splicing events involving in the defence response to GSB. Totally, 910 metabolites were identified in Payzawat and PI511890, and flavonoids were the dominant metabolites. Integrated full-length transcriptome and metabolome analysis showed eriodictyol and oxalic acid were the potential marker metabolites for GSB resistance in melon. Moreover, posttranscription regulation was widely involved in the defence response of melon to GSB pathogen infection. These results not only improve our understanding on the interaction between melon and GSB, but also facilitate the genetic improvement of melon with GSB resistance.

Characterization and expression profiles of toll-like receptor genes (TLR2 and TLR5) in immune tissues of hybrid yellow catfish under bacterial infection.

The yellow catfish (Pelteobagrus fulvidraco) is one of the most economically important freshwater species in Asia. However, pathogenic bacterial infections often cause high rates of mortality and economic losses in practical aquaculture. Previous studies in mammals have shown that Toll-like receptor 2 (TLR2) and Toll-like receptor 5 (TLR5) are involved in the recognition of cell wall components such as lipopolysaccharides and flagella of various bacteria, thereby acting as key regulators in the innate immunity response. However, TLR2 and TLR5 in yellow catfish have not been characterized. In the present study, TLR2 and TLR5 were examined through comparative genomic approaches. The gene structure, collinearity, protein spatial structure, and phylogenetic relationships were compared with those in multiple representative vertebrates. Meanwhile, quantitative real-time PCR was conducted to explore transcriptional changes in TLR2 and TLR5 in immune tissues after infection with exogenous A. hydrophila and E. tarda. The results demonstrated the presence of TLR2 and TLR5 in yellow catfish. However, a systematic analysis showed that TLR2 was not associated with the arrangement of diverse neighboring genes. The expression of hybrid yellow catfish TLR2 transcripts in multiple tissues (including liver, spleen, kidney, and intestine) was significantly up-regulated after infection with A. hydrophila and E. tarda, suggesting that hybrid yellow catfish TLR2 and TLR5 may participate in the immune process. Taken together, the results indicate that TLR2 and TLR5 are conserved in terms of evolution and possess significant antibacterial activity as well as regulatory properties in immune-related tissues and thus play key roles in host defense against pathogen invasion.

The benefit of omeprazole exposure on all-cause mortality and length of ICU/hospital stay might vary with age in critically ill pediatric patients: A cohort study.

PURPOSE: To investigate the association between proton pump inhibitors (PPIs) administration during hospitalization and mortality and length of stay in critically ill pediatric patients. MATERIALS AND METHODS: This is a retrospective observational cohort study on pediatric ICU patients (0 to 18 years). Propensity score matching (PSM), Kaplan-Meier curves, Cox proportional hazards model and Linear regression model was applied for assessing the effects of PPIs on mortality and other outcomes during hospitalization. RESULTS: A total of 2269 pediatric ICU patients were included, involving 1378 omeprazole (OME) users and 891 non-OME users. The results showed significant association between OME exposure and decreased ICU stay (ß -0.042; 95% CI -0.073--0.011; P = 0.008) but prolonged non-ICU hospital stay (ß 0.121; 95% CI 0.097-0.155; P = 0.040). No statistical significance was observed between OME exposure and reduced mortality, but the OME group had a slightly decreased tendency in 28-day mortality (HR 0.701; 95% CI 0.418-1.176) and in-hospital mortality (HR 0.726; 95% CI 0.419-1.257). Furthermore, subgroup analyses revealed that the decreased tendency of mortality were more obvious in patients less than 1 year old compared with older pediatric patients, although not statistically significant. In addition, we also observed that OME exposure was significantly associated with reduced mortality of general ICU subgroup. CONCLUSIONS: This study provided a sign that PPIs used only in the ICU, rather than throughout hospital stay, might provide more benefit for critically ill pediatric patients. Additionally, younger pediatric patients might gain relatively more benefit than older children when receiving PPIs.

Distinctive cortical morphological patterns in primary trigeminal neuralgia: a cross-sectional clinical study.

PURPOSE: The characteristics of surface-based morphological patterns to primary trigeminal neuralgia (PTN) are still not well understood. This study aims to screen the useful cortical indices for the prediction of PTN and the quantification of pain severity. METHODS: Fifty PTN patients and 48 matched healthy subjects enrolled in the study from March 2016 to August 2021. High-resolution T1 data were performed at 3.0 Tesla scanner and were analyzed with FreeSurfer software to detect the abnormalities of cortical mean curve (CMC), cortical thickness (CT), surface area (SA), and cortical volume (CV) in PTN patients compared to healthy controls. Logistic regression analysis was conducted to determine whether certain morphological patterns could predict PTN disorder. Then, the relationships of cortical indices to the pain characteristics in patient group were examined using linear regression model. RESULTS: Distinctive cortical alterations were discovered through surface-based analysis, including increased temporal CMC, decreased insular CT and fusiform SA, along with decreased CV in several temporal and occipital areas. Moreover, the difference of temporal CMC was greater than other cortical parameters between the two groups, and the combination of certain morphological indices was of good value in the diagnosis for PTN. Besides, CT of left insula was negatively associated with the pain intensity in PTN patients. CONCLUSION: The patients with PTN demonstrate distinctive morphological patterns in several cortical regions, which may contribute to the imaging diagnosis of this refractory disorder and be useful for the quantification of the orofacial pain. CLINICAL TRIALS: The registry name of this study in https://clinicaltrials.gov/ : Magnetic Resonance Imaging Study on Patients with Trigeminal Neuralgia (MRI-TN) https://clinicaltrials.gov/ ID: NCT02713646 A link to the full application: https://clinicaltrials.gov/ct2/results?cond=&term=NCT02713646&cntry=&state=&city=&dist= The first patient with primary trigeminal neuralgia was recruited on November 28, 2016.

Achieving Stable Lithium Metal Anode at 50 mA cm-2 Current Density by LiCl Enriched SEI.

Lithium metal batteries are intensively studied due to the potential to bring up breakthroughs in high energy density devices. However, the inevitable growth of dendrites will cause the rapid failure of battery especially under high current density. Herein, the utilization of tetrachloroethylene (C2 Cl4 ) is reported as the electrolyte additive to induce the formation of the LiCl-rich solid electrolyte interphase (SEI). Because of the lower Li ion diffusion barrier of LiCl, such SEI layer can supply sufficient pathway for rapid Li ion transport, alleviate the concentration polarization at the interface and inhibit the growth of Li dendrites. Meanwhile, the C2 Cl4 can be continuously replenished during the cycle to ensure the stability of the SEI layer. With the aid of C2 Cl4 -based electrolyte, the Li metal electrodes can maintain stable for >300 h under high current density of 50 mA cm-2 with areal capacity of 5 mAh cm-2 , broadening the compatibility of lithium metal anode toward practical application scenarios.

BCG-induced trained immunity: history, mechanisms and potential applications.

The Bacillus Calmette-Guérin (BCG) vaccine was discovered a century ago and has since been clinically applicable. BCG can not only be used for the prevention of tuberculosis, but also has a non-specific protective effect on the human body called trained immunity that is mediated by innate immune cells such as monocytes, macrophages, and natural killer cells. Mechanisms of trained immunity include epigenetic reprogramming, metabolic reprogramming, and long-term protection mediated by hematopoietic stem cells. Trained immunity has so far shown beneficial effects on cancer, viral-infections, autoimmune diseases, and a variety of other diseases, especially bladder cancer, respiratory viruses, and type 1 diabetes. The modulation of the immune response by BCG has led to the development of a variety of recombinant vaccines. Although the specific mechanism of BCG prevention on diseases has not been fully clarified, the potential role of BCG deserves further exploration, which is of great significance for prevention and treatment of diseases.

A meta-analysis of associations of IL-10 gene polymorphisms with acute leukemia susceptibility.

BACKGROUND: Recently, increasing evidence has demonstrated that IL-10 single nucleotide polymorphisms (SNPs) are associated with the risk of acute leukemia (AL), but the findings of different articles remain controversial. Thus, we performed a meta-analysis to further investigate the exact roles of IL-10 SNPs in AL susceptibility. METHODS: Six common Chinese and English databases were utilized to retrieve eligible studies. The strength of the association was assessed by calculating odds ratios and 95 % confidence intervals. All analyses were carried out using Review Manager (version 5.3) and STATA (version 15.1). The registered number of this research is CRD42022373362. RESULTS: A total of 6391 participants were enrolled in this research. The results showed that the AG genotype of rs1800896 increased AL risk in the heterozygous codominant model (AG vs. AA, OR = 1.41, 95 % CI = 1.04-1.92, P = 0.03) and overdominant model (AG vs. AA + GG, OR = 1.32, 95 % CI = 1.04-1.70, P = 0.03). In the subgroup analysis, associations between the G allele, GG genotype, AG genotype, AG + GG genotype of rs1800896 and increased AL risk were also observed in the mixed population based on allelic, homozygote codominant, heterozygous codominant, dominant, and overdominant models. Furthermore, an association between the AC genotype of rs1800872 and increased AL risk was observed in the Caucasian population in the overdominant model. However, the rs1800871, rs3024489 and rs3024493 polymorphisms did not affect AL risk. CONCLUSION: IL-10 rs1800896 and rs1800872 affected the susceptibility of AL and therefore may be biomarkers for early screening and risk prediction of AL.

Causal associations between prodromal infection and neuromyelitis optica spectrum disorder: A Mendelian randomization study.

BACKGROUND AND PURPOSE: Prodromal infections are associated with neuromyelitis optica spectrum disorder (NMOSD), but it remains unclear which type of infection has a causal association with NMOSD. We aimed to explore the causal associations between four herpesvirus infections (chickenpox, cold sores, mononucleosis and shingles) and NMOSD, as well as between other types of infections and NMOSD. METHODS: For data on infections, we used the genome-wide association study (GWAS) summary statistics from the 23andMe cohort. For outcomes, we used the GWAS data of participants of European ancestry, including 215 NMOSD patients (132 anti-aquaporin-4 antibody [AQP4-ab]-positive patients and 83 AQP4-ab-negative patients) and 1244 normal controls. Single-nucleotide polymorphism (SNP) identification and two-sample Mendelian randomization (MR) analyses were then performed. RESULTS: In the 23andMe cohort, we identified one SNP for chickenpox (rs9266089 in HLA-B gene), one SNP for cold scores (rs885950 in the POU5F1 gene), one SNP for mononucleosis (rs2596465 in the HCP5 gene), and three SNPs for shingles (rs2523591 in the HLA-B gene; rs7047299 in the IFNA21 gene; rs9260809 in the MICD gene). The association between cold sores and AQP4-ab-positive NMOSD reached statistical significance (odds ratio [OR] 745.318; 95% confidence interval [CI] 22.176, 25,049.53 [p < 0.001, Q < 0.001]). The association between shingles and AQP4-ab-positive NMOSD was also statistically significant (OR 21.073; 95% CI 4.271, 103.974 [p < 0.001, Q < 0.001]). No significant association was observed between other infections and AQP4-ab-positive or AQP4-ab-negative NMOSD. CONCLUSION: These findings suggest there are positive associations between cold sores and shingles and AQP4-ab-positive NMOSD, indicating there may be causal links between herpes simplex virus and varicella-zoster virus infection and AQP4-ab-positive NMOSD.

[Preparation and Tumor Targeting Analysis of Cell Membrane Nanovesicles Derived from Breast Cancer Cells].

Objective: To prepare cell membrane nanovesicles (NVs) derived from breast cancer cells, to explore their basic characteristics, tumor cell endocytosis, and in vivo distribution in a tumor-bearing mouse model, and to investigate their tumor targeting properties. Methods: 4T1 breast cancer cells were cultured in vitro. The cell membrane of 4T1 cells was isolated through ultracentrifugation and NVs were formulated with a liposome extruder. The size distribution of NVs was determined by way of dynamic light scattering, and the morphology properties of the NVs were examined with transmission electron microscope. The stability of NVs was analyzed by measuring the diameter changes of NVs submerged in phosphate-buffered saline (PBS). The biocompatibility of NVs was investigated by measuring the viability of dendritic cells treated with NVs at different concentrations (5, 10, 20, 50, and 100 mg·L -1) by CCK-8 assay. Fluorescence microscopy was used to analyze the cellular uptake of NVs by breast cancer cells. A mice model of breast cancer model was established with mice bearing subcutaneous xenograft of 4T1 cells. The mice were treated with Cy5.5-labeled NVs injected via the tail vein and the in vivo distribution of NVs was analyzed with an imaging system for small live animals. Results: The results showed that NVs derived from 4T1 breast cancer cells were successfully prepared. The NVs had a mean diameter of 123.2 nm and exhibited a hollow spherical structure under transmission electron microscope. No obvious change in the size of the NVs was observed after 7 days of incubation in PBS solution. CCK-8 assay results showed that the viability of dendritic cells treated with NVs at different concentrations was always higher than 90%. Fluorescence microscopic imaging showed that NVs could be efficiently internalized into breast cancer cells. in vivo biodistribution analysis revealed that breast cancer cell-derived NVs showed higher distribution in tumor tissue than the NVs prepared with normal cells did. Conclusion: We successfully prepared cell membrane NVs derived from 4T1 breast cancer cells. These NVs had efficient cellular uptake by breast cancer cells and sound tumor targeting properties.

Mapping Techniques for the Design of Lithium-Sulfur Batteries.

Mapping technique has been the powerful tool for the design of next-generation energy storage devices. Unlike the traditional ion-insertion based lithium batteries, the Li-S battery is based on the complex conversion reactions, which require more cooperation from mapping techniques to elucidate the underlying mechanism. Therefore, in this review, the representative works of mapping techniques for Li-S batteries are summarized, and categorized into the studies of lithium metal anode and sulfur cathode, with sub-sections based on shared characterization mechanisms. Due to specific features of mapping techniques, various aspects such as compositional distribution, in-plain/cross section characterization, coin cell/pouch cell configuration, and structural/mechanical analysis are emphasized in each study, aiming for the guidance for developing strategies to improve the battery performances. Benefited from the achieved progresses, suggestions for future studies based on mapping techniques are proposed to accelerate the development and commercialization of the Li-S battery.

Single Nickel Atom Catalysts Enable Fast Polysulfide Redox for Safe and Long-Cycle Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries have attracted great interest due to their low cost, high theoretical energy density, and environmental friendliness. However, the sluggish conversion of lithium polysulfides (LiPS) to S and Li2 S during the charge/discharge process leads to unsatisfactory rate performance of lower to 0.1 C (1 C = 1675 mA g-1 ) especially for Li-S pouch batteries, thus hindering their practical applications in high power batteries. Here, well-defined and monodispersed Ni single-atom catalysts (SACs) embedded in highly porous nitrogen-doped graphitic carbons (NiSA-N-PGC) are designed and synthesized to form Ni-N4 catalytic sites at the atomic level. When serving as a bifunctional electrocatalyst, the Ni-N4 catalytic sites cannot only promote the interfacial conversion redox of LiPS by accelerating the transformation kinetics, but also suppress the undesirable shuttle effect by immobilizing LiPS. These findings are verified by both experimental results and DFT theoretical calculations. Furthermore, Li ions show low diffusion barrier on the surface of Ni-N4 sites, resulting in enhanced areal capacity of batteries. As a result, the Li-S battery delivers stable cycling life of more than 600 cycles with 0.069% capacity decay per cycle at a rate of 0.5 C. More importantly, the Li-S pouch cells with NiSA-N-PGC show an initial capacity of 1299 mAh g-1 at a rate of 0.2 C even with high sulfur loading of 6 mg cm-2 . This work opens up an avenue for developing single-atom catalysts to accelerate the kinetic conversion of LiPS for highly stable Li-S batteries.

A case of atypical reninoma with mild hypertension and normal plasma renin activity but elevated plasma renin concentration.

BACKGROUND: Reninoma is a rare, benign renal neoplasm. Typical clinical features include severe hypertension, secondary hyperaldosteronism, hypokalaemia and metabolic alkalosis caused by the overproduction of renin. CASE PRESENTATION: A 25-year-old lean Chinese woman with no family history of hypertension was hospitalized for stage 1 hypertension that gradually developed over two years. Endocrine investigation showed hyperreninemia without hyperaldosteronism and hypokalaemia. Interestingly, although the patient had an elevated plasma renin concentration (PRC), her plasma renin activity (PRA) was in the normal range. Abdominal contrast-enhanced computed tomography (CT) scanning revealed a solid, low-density, renal cortical mass with delayed enhancement. Selective renal vein sampling (SRVS) was performed, and a lateralization of the renin secretion from the left kidney was found. Enucleation of the tumour led to a rapid remission of hypertension and hyperreninemia. Based on pathological findings, the patient was diagnosed with reninoma. Immunohistochemical staining of the tumour was positive for Renin, CD34, Vimentin, and synaptophysin (Syn) and negative for somatostatin receptor 2 (SSTR2) and chromogranin A (CgA). CONCLUSIONS: Reninoma can present as mild hypertension without hyperaldosteronism and hypokalaemia. The clinical features of reninoma may depend on the degree of activation of the renin-angiotensin-aldosterone system (RAAS). PRC should be incorporated in the differential diagnosis of secondary hypertension.

NtbHLH1, a JAF13-like bHLH, interacts with NtMYB6 to enhance proanthocyanidin accumulation in Chinese Narcissus.

BACKGROUND: Flavonoid biosynthesis in plants is primarily regulated at the transcriptional level by transcription factors modulating the expression of genes encoding enzymes in the flavonoid pathway. One of the most studied transcription factor complexes involved in this regulation consists of a MYB, bHLH and WD40. However, in Chinese Narcissus (Narcissus tazetta L. var. chinensis), a popular monocot bulb flower, the regulatory mechanism of flavonoid biosynthesis remains unclear. RESULTS: In this work, genes related to the regulatory complex, NtbHLH1 and a R2R3-MYB NtMYB6, were cloned from Chinese Narcissus. Phylogenetic analysis indicated that NtbHLH1 belongs to the JAF13 clade of bHLH IIIf subgroup, while NtMYB6 was highly homologous to positive regulators of proanthocyanidin biosynthesis. Both NtbHLH1 and NtMYB6 have highest expression levels in basal plates of Narcissus, where there is an accumulation of proanthocyanidin. Ectopic over expression of NtbHLH1 in tobacco resulted in an increase in anthocyanin accumulation in flowers, and an up-regulation of expression of the endogenous tobacco bHLH AN1 and flavonoid biosynthesis genes. In contrast, the expression level of LAR gene was significantly increased in NtMYB6-transgenic tobacco. Dual luciferase assays showed that co-infiltration of NtbHLH1 and NtMYB6 significantly activated the promoter of Chinese Narcissus DFR gene. Furthermore, a yeast two-hybrid assay confirmed that NtbHLH1 interacts with NtMYB6. CONCLUSIONS: Our results suggest that NtbHLH1 may function as a regulatory partner by interacting directly with NtMYB6 to enhance proanthocyanidin accumulation in Chinese Narcissus.

Association between asthma control trajectories in preschoolers and disease remission.

INTRODUCTION: Early disease morbidity has been associated with asthma persistence in wheezing preschoolers; however, whether asthma control trajectories shortly after diagnosis could influence remission is unknown. We examined the association between asthma control trajectories 2 years post-diagnosis in preschoolers and subsequent disease remission. METHODS: We conducted a multicentre population-based retrospective cohort study consisting of 48 687 children with asthma diagnosed before 5 years old and born between 1990 and 2013 in four Canadian provinces who had prolonged disease activity post-diagnosis. Prolonged disease activity was defined as one or more medical visits or medications for asthma every 6-month period for at least four of the six periods post-diagnosis. Follow-up began at 3 years post-diagnosis (at cohort entry). Remission was defined as 2 consecutive years without drug claims or medical visits for asthma or asthma-like conditions following cohort entry. Asthma control trajectories, ascertained over four 6-month periods following diagnosis using a validated index, were classified as: "controlled throughout", "improving control", "worsening control", "out of control throughout" and "fluctuating control". Adjusted Cox models estimated associations between asthma control trajectories and time to remission. A random effects meta-analysis summarised province-specific hazard ratios (HRs). RESULTS: The pooled remission rate was 8.91 (95% CI 8.80-9.02) per 100 person-years. Compared with children controlled throughout, poorer asthma control was associated with incrementally lower hazard ratios of remission in four other trajectories: improving control (HR 0.89, 95% CI 0.82-0.96), fluctuating control (HR 0.78, 95% CI 0.71-0.85), worsening control (HR 0.68, 95% CI 0.62-0.75) and out of control throughout (HR 0.52, 95% CI 0.45-0.59). CONCLUSIONS: Asthma control trajectories 2 years following a diagnosis in preschoolers were associated with remission, highlighting the clinical relevance of documenting control trajectories in early life.

Ion-Inserted Metal-Organic Frameworks Accelerate the Mass Transfer Kinetics in Lithium-Sulfur Batteries.

Lithium-sulfur battery promises great potential to promote the reform of energy storage field. Modified functional interlayer on separator has been recognized as efficient method to promote battery performances, mainly focusing on the entrapment and catalytic effect toward lithium polysulfide, while the mass transfer property across the interlayers has not been carefully considered. Herein, a dense layer composed of ion-inserted metal-organic frameworks is used to facilitate mass transfer across the layer and ensure high polysulfides entrapment efficiency. In situ Raman study reveals that the dense functional layer blocks the transfer of Li ions, while the ion-inserted layer can accelerate the ion-transfer kinetics and avoid the ion depletion caused polarization. As a result, a specific capacity of 742 mAh g-1 is obtained at 2 C, with the decay rate of 0.089% per cycle at 1 C over 600 cycles, demonstrating great potential for the application in advanced Li-S batteries.

An updated chronology and paleoenvironmental background for the Paleolithic Loufangzi site, North China.

The relationship between the environment and human activities during Marine Isotope Stage (MIS) 4 is important for understanding the origins of modern humans (Homo sapiens) in East Asia, an area where various hypotheses of human origins have been vigorously debated over the past three decades. Unfortunately, only a handful of Paleolithic sites date to MIS 4 in East Asia, hampering our understanding of how environmental changes affected human activities during this time period. Here, we used stratigraphic correlation analysis and optically stimulated luminescence to date the Loufangzi site, an important Paleolithic site in North China that has had an unreliable chronology. Pollen analysis, grain size, and magnetic susceptibility were also used to reconstruct environmental conditions at the Loufangzi site area. Our results show that (1) the age of the upper culture layer of the Loufangzi site is bracketed between ∼70 ka and ∼60 ka and dates to MIS 4 and (2) the regional vegetation from MIS 5 to MIS 4 to MIS 3 was mainly dominated by forest steppe, desert steppe/desert, and steppe, respectively, indicating harsh environmental conditions during MIS 4. Combined with the discovery of Mousterian-like scrapers in the upper culture layer of MIS 4, our results challenge the view that the area was unsuitable for human survival during the Last Glacial period and instead suggest that humans used new technologies to increase their resilience to the cooling climate.

Generation and identification of endothelial-specific Hrh2 knockout mice.

Histamine H2 receptor (HRH2) is closely associated with the development of cardiovascular and cerebrovascular diseases. However, systematic Hrh2 knockout mice did not exactly reflect the HRH2 function in specific cell or tissue types. To better understand the physiological and pathophysiological functions of endothelial HRH2, this study constructed a targeting vector that contained loxp sites flanking the ATG start codon located in Hrh2 exon 2 upstream and a neomycin (Neo) resistance gene flanked by self-deletion anchor sites within the mouse Hrh2 allele. The targeting vector was then electroporated into C57BL/6J embryonic stem (ES) cells, and positively targeted ES cell clones were micoinjected into C57BL/6J blastocysts, which were implanted into pseudopregnant females to obtain chimeric mice. The F1 generation of Hrh2flox/+ mice was generated via crossing chimeric mice with wild-type mice to excise Neo. We also successfully generated endothelial cell-specific knockout (ECKO) mice by crossing Hrh2flox/+ mice with Cdh5-Cre mice that specifically express Cre in endothelial cells and identified that Hrh2 deletion was only observed in endothelial cells. Hrh2flox/+ and Hrh2ECKO mice were normal, healthy and fertile and did not display any obvious abnormalities. These novel animal models will create new prospects for exploring roles of HRH2 during the development and treatment of related diseases.

Risk of sudden cardiac death in EXOSC5-related disease.

The RNA exosome is a multi-subunit complex involved in the processing, degradation, and regulated turnover of RNA. Several subunits are linked to Mendelian disorders, including pontocerebellar hypoplasia (EXOSC3, MIM #614678; EXOSC8, MIM #616081: and EXOSC9, MIM #618065) and short stature, hearing loss, retinitis pigmentosa, and distinctive facies (EXOSC2, MIM #617763). More recently, EXOSC5 (MIM *606492) was found to underlie an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies. An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals. Here, we provide a detailed clinical and molecular characterization of two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination, with cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT) due to compound heterozygous variants in EXOSC5: (1) NM_020158.4:c.341C > T (p.Thr114Ile; pathogenic, previously reported) and (2) NM_020158.4:c.302C > A (p.Thr101Lys; novel variant). A review of the literature revealed an additional family with biallelic EXOSC5 variants and cardiac conduction abnormalities. These clinical and molecular data provide compelling evidence that cardiac conduction abnormalities and arrhythmias are part of the EXOSC5-related disease spectrum and argue for proactive screening due to potential risk of sudden cardiac death.

Antibiotic prophylaxis for prevention against Lyme disease following tick bite: an updated systematic review and meta-analysis.

BACKGROUND: In areas where Lyme disease is endemic, bites from ticks are common, but no vaccine is currently available against Lyme disease for humans. Therefore, the feasibility of using antibiotic prophylaxis to prevent Lyme disease after a tick bite is worth further exploration. Previous meta-analyses lack sufficient power to demonstrate the efficacy of about antibiotic prophylaxis for the prevention of Lyme disease following a tick bite. In this study, we explored more precise evidence and attempted to identify and update optimum treatment strategies. METHODS: We searched PubMed, Embase, and the Cochrane Library for studies until March 23, 2021. We included studies if the enrolled patients were randomly allocated to a treatment or control group within 72 h following a tick bite and had no clinical evidence of Lyme disease at enrolment. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for data abstraction. Two authors (GZZ and XX) independently reviewed the abstracts and identified articles for detailed assessment. We used a random-effects model to calculate the pooled results and reported the 95% confidence interval (CI). Study quality was assessed using a modified Jadad scale, and publication bias was assessed using Egger's test. We calculated the risk ratio (RR) for the rates of unfavorable events in patients who received intervention versus the control group. This study is registered with PROSPERO, number CRD42021245002. RESULTS: Six studies (3,766 individuals) were included. The pooled rate of unfavorable events in persons receiving treatment and the control group were 0.4% (95%CI: 0.1-1.1%) and 2.2% (95%CI: 1.6-3.0%), respectively. The pooled RR was 0.38 (95%CI: 0.22-0.66). Subgroup analysis revealed that the pooled RR was 0.29 (95%CI: 0.14-0.60) in the single-use 200-mg doxycycline group; 0.28 (95%CI: 0.05-1.67) in a 10-day course group (Amoxicillin, Penicillin or tetracycline); and 0.73 (95%CI: 0.25-2.08) in a topical antibiotic treatment group (Azithromycin). CONCLUSIONS: The available evidence supports the use of antibiotics for the prevention of Lyme disease, and reveals advantages of using single-dose; however, further confirmation is needed.