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Ran Ma, Xuefang Gong, Hua Jiang, Chunyi Lin, Yuqin Chen, Xiaoming Xu, Chenting Zhang, Jian Wang, Wenju Lu, Nanshan ZhongGuangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The 1st Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaAbstract: Skeletal muscle atrophy and dysfunction are common complications in the chronic obstructive pulmonary disease (COPD). However, the underlying molecular mechanism remains elusive. Serum response factor (SRF) is a transcription factor which is critical in myocyte differentiation and growth. In this study, we established a mouse COPD model induced by cigarette smoking (CS) exposure for 24 weeks, with apparent pathophysiological changes, including increased airway resistance, enlarged alveoli, and skeletal muscle atrophy. Levels of upstream regulators of SRF, striated muscle activator of Rho signaling (STARS), and ras homolog gene family, member A (RhoA) were decreased in quadriceps muscle of COPD mice. Meanwhile, the nucleic location of SRF was diminished along with its cytoplasmic accumulation. There was a downregulation of the target muscle-specific gene, Igf1. These results suggest that the CS is one of the major cause for COPD pathogenesis, which induces the COPD-associated skeletal muscle atrophy which is closely related to decreasing SRF nucleic translocation, consequently downregulating the SRF target genes involved in muscle growth and nutrition. The STARS/RhoA signaling pathway might contribute to this course by impacting SRF subcellular distribution. Keywords: SRF, chronic obstructive pulmonary disease, skeletal muscle atrophy, cigarette smoking

Ma R, Gong XF, Jiang H, et al. Reduced nuclear translocation of serum response factor is associated with skeletal muscle atrophy in a cigarette smoke-induced mouse model of COPD. International Journal of COPD. 2017;12:581–587. On page 583, left column, last paragraph, the primer for the Igf1 gene forward: 5′-tgctgtccctctatgcttcc-3′, reverse: 5′-gaaggaatagccacgctcag-3′ should be forward: 5′-tggatgctcttcagttcgtg-3′, reverse: 5′-cacaatgcctgtctgaggtg-3′.Read the original article

Introduction: Adult patients who have suffered acute cardiac or pulmonary failure are increasingly being treated using extracorporeal membrane oxygenation (ECMO), a cardiopulmonary bypass technique. While ECMO has improved the long-term outcomes of these patients, neurological injuries can occur from underlying illness or ECMO itself. Cerebral autoregulation (CA) allows the brain to maintain steady perfusion during changes in systemic blood pressure. Dysfunctional CA is a marker of acute brain injury and can worsen neurologic damage. Monitoring CA using invasive modalities can be risky in ECMO patients due to the necessity of anticoagulation therapy. Diffuse correlation spectroscopy (DCS) measures cerebral blood flow continuously, noninvasively, at the bedside, and can monitor CA. In this study, we compare DCS-based markers of CA in veno-arterial ECMO patients with and without acute brain injury., Methods: Adults undergoing ECMO were prospectively enrolled at a single tertiary hospital and underwent DCS and arterial blood pressure monitoring during ECMO. Neurologic injuries were identified using brain computerized tomography (CT) scans obtained in all patients. CA was calculated over a twenty-minute window via wavelet coherence analysis (WCA) over 0.05 Hz to 0.1 Hz and a Pearson correlation (DCSx) between cerebral blood flow measured by DCS and mean arterial pressure., Results: Eleven ECMO patients who received CT neuroimaging were recruited. 5 (45%) patients were found to have neurologic injury. CA indices WCOH, the area under the curve of the WCA, were significantly higher for patients with neurological injuries compared to those without neurological injuries (right hemisphere p = 0.041, left hemisphere p = 0.041). %DCSx, percentage of time DCSx was above a threshold 0.4, were not significantly higher (right hemisphere p = 0.268, left hemisphere p = 0.073)., Conclusion: DCS can be used to detect differences in CA for ECMO patients with neurological injuries compared to uninjured patients using WCA., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Soil organic carbon （SOC） variation is a significant indicator for the soil quality dynamic and global carbon cycle. Therefore, it is necessary to study the regional temporal and spatial distribution of SOC pool and the influencing factors. In this study, a total of 540 soil data and environmental variables were collected from Shaanxi Province during a 30-year period from 1985 to 2015, and univariate analysis of variance and path analysis were used to explore the temporal and spatial distribution characteristics of SOC content and the influencing factors of SOC change. The results showed that the SOC contents of Shaanxi Province in both 1985 and 2015 were the highest in central Shaanxi, followed by those in southern Shaanxi, and they were significantly higher than those in northern Shaanxi. From 1985 to 2015, the increase in SOC in southern Shaanxi was the highest （21.28%）, and that in central Shaanxi was 15.33%. The content of SOC in northern Shaanxi was decreased by 10.23%, caused by significant decrements in the bottom horizons of 60-80 cm and 80-100 cm. Compared with that in 1985, the increases in SOC content in the 0-100 cm soil profile （with every 20 cm as a horizon） ranged from 3.21% to 29.39% in 2015. The increase in SOC content of skeletal soils was largest, followed by that of alluvial soils. Correlation analysis and path analysis showed that SOC content was positively correlated with altitude, average annual precipitation, normalized vegetation index, and total nitrogen content and was in significant negative correlation with curvature, bulk density, and pH. Total nitrogen content was the main controlling factor affecting SOC content. The results of the study can provide reference for future carbon management measures in the region.

Persistent plant viruses are widespread in natural ecosystems. However, little is known about why persistent infection with these viruses may cause little or no harm to their host. Here, we discovered a new polerovirus that persistently infected wild rice plants by deep sequencing and assembly of virus-derived small-interfering RNAs (siRNAs). The new virus was named Rice tiller inhibition virus 2 (RTIV2) based on the symptoms developed in cultivated rice varieties following Agrobacterium-mediated inoculation with an infectious RTIV2 clone. We showed that RTIV2 infection induced antiviral RNA interference (RNAi) in both the wild and cultivated rice plants as well as Nicotiana benthamiana. It is known that virulent virus infection in plants depends on effective suppression of antiviral RNAi by viral suppressors of RNAi (VSRs). Notably, the P0 protein of RTIV2 exhibited weak VSR activity and carries alanine substitutions of two amino acids broadly conserved among diverse poleroviruses. Mixed infection with umbraviruses enhanced RTIV2 accumulation and/or enabled its mechanical transmission in N. benthamiana. Moreover, replacing the alanine at either one or both positions of RTIV2 P0 enhanced the VSR activity in a co-infiltration assay, and RTIV2 mutants carrying the corresponding substitutions replicated to significantly higher levels in both rice and N. benthamiana plants. Together, our findings show that as a persistent plant virus, RTIV2 carries specific mutations in its VSR gene to weaken viral suppression of antiviral RNAi. Our work reveals a new strategy for persistent viruses to maintain long-term infection by weak suppression of the host defence response., (© 2024 The Author(s). Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.)

Objective: As people get older, the innate and acquired immunity of the elderly are affected, resulting in immunosenescence. Prealbumin (PAB), transferrin (TRF), and albumin (ALB) are commonly used markers to monitor protein energy malnutrition (PEM). However, their relationship with the immune system has not been fully explored., Methods: In our study, a total of 93 subjects (≥65 years) were recruited from Tongji Hospital between January 2015 and February 2017. According to the serum levels of these proteins (PAB, TRF, and ALB), we divided the patients into the high serum protein group and the low serum protein group. Then, we compared the percent expression of lymphocyte subsets between two groups., Results: All the low serum protein groups (PAB, TRF, and ALB) had significant decreases in the percentage of CD4+ cells, CD3 + CD28 + cells, CD4 + CD28 + cells and significant increases in the percentage of CD8 + cells, CD8 + CD28 - cells. PAB, TRF, and ALB levels revealed positive correlations with CD4/CD8 ratio, proportions of CD4 + cells, CD3 + CD28 + cells, CD4 + CD28 + cells, and negative correlation with proportions of CD8 + cells, CD8 + CD28 - cells., Conclusions: This study suggested PAB, TRF, and ALB could be used as immunosenescence indicators. PEM might accelerate the process of immunosenescence in elderly males.

Parkinson's disease (PD) is a severe neurodegenerative disease associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although its pathogenesis remains unclear, microglia-mediated neuroinflammation significantly contributes to the development of PD. Here we showed that the sine oculis homeobox (SIX) homologue family transcription factors SIX2 exerted significant effects on neuroinflammation. The SIX2 protein, which is silenced during development, was reactivated in lipopolysaccharide (LPS)-treated microglia. The reactivated SIX2 in microglia mitigated the LPS induced inflammatory effects, and then reduced the toxic effect of conditioned media (CM) of microglia on co-cultured MES23.5 DA cells. Using the LPS-stimulated Cx3cr1-Cre ERT2 mouse model, we also demonstrated that the highly-expressed SIX2 in microglia obviously attenuated neuroinflammation and protected the DA neurons in SN. Further RNA-Seq analysis on the inflammatory activated microglia revealed that the SIX2 exerted these effects via up-regulating the FXYD domain containing ion transport regulator 2 (FXYD2). Taken together, our study demonstrated that SIX2 was an endogenous anti-inflammatory factor in microglia, and it exerted anti-neuroinflammatory effects by regulating the expression of FXYD2, which provides new ideas for anti-neuroinflammation in PD., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

HLA-DPB1*1553:01 differs from HLA-DPB1*09:01:01:01 by one nucleotide in exon 3., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: By conducting a retrospective analysis of the clinical data of 14 patients diagnosed with invasive fungal rhinosinusitis (IFRS) confirmed by metagenomics next generation sequencing (mNGS) technology, we aim to explore the rapid diagnosis value of mNGS in IFRS. Methods: The clinical data of 14 IFRS patients admitted to TianJin First Central Hospital were retrospectively analyzed from February 2021 to October 2023. The study cohort comprised 8 males and 6 females, with ages ranging from 14 to 77 years. All patients were diagnosed as IFRS by performing mNGS sequencing technology of nasal sinus lesion biopsy specimens. Clinical data such as laboratory examination, imaging examination, histopathological examination results, treatment plan and prognosis were summarized and analyzed. Results: All 14 patients were diagnosed as IFRS, with mNGS detecting pathogens such as Rhizopus (7 cases), Aspergillus (5 cases), Trichoderma (1 case), and Scedosporium apiospermum (1 case). Follow-up evaluations were conducted for a period ranging from 2 months to 2 years post-treatment. At the end of follow-up, 11 out of 14 IFRS patients achieved a complete cure with no signs of recurrence, while the symptoms of the remaining 3 patients significantly improved with comprehensive treatment. Conclusion: mNGS emerges as a highly effective diagnostic tool for IFRS, providing valuable microbiological evidence for clinical diagnosis and demonstrating promising clinical utility.

Purpose: The Tongji Cardiovascular Health Study aimed to further explore the onset and progression mechanisms of cardiovascular disease (CVD) through a combination of traditional cohort studies and multiomics analysis, including genomics, metabolomics and metagenomics., Study Design and Participants: This study included participants aged 20-70 years old from the Geriatric Health Management Centre of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. After enrollment, each participant underwent a comprehensive series of traditional and novel cardiovascular risk factor assessments at baseline, including questionnaires, physical examinations, laboratory tests, cardiovascular health assessments and biological sample collection for subsequent multiomics analysis (whole genome sequencing, metabolomics study from blood samples and metagenomics study from stool samples). A biennial follow-up will be performed for 10 years to collect the information above and the outcome data., Findings to Date: A total of 2601 participants were recruited in this study (73.4% men), with a mean age of 51.5±11.5 years. The most common risk factor is overweight or obesity (54.8%), followed by hypertension (39.7%), hyperlipidaemia (32.4%), current smoking (23.9%) and diabetes (12.3%). Overall, 13.1% and 48.7% of men and women, respectively, did not have any of the CVD risk factors (hypertension, hyperlipidaemia, diabetes, cigarette smoking and overweight or obesity). Additionally, multiomics analyses of a subsample of the participants (n=938) are currently ongoing., Future Plans: With the progress of the cohort follow-up work, it is expected to provide unique multidimensional and longitudinal data on cardiovascular health in China., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Osimertinib is a third-generation covalent EGFR inhibitor that is used in treating non-small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34- cells in EGFR-negative AML and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared with their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of patients with AML with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two patients with CD34high AML who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia., Significance: Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients., (©2023 The Authors; Published by the American Association for Cancer Research.)

Sprouting of mossy fibers, one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy, exhibits several uncommon axonal growth features and has been considered a paradigmatic example of circuit plasticity that occurs in the adult brain. Clarifying the mechanisms responsible may provide new insight into epileptogenesis as well as axon misguidance in the central nervous system. Methyl-CpG-binding protein 2 (MeCP2) binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. However, exploring the potential role of MeCP2 in the documented misguidance of axons in the dentate gyrus has not yet been attempted. In this study, a status epilepticus-induced decrease of neuronal MeCP2 was observed in the dentate gyrus (DG). An essential regulatory role of MeCP2 in the development of functional mossy fiber sprouting (MFS) was confirmed through stereotaxic injection of a recombinant adeno-associated virus (AAV) to up- or down-regulate MeCP2 in the dentate neurons. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to identify the binding profile of native MeCP2 using micro-dissected dentate tissues. In both dentate tissues and HT22 cell lines, we demonstrated that MeCP2 could act as a transcription repressor on miR-682 with the involvement of the DNA methylation mechanism. Further, we found that miR-682 could bind to mRNA of phosphatase and tensin homolog (PTEN) in a sequence specific manner, thus leading to the suppression of PTEN and excessive activation of mTOR. This study therefore presents a novel epigenetic mechanism by identifying MeCP2/miR-682/PTEN/mTOR as an essential signal pathway in regulating the formation of MFS in the temporal lobe epileptic (TLE) mice. SIGNIFICANCE STATEMENT: Understanding the mechanisms that regulate axon guidance is important for a better comprehension of neural disorders. Sprouting of mossy fibers, one of the most consistent findings in patients with mesial temporal lobe epilepsy, has been considered a paradigmatic example of circuit plasticity in the adult brain. Although abnormal regulation of DNA methylation has been observed in both experimental rodents and humans with epilepsy, the potential role of DNA methylation in this well-documented example of sprouting of dentate axon remains elusive. This study demonstrates an essential role of methyl-CpG-binding protein 2 in the formation of mossy fiber sprouting. The underlying signal pathway has been also identified. The data hence provide new insight into epileptogenesis as well as axon misguidance in the central nervous system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Anesthetics-induced disruption of dentate neurogenesis in the young brain is strongly suggested to contribute to delayed neurocognitive deficit. In postnatal rodents, the neurogenesis of the dentate gyrus (DG) is sequentially derived from the secondary dentate matrix, tertiary dentate matrix and subgranular zone (SGZ). However, the effects of anesthetics on the dentate neurogenesis derived from specific sites are poorly understood. To trace the new cells generated from the postnatal secondary dentate matrix, peak stage of the tertiary dentate matrix and early stage of the SGZ after isoflurane exposure, mice at postnatal day 1 (P1), P7 and P31 were injected with BrdU at 12 h before the exposure. We found that isoflurane exposure significantly reduced the numbers of proliferating cells (1 day old), immature granule cells (21 days old) or mature granule cells (42 days old) derived from the peak stage of the tertiary dentate matrix and postnatal secondary dentate matrix, but not from the SGZ. Quantitative assessment of BrdU-/BrdU+NeuN-positive cells and cleaved caspase-3 level in the DG indicated that the reduction was correlated with cell loss rather than neuronal differentiation. Mechanistically, we demonstrated that the PI3K/Akt/GSK-3β pathway enriched by mRNA-sequencing is a requirement for the isoflurane-induced loss of 1-day-old proliferating cells generated from the tertiary dentate matrix. In addition, this study demonstrated that P1 and P7 mice, but not P31 mice exposure to isoflurane resulted in subsequent deficits in performance of the tasks of the Morris Water Maze., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD), recognized as the leading cause of dementia, occupies a prominent position on the list of significant neurodegenerative disorders, representing a significant global health concern with far-reaching implications at both individual and societal levels. The primary symptom of Alzheimer's disease is a decrease in synaptic potency along with synaptic connection loss. Synapses, which act as important linkages between neuronal units within the cerebral region, are critical in signal transduction processes essential to orchestrating cognitive tasks. Synaptic connections act as critical interconnections between neuronal cells inside the cerebral environment, facilitating critical signal transduction processes required for cognitive functions. The confluence of axonal and dendritic filopodial extensions culminates in the creation of intercellular connections, coordinated by various signals and molecular mechanisms. The progression of synaptic maturation and plasticity is a critical determinant in maintaining mental well-being, and abnormalities in these processes have been linked to the development of neurodegenerative diseases. Wnt signaling pathways are important to the orchestration of synapse development. This review examines the complicated interplay between Wnt signaling and dendritic filopodia, including an examination of the regulatory complexities and molecular machinations involved in synaptogenesis progression. Then, these findings are contextualized within the context of AD pathology, allowing for the consideration of prospective therapeutic approaches based on the findings and development of novel avenues for future scientific research., Competing Interests: Cheng‐Ting Zhang is an editorial member of Ibrain and Wen‐Yuan Wang is the Associate editor of Ibrain; they are co‐authors of this article. They were excluded from editorial decision‐making related to the acceptance and publication of this article. The authors declare no conflicts of interest., (© 2023 The Authors. Ibrain published by Affiliated Hospital of Zunyi Medical University (AHZMU) and Wiley‐VCH GmbH.)

Parkinson's disease (PD) is a neurodegenerative disease characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). We recently reported that Six2 could reverse the degeneration of DA neurons in a dephosphorylation state. Here we further identified that Eya1 was the phosphatase of Six2 that could dephosphorylate the tyrosine 129 (Y129) site by forming a complex with Six2 in damaged DA cells. Dephosphorylated Six2 then translocates from the cytoplasm to the nucleus. Using ChIP-qPCR and dual luciferase assay, we found that dephosphorylated Six2 down-regulates TEA domain1 (Tead1) expression, thus inhibiting 6-hydroxydopamine (6-OHDA)-induced apoptosis in DA cells. Furthermore, we showed Six2Y129F/Tead1 signaling could protect against the loss of SNpc tyrosine hydroxylase-positive (TH + ) cells and improve motor function in PD model rats. Our results demonstrate a dephosphorylation-dependent mechanism of Six2 that restores the degeneration of DA neurons, which could represent a potential therapeutic target for PD., Competing Interests: The authors declare no competing interest., (© 2023 The Authors.)

Implantable tubes, shunts, and other medical conduits are crucial for treating a wide range of conditions from ears and eyes to brain and liver but often impose serious risks of device infection, obstruction, migration, unreliable function, and tissue damage. Efforts to alleviate these complications remain at an impasse because of fundamentally conflicting design requirements: Millimeter-scale size is required to minimize invasiveness but exacerbates occlusion and malfunction. Here, we present a rational design strategy that reconciles these trade-offs in an implantable tube that is even smaller than the current standard of care. Using tympanostomy tubes (ear tubes) as an exemplary case, we developed an iterative screening algorithm and show how unique curved lumen geometries of the liquid-infused conduit can be designed to co-optimize drug delivery, effusion drainage, water resistance, and biocontamination/ingrowth prevention in a single subcapillary-length-scale device. Through extensive in vitro studies, we demonstrate that the engineered tubes enabled selective uni- and bidirectional fluid transport; nearly eliminated adhesion and growth of common pathogenic bacteria, blood, and cells; and prevented tissue ingrowth. The engineered tubes also enabled complete eardrum healing and hearing preservation and exhibited more efficient and rapid antibiotic delivery to the middle ear in healthy chinchillas compared with current tympanostomy tubes, without resulting in ototoxicity at up to 24 weeks. The design principle and optimization algorithm presented here may enable tubes to be customized for a wide range of patient needs.

Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from a patient with AML presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset, which was enriched within cutis and existed in BM before EMI manifestations, was identified and further verified in multiple patients with AML. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of patients with EMI that expressed high levels of C1Q. RNA sequencing and quantitative proteomic analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAF BZIP transcription factor B, endowed leukemia cells with tissue infiltration ability, which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft and cell line-derived xenograft models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q-globular C1Q receptor recognition and subsequent stimulation of transforming growth factor β1. This cell-to-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as a marker for AML with adverse prognosis, orchestrating cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The age-related decline in T-cell function among elderly individuals remains unclear. We thus investigated the interrelationship between T-cell subsets and age to identify the changes in T-cell phenotypes and develop an age prediction model for the elderly population. A total of 127 individuals aged >60 years were divided into three groups (youngest-old group, 61-70 years, n = 34; middle-old group, 71-80 years, n = 53; and oldest-old group, ≥ 81 years, n = 40). The percentage of CD8+CD28- cells ( P = 0.001) was highest in the oldest-old group and then followed by the middle-old group, while the youngest-old group was the lowest. Both females and males demonstrated significant decreases in the absolute counts of CD4+CD45RA+ cells ( P = 0.020; P = 0.002) and CD8+CD28+ cells ( P = 0.015; P = 0.005) with age. Multivariate linear regression showed that the percentage of CD8+CD28- cells ( P < 0.001) was an independent predictor of aging after adjusting for sex, body mass index, hospitalization duration, smoking, drinking, chronic medical illness, and medications at admission. In conclusion, our results suggest that aging in elderly individuals is accompanied by a decrease in the counts of T-cell subpopulations. CD8+CD28- cells may be potential targets for elderly individuals in antiaging-related immunosenescence., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter.)

Cerebral small vessel disease (CSVD) is a senile brain lesion caused by the abnormal structure and function of arterioles, venules and capillaries in the aging brain. The etiology of CSVD is complex, and disease is often asymptomatic in its early stages. However, as CSVD develops, brain disorders may occur, such as stroke, cognitive dysfunction, dyskinesia and mood disorders, and heart, kidney, eye and systemic disorders. As the population continues to age, the burden of CSVD is increasing. Moreover, there is an urgent need for better screening methods and diagnostic markers for CSVD, in addition to preventive and asymptomatic- and mild-stage treatments. Integrative medicine (IM), which combines the holistic concepts and syndrome differentiations of Chinese medicine with modern medical perspectives, has unique advantages for the prevention and treatment of CSVD. In this review, we summarize the biological markers, ultrasound and imaging features, disease-related genes and risk factors relevant to CSVD diagnosis and screening. Furthermore, we discuss IM-based CSVD prevention and treatment strategies to stimulate further research in this field., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Infantile epileptic spasms syndrome (IESS) is an age-specific and severe epileptic encephalopathy. Although adrenocorticotropic hormone (ACTH) is currently considered the preferred first-line treatment, it is not always effective and may cause side effects. Therefore, seeking a reliable biomarker to predict the treatment response could benefit clinicians in modifying treatment options., Methods: In this study, the complexities of electroencephalogram (EEG) recordings from 15 control subjects and 40 patients with IESS before and after ACTH therapy were retrospectively reviewed using multiscale entropy (MSE). These 40 patients were divided into responders and nonresponders according to their responses to ACTH., Results: The EEG complexities of the patients with IESS were significantly lower than those of the healthy controls. A favorable response to treatment showed increasing complexity in the γ band but exhibited a reduction in the β/α-frequency band, and again significantly elevated in the δ band, wherein the latter was prominent in the parieto-occipital regions in particular. Greater reduction in complexity was significantly linked with poorer prognosis in general. Occipital EEG complexities in the γ band revealed optimized performance in recognizing response to the treatment, corresponding to the area under the receiver operating characteristic curves as 0.8621, while complexities of the δ band served as a fair predictor of unfavorable outcomes globally., Conclusion: We suggest that optimizing frequency-specific complexities over critical brain regions may be a promising strategy to facilitate predicting treatment response in IESS., (© 2022. The Author(s).)

Background: Even though adrenocorticotropic hormone (ACTH) demonstrated powerful efficacy in the initially successful treatment of infantile spasms (IS), nearly half of patients have experienced a relapse. We sought to investigate whether features of electroencephalogram (EEG) predict relapse in those IS patients without structural brain abnormalities., Methods: We retrospectively reviewed data from children with IS who achieved initial response after ACTH treatment, along with EEG recorded within the last two days of treatment. The recurrence of epileptic spasms following treatment was tracked for 12 months. Subjects were categorized as either non-relapse or relapse groups. General clinical and EEG recordings were collected, burden of amplitudes and epileptiform discharges (BASED) score and multiscale entropy (MSE) were carefully explored for cross-group comparisons., Results: Forty-one patients were enrolled in the study, of which 26 (63.4%) experienced a relapse. The BASED score was significantly higher in the relapse group. MSE in the non-relapse group was significantly lower than the relapse group in the γ band but higher in the lower frequency range (δ, θ, α). Sensitivity and specificity were 85.71% and 92.31%, respectively, when combining MSE in the δ/γ frequency of the occipital region, plus BASED score were used to distinguish relapse from non-relapse groups., Conclusions: BASED score and MSE of EEG after ACTH treatment could be used to predict relapse for IS patients without brain structural abnormalities. Patients with BASED score ≥ 3, MSE increased in higher frequency, and decreased in lower frequency had a high risk of relapse., (© 2022. Children's Hospital, Zhejiang University School of Medicine.)

Surfaces with tunable microscale textures are vital in a large variety of technological applications, including heat transfer, antifouling and adhesion. To facilitate such broad-scale use, there is a need to create surfaces that undergo reconfigurable changes in topology and thus, enable switchable functionality. To date, there is a relative dearth of methods for engineering surfaces that can be actuated to change topography over a range of length scales, and hence, form tunable hierarchically structured layers. Combining modeling and experiments, we design a geometrically patterned, thermo-responsive poly ( N -isopropylacrylamide) gel film that undergoes controllable hierarchical changes in topology with changes in temperature. At the bottom, the film is covalently bound to a solid, curved substrate; at the top, the film encompasses longitudinal rectangular ridges that are oriented perpendicular to the underlying cylindrical curves. At temperatures below lower critical solution temperature (LCST), the swollen gel exhibits 3D variations in polymer density and thickness defined by the gel's top and bottom topography. As the temperature rises above LCST, the interplay between the upper ridges and lower curves in the gel drives non-uniform, directional solvent transport, the nucleation and propagation of a phase-separated higher-density skin layer, and the resulting pressure buildup within the film. These different, interacting kinetic processes lead to an instability, which produces transient microscopic blisters in the film. Through simulations, we show how tuning the width of the ridges modifies the propagation of a skin layer and creates localized pressure build-up points, which enables control over the emergence, distribution, and alignment of the microscopic blisters. Additionally, we provide a simple argument to predict the size of such microscopic features. Experiments confirm our predictions and further highlight how our computational model enables the rational design of topographical transitions in these tunable films. The development of actuatable, hierarchically structured films provides new routes for achieving switchable functionality in actuators, drug release systems and adhesives.

Introduction: Even though adrenocorticotropic hormone (ACTH) demonstrated powerful efficacy in the initially successful treatment of infantile spasms (IS), nearly one-half of patients whose spasms were once suppressed experienced relapse. There is currently no validated method for the prediction of the risk of relapse. The Burden of Amplitudes and Epileptiform Discharges (BASED) score is an electroencephalogram (EEG) grading scale for children with infantile spasms. We sought to determine whether an association exists between the BASED score after ACTH treatment and relapse after initial response with ACTH., Methods: Children with IS who achieved initial response after ACTH treatment were selected as the study subjects. Those who experienced relapse within 12 months after ACTH treatment were categorized as the relapse group, and those who did not were categorized as the non-relapse group. Their general clinical data and EEG data (using BASED scoring) after ACTH treatment were collected, and compared between groups. Cox proportional hazards models were fit to determine factors associated with relapse., Results: A total of 64 children with IS were enrolled in the study, of which 37 (57.8%) experienced a relapse, and the median duration after ACTH treatment was 3 (1.5, 6) months. The BASED score was significantly higher in the relapse group than in the non-relapse group. Cox modeling demonstrated that BASED score was independently associated with relapse. The patients with a score greater than or equal to 3 showed a high rate (89.3%) of relapse. The relapse group had stronger, more stable EEG functional networks than the non-relapse group, and there were obvious correlations between BASED score and functional connectivity., Conclusion: This study suggests the BASED score after ACTH treatment has potential value as a predictor for relapse after initial response. Children with IS who have a BASED score greater than or equal to 3 after the initial response of ACTH carry a high risk of relapse within 1 year., (© 2022. The Author(s).)

Objective: To investigate the relationship between the mechanical circulatory support (MCS) combined with immunomodulation and the prognosis of patients with fulminant myocarditis. Methods: This is a retrospective study. A total of 88 patients with fulminant myocarditis admitted to Dongguan Kanghua hospital from Aug. 2008 to Dec. 2020 were included. Medical histories, results of laboratory tests, treatment regimens and clinical outcomes of these patients during their hospitalization were collected from the medical record system. According to the treatment methods, the patients were divided into MCS+immunomodulation group (38 cases), MCS group (20 cases) and traditional treatment group (30 cases). Patients in the MCS+immunomodulation group received intra-aortic balloon pump (IABP) or IABP combined with extracorporeal membrane oxygenation (ECMO) and immunoglobulin or glucocorticoid. Patients in the MCS group only received mechanical circulatory support. Patients in the traditional treatment group received neither mechanical circulatory support nor immunomodulatory therapy, and only used vasoactive drugs and cardiotonic drugs. The in-hospital mortality and length of stay were compared among the three groups. Results: A total of 88 patients with fulminant myocarditis aged (35.0±10.8) years were included, and there were 46 males (52.3%). The mortality of MCS+immunomodulation group (7.9% (3/38) vs. 56.7% (17/30), P =0.001 2) and MCS group (30.0% (6/20) vs. 56.7% (17/30), P =0.002 8) were lower than that of traditional treatment group. Compared with the MCS group, the in-hospital mortality in the MCS+immunomodulation group was lower ( P =0.005 4). The most common cause of death was multiple organ dysfunction syndrome (MODS). The constituent ratios of death in MCS+immunomodulation group, MCS group and traditional treatment group were 3/3, 4/6 and 12/17, respectively. The incidence of MODS in the MCS group (20% (4/20)) and the traditional treatment group (40% (12/30)) was significantly higher than that in the MCS+immunomodulation group (7.9% (3/38)) (both P <0.01). In discharged patients, the hospitalization time of MCS+immunomodulation group was shorter than that of traditional treatment group ((13.4±5.5)d vs. (18.5±7.4)d, P <0.05) and MCS group ((13.4±5.5)d vs. (16.9±8.5)d, P <0.05). Conclusion: MCS combined with immunomodulatory therapy is associated with lower in-hospital mortality and shorter hospital stay in patients with fulminant myocarditis.

Chronic obstructive pulmonary disease (COPD) is one of the major diseases threatening human life and health. According to the report released by the World Health Organization (WHO) in 2020, COPD has become the third leading cause of death in the world, featuring a sustainable growth of incidence rate as well as population age. The purpose of this review focuses on the advancement of bioactive natural compounds, such as baicalin, quercetin, resveratrol, and curcumin, which demonstrate promising therapeutic/interventional effects on CODP in vitro and in vivo . Information emphasizing on COPD was systematically collected from several authoritative internet databases including Web of Science, PubMed, Elsevier, Wiley Online Library, and Europe PMC, with a combination of keywords containing "COPD" and "natural small molecular compounds". The new evidence indicated that these valuable molecules featured unique functions in the treatment of COPD through various biological processes such as anti-inflammatory, anti-oxidant, anti-apoptosis, and anti-airway fibrosis. Moreover, we found that the promising effects of these natural compounds on COPD were mainly achieved through JAK3/STAT3/NF-κB and MAPK inflammatory signaling pathways, Nrf2 oxidative stress signaling pathway, and TGF-β1/Smad 2/3 fibrosis signaling pathway, which referenced to multiple targets like TNF-α, IL-6, IL-8, TIMP-1, MMP, AKT, JAK3, IKK, PI3K, HO-1, MAPK, P38, ERK, etc. Current challenges and future directions in this promising field are also discussed at the end of this review. For the convenience of the readers, this review is divided into ten parts according to the structures of potential natural small molecular compounds. We hope that this review brings a quick look and provides some inspiration for the research of COPD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zhang, Zhu, Zheng, Liu, Liu, Zhang and Zhang.)

Both HIV and DENV are serious threats to human life, health and social economy today. So far, no vaccine for either HIV or DENV has been developed successfully. The research on anti-HIV or DENV drugs is still of great significance. In this study we developed a series of novel 2-Aryl-1H-pyrazole-S-DABOs with C6-strucutral optimizations as potent NNRTIs, among which, 8 compounds had low cytotoxicity and EC 50 values in the range of 0.0508 ∼ 0.0966 μM, and their selectivity index was SI > 1415 ∼ 3940. In particular, two compounds 4a and 4b were identified to have good inhibitory effects on DENV of four serotypes. The EC 50 of compound 4a and 4b against DENV-II (13.2 μM and 9.23 μM, respectively) were better than that of the positive control ribavirin (EC 50  = 40.78 μM). In addition, the effect of C-6 substituents on the anti-HIV or anti-DENV activity of these compounds was also discussed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The combined hyperpolarized (HP) 13 C pyruvate and urea MRI has provided a simultaneous assessment of glycolytic metabolism and tissue perfusion for improved cancer diagnosis and therapeutic evaluation in preclinical studies. This work aims to translate this dual-probe HP imaging technique to clinical research., Methods: A co-polarization system was developed where [1- 13 C]pyruvic acid (PA) and [ 13 C, 15 N 2 ]urea in water solution were homogeneously mixed and polarized on a 5T SPINlab system. Physical and chemical characterizations and toxicology studies of the combined probe were performed. Simultaneous metabolic and perfusion imaging was performed on a 3T clinical MR scanner by alternatively applying a multi-slice 2D spiral sequence for [1- 13 C]pyruvate and its downstream metabolites and a 3D balanced steady-state free precession (bSSFP) sequence for [ 13 C, 15 N 2 ]urea., Results: The combined PA/urea probe has a glass-formation ability similar to neat PA and can generate nearly 40% liquid-state 13 C polarization for both pyruvate and urea in 3-4 h. A standard operating procedure for routine on-site production was developed and validated to produce 40 mL injection product of approximately 150 mM pyruvate and 35 mM urea. The toxicology study demonstrated the safety profile of the combined probe. Dynamic metabolite-specific imaging of [1- 13 C]pyruvate, [1- 13 C]lactate, [1- 13 C]alanine, and [ 13 C, 15 N 2 ]urea was achieved with adequate spatial (2.6 mm × 2.6 mm) and temporal resolution (4.2 s), and urea images showed reduced off-resonance artifacts due to the J CN coupling., Conclusion: The reported technical development and translational studies will lead to the first-in-human dual-agent HP MRI study and mark the clinical translation of the first HP 13 C MRI probe after pyruvate., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Studies on rodents and nonhuman primates suggest that exposure to anesthetics, particularly in the young brain, is associated with neuronal apoptosis as well as hippocampal‑dependent cognitive dysfunction. Disruption of the development of dentate gyrus may play an important role in anesthetics‑induced neurotoxicity. However, the anesthetics triggered molecular events in the dentate gyrus of the developing brain are poorly understood. By integrating two independent data sets obtained from miRNA‑seq and mRNA‑seq respectively, this study aims to profile the network of miRNA and potential target genes, as well as relevant events occurring in the dentate gyrus of isoflurane exposed 7‑day‑old mice. We found that a single four hours exposure to isoflurane yielded 1059 pairs of differently expressed miRNAs/target genes in the dentate gyrus. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis further indicates that dysregulated miRNAs/target genes have far‑reaching effects on the cellular pathophysiological events, such as cell apoptosis, axon development, and synaptic transmission. Our results would greatly broaden our functional understanding of the role of miRNA/target gene in the context of anesthetics‑induced neurotoxicity.

Glial cell line-derived neurotrophic factor (GDNF) played critical roles in the survival and repair of dopaminergic (DA) neurons. Transcription factor Six2 could repair injured DA cells by promoting the expression of GDNF, however, the underlying molecular mechanisms remain largely unknown. In this study, we screened forty-three proteins that interacted with Six2 in MES23.5 DA cells treated with 6-OHDA by liquid chromatography - electrospray - ionization tandem mass spectrometry (LC-ESI-ITMS/MS). Among these proteins, Smarcd1 is a member of SWI/SNF chromatin-remodeling complex family. Our results confirmed that Smarcd1 formed a transcription complex with Six2, and Smarcd1 mainly binded to the 2840 bp-2933 bp region of the GDNF promoter. Furthermore, knockdown of Smarcd1 inhibited the effect of Six2 on GDNF expression, and resulted in decreased cell viability and increased the apoptosis of injured DA neurons, and the result of overexpression of Smarcd1 is opposite to knockdown. Taken together, our results indicate that smarcd1 can be recruited to the promoter region of GDNF by transcription factor Six2 to promote the effect of Six2 on GDNF expression and protect injured MES23.5 DA cells, which could be useful in identifying potential drug targets for promoting endogenous GDNF expression., (Copyright © 2021. Published by Elsevier B.V.)

Oridonin, as a natural terpenoids found in traditional Chinese herbal medicine Isodon rubescens (Hemsl.) H.Hara, is widely present in numerous Chinese medicine preparations. The purpose of this review focuses on providing the latest and comprehensive information on the pharmacology, pharmacokinetics and toxicity of oridonin, to excavate the therapeutic potential and explore promising ways to balance toxicity and efficacy of this natural compound. Information concerning oridonin was systematically collected from the authoritative internet database of PubMed, Elsevier, Web of Science, Wiley Online Library and Europe PMC applying a combination of keywords involving "pharmacology," "pharmacokinetics," and "toxicology". New evidence shows that oridonin possesses a wide range of pharmacological properties, including anticancer, anti-inflammatory, hepatorenal activities as well as cardioprotective protective activities and so on. Although significant advancement has been witnessed in this field, some basic and intricate issues still exist such as the specific mechanism of oridonin against related diseases not being clear. Moreover, several lines of evidence indicated that oridonin may exhibit adverse effects, even toxicity under specific circumstances, which sparked intense debate and concern about security of oridonin. Based on the current progress, future research directions should emphasize on 1) investigating the interrelationship between concentration and pharmacological effects as well as toxicity, 2) reducing pharmacological toxicity, and 3) modifying the structure of oridonin-one of the pivotal approaches to strengthen pharmacological activity and bioavailability. We hope that this review can provide some inspiration for the research of oridonin in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Zhang, Ma, Xie and Huang.)

Background: The concordance between mutations detected from plasma and tissue is critical for treatment choices of patients with advanced lung adenocarcinoma., Methods: We prospectively analyzed the association of the serum tumor markers with the concordance between blood and tissue genomic profiles from 185 patients with advanced lung adenocarcinoma. The concordance was defined according to 3 criteria. Class 1 included all targetable driver mutations in 8 genes; class 2 included class 1 mutations plus mutations in KRAS , STK11 , and TP53 ; class 3 included class 2 mutations plus tumor mutation burden (TMB) status., Results: Collectively, 150 out of 185 patients had mutations in both tissue and plasma samples, while one patient was mutation-negative for both, resulting a concordance of 81.6%. The concordance rate for class 1 mutations was 80%, and 65% and 69% for class 2 and class 3, respectively. Carbohydrate antigen 19-9 (CA19-9) or cytokeratin 19 (CYFRA21-1) levels higher than the normal upper limit predicted the concordance of tissue and blood results in class 1 (P=0.005, P=0.011), class 2 (P=0.011, P<0.001), and class 3 (P=0.001, P=0.014). In class 1, the cutoff values of CA19-9 were 30, 36, and 284 U/mL to reach the concordance thresholds of 90%, 95%, and 100%, respectively (P=0.032, P=0.003, P=0.043). For CYFRA21-1, the cutoff values were 6, 18, and 52 µg/L (P=0.005, P=0.051, P=0.354). In class 2, the cutoff values for CYFRA21-1 were 18, 22, and 52 µg/L (P=0.001, P=0.001, P=0.052). In class 3, the cutoff values for CA19-9 were 36, 39, and 85 U/mL (P=0.003, P=0.001, P=0.008). For CYFRA21-1, the cutoff values were 22, 52, and 52 µg/L (P=0.900, P>0.99, P>0.99). When the sum score for 4 serum tumor markers was greater than 35, both class 1, class 2, and class 3 reached a predictive threshold of 90%., Conclusions: Serum tumor markers can be used as easy and practical clinical predictors of concordance in mutation profiles between blood and tissue samples from patients with advanced lung adenocarcinoma., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-543). Dr. XDJ reported funding support from the Logistics Support Department of PLA (19BJZ03) and Changzheng Hospital (2019CZJS208-1). Dr. YSZ reported funding support from the Project of Ministry of Science and Technology of China (2017YFC1309202), the Shanghai Distinguished Young Medical Talents Training Program (QNYXRC01) and the Medical Innovation Research Project of Shanghai Science and Technology Commission (20Y11914400). Dr. NI reported that he had got grants from Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim, TAIHO Pharmaceutical Co., Ltd.; and received fee from Eli Lilly Japan K.K, MSD K.K. Dr. BDQ reported funding support from Chinese National Natural Science Funding (grant number 81702249, 2017). The funder has no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. LS, HZW, YC, and JJZ reported that they are employees of Burning Rock Biotech. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Methylorubrum extorquens AM1 can be engineered to convert methanol to value-added chemicals. Most of these chemicals derive from acetyl-CoA involved in the serine cycle. However, recent studies on methylotrophic metabolism have suggested that C3 pyruvate is a good potential precursor for broadening the types of synthesized products., Methods and Results: In the present study, we found that isobutanol was a model chemical that could be generated from pyruvate through a 2-keto acid pathway. Initially, the engineered M. extorquens AM1 could only produce a trace amount of isobutanol at 0.62 mgL -1 after introducing the heterologous 2-ketoisovalerate decarboxylase and alcohol dehydrogenase. Furthermore, the metabolomic analysis revealed that insufficient carbon fluxes through 2-ketoisovalerate and pyruvate were the key limitation steps for efficient biosynthesis of isobutanol. Based on this analysis, the titer of isobutanol was improved by over 20-fold after overexpressing alsS gene encoding acetolactate synthase and deleting ldhA gene for lactate dehydrogenase. Moreover, substituting the cell chassis with the isobutanol-tolerant strain isolated from adaptive evolution of M. extorquens AM1 further increased the production of isobutanol by 1.7-fold, resulting in the final titer of 19 mgL -1 in flask cultivation., Conclusion: Our current findings provided promising insights into engineering methylotrophic cell factories capable of converting methanol to isobutanol or value-added chemicals using pyruvate as the precursor., (© 2021 Wiley-VCH GmbH.)

Method: This was a study recording 637 patients who were diagnosed with acute myocardial infarction. Our patients were grouped according to the combination of platelet count and neutrophil-to-lymphocyte ratio. The prognostic role of the combination of platelet count and neutrophil-to-lymphocyte ratio on mortality was assessed by the univariate and multivariate Cox regression analysis., Result: Our study population was divided into three parts according to the median values of platelet count and neutrophil-to-lymphocyte ratio. It was indicated that platelet count and neutrophil-to-lymphocyte ratio were correlative mutually to a certain degree ( p =0.010). The Kaplan-Meier analysis showed that the combination of high platelet count and high neutrophil-to-lymphocyte ratio had a greater risk of death in short- and long-term endpoints (log-rank p =0.046, p < 0.001, respectively). Moreover, by multivariate analysis, both high platelet count and high neutrophil-to-lymphocyte ratio groups were an independent predictor (hazard ratio: 2.132, 95% confidence interval: 1.020-4.454, p =0.044) and long-term mortality (hazard ratio: 2.791, 95% confidence interval: 1.406-5.538, p =0.003)., Conclusion: The combination of platelet count and neutrophil-to-lymphocyte ratio could be a useful predictor for the prediction of in-hospital and long-term mortality in aged patients with acute myocardial infarction., Competing Interests: The authors declare that they have no conflicts of interest regarding this submission., (Copyright © 2021 Xiao-Qing Quan et al.)

The fundamental topology of cellular structures-the location, number and connectivity of nodes and compartments-can profoundly affect their acoustic 1-4 , electrical 5 , chemical 6,7 , mechanical 8-10 and optical 11 properties, as well as heat 1,12 , fluid 13,14 and particle transport 15 . Approaches that harness swelling 16-18 , electromagnetic actuation 19,20 and mechanical instabilities 21-23 in cellular materials have enabled a variety of interesting wall deformations and compartment shape alterations, but the resulting structures generally preserve the defining connectivity features of the initial topology. Achieving topological transformation presents a distinct challenge for existing strategies: it requires complex reorganization, repacking, and coordinated bending, stretching and folding, particularly around each node, where elastic resistance is highest owing to connectivity. Here we introduce a two-tiered dynamic strategy that achieves systematic reversible transformations of the fundamental topology of cellular microstructures, which can be applied to a wide range of materials and geometries. Our approach requires only exposing the structure to a selected liquid that is able to first infiltrate and plasticize the material at the molecular scale, and then, upon evaporation, form a network of localized capillary forces at the architectural scale that 'zip' the edges of the softened lattice into a new topological structure, which subsequently restiffens and remains kinetically trapped. Reversibility is induced by applying a mixture of liquids that act separately at the molecular and architectural scales (thus offering modular temporal control over the softening-evaporation-stiffening sequence) to restore the original topology or provide access to intermediate modes. Guided by a generalized theoretical model that connects cellular geometries, material stiffness and capillary forces, we demonstrate programmed reversible topological transformations of various lattice geometries and responsive materials that undergo fast global or localized deformations. We then harness dynamic topologies to develop active surfaces with information encryption, selective particle trapping and bubble release, as well as tunable mechanical, chemical and acoustic properties.

Methanol is assimilated through the serine cycle to generate acetyl-CoA without carbon loss. However, a highly active serine cycle requires high consumption of reducing equivalents and ATP, thereby leading to the impaired efficiency of methanol conversion to reduced chemicals. In the present study, a genome-scale flux balance analysis (FBA) predicted that the introduction of the heterologous ribulose monophosphate (RuMP) cycle, a more energy-efficient pathway for methanol assimilation, could theoretically increase growth rate by 31.3% for the model alphaproteobacterial methylotroph Methylorubrum extorquens AM1. Based on this analysis, we constructed a novel synergistic assimilation pathway in vivo by incorporating the RuMP cycle into M. extroquens metabolism with the intrinsic serine cycle. We demonstrated that the operation of the synergistic pathway could increase cell growth rate by 16.5% and methanol consumption rate by 13.1%. This strategy rewired the central methylotrophic metabolism through adjusting core gene transcription, leading to a pool size increase of C2 to C5 central intermediates by 1.2- to 3.6-fold and an NADPH cofactor improvement by 1.3-fold. The titer of 3-hydroxypropionic acid (3-HP), a model product in the newly engineered chassis of M. extorquens AM1, was increased to 91.2 mg/L in shake-flask culture, representing a 3.1-fold increase compared with the control strain with only the serine cycle. The final titer of 3-HP was significantly improved to 0.857 g/L in the fed-batch bioreactor, which was more competitive compared with the other 3-HP producers using methane and CO 2 as C1 sources. Collectively, our current study demonstrated that engineering the synergistic methanol assimilation pathway was a promising strategy to increase the carbon assimilation and the yields of reduced chemicals in diverse host strains for C1 microbial cell factories., (Copyright © 2021 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

Fibulin-1 (FBLN-1), an elastin-associated extracellular matrix protein, has been found in blood and may play a role in the pathophysiological processes leading to cardiovascular disease (CVD). We aimed to investigate the relationship between fibulin-1 levels and the risk of CVD by evaluating vascular age derived from the Framingham Heart Study and brachial-ankle Pulse Wave Velocity (baPWV) in patients with asymptomatic hyperuricemia (AHU). In total, 66 patients with AHU and 66 gender- and age-matched healthy individuals were enrolled. The plasma fibulin-1 levels were measured by immunochemistry. Patients with AHU presented significantly higher vascular age [median (interquartile range): 54 (22) vs. 48 (14) years, P=0.01] and baPWV [mean±SD: 1373±223 vs. 1291±177 cm/s, P=0.02] than the healthy subjects; however, no significant difference was observed in the plasma fibulin-1 level between the patients with AHU and healthy subjects [median (interquartile range): 4018 (3838) vs. 3099 (3405) ng/mL, P=0.31]. A correlation between fibulin-1 levels and baPWV was observed only in patients with AHU (r=0.29, P=0.02); and there was also a suggestively statistically significant correlation between fibulin-1 levels and vascular age (r=0.22, P=0.08). However, these associations were rendered insignificant after adjustments for potential confounders. In healthy subjects, no correlation was observed between fibulin-1 levels and CVD risk. This study reveals that plasma fibulin-1 levels may reflect the CVD risk in patients with AHU, but the relationship is not robust.

Essential genes refer to genes that are required by an organism to survive under specific conditions. Studies of the minimal-gene-set for bacteria have elucidated fundamental cellular processes that sustain life. The past five years have seen a significant progress in identifying human essential genes, primarily due to the successful use of CRISPR/Cas9 in various types of human cells. DEG 15, a new release of the Database of Essential Genes (www.essentialgene.org), has provided major advancements, compared to DEG 10. Specifically, the number of eukaryotic essential genes has increased by more than fourfold, and that of prokaryotic ones has more than doubled. Of note, the human essential-gene number has increased by more than tenfold. Moreover, we have developed built-in analysis modules by which users can perform various analyses, such as essential-gene distributions between bacterial leading and lagging strands, sub-cellular localization distribution, enrichment analysis of gene ontology and KEGG pathways, and generation of Venn diagrams to compare and contrast gene sets between experiments. Additionally, the database offers customizable BLAST tools for performing species- and experiment-specific BLAST searches. Therefore, DEG comprehensively harbors updated human-curated essential-gene records among prokaryotes and eukaryotes with built-in tools to enhance essential-gene analysis., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Chlamydia pneumoniae (C. pneumoniae) is a common respiratory pathogen associated with many inflammatory diseases. There are few data concerning the lymphocyte subsets in middle-aged and elderly individuals with C. pneumoniae infection. A total of 191 patients were included in this study. The study population was categorized into the middle-aged group (40-64 years old) and the elderly group (65-89 years old). Lymphocyte subsets in peripheral blood were examined with multi-colored flow cytometry. Immunological monitoring included lymphocyte subsets, C. pneumoniae IgG and IgM serology. In the middle-aged group, 69.83% individuals presented IgG positivity, which was associated with the inverted CD4/CD8 ratio. Individuals with C. pneumoniae IgG positivity also presented an increased percentage of CD8 + CD28 -  cells and a decreased CD4/CD8 ratio when compared to weakly-positive individuals. In the elderly group, C. pneumoniae IgG positivity was associated with a significant increase in the percentage of CD3 + CD56 + CD45 + (NKT) cells. In conclusion, altered lymphocyte homeostasis was shown in middle-aged individuals with C. pneumoniae IgG positivity. The senescent phenotypes of T cells might be associated with C. pneumoniae infection in middle-aged individuals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hydroxide exchange membrane fuel cells offer possibility of adopting platinum-group-metal-free catalysts to negotiate sluggish oxygen reduction reaction. Unfortunately, the ultrafast hydrogen oxidation reaction (HOR) on platinum decreases at least two orders of magnitude by switching the electrolytes from acid to base, causing high platinum-group-metal loadings. Here we show that a nickel-molybdenum nanoalloy with tetragonal MoNi 4 phase can catalyze the HOR efficiently in alkaline electrolytes. The catalyst exhibits a high apparent exchange current density of 3.41 milliamperes per square centimeter and operates very stable, which is 1.4 times higher than that of state-of-the-art Pt/C catalyst. With this catalyst, we further demonstrate the capability to tolerate carbon monoxide poisoning. Marked HOR activity was also observed on similarly designed WNi 4 catalyst. We attribute this remarkable HOR reactivity to an alloy effect that enables optimum adsorption of hydrogen on nickel and hydroxyl on molybdenum (tungsten), which synergistically promotes the Volmer reaction.