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Objective: To investigate the substantial changes in cell types, pathways, and cell-cell interactions occurring in the irradiation-induced alopecia and dermatitis (IRIAD) mouse model and to identify potential targets for patients experiencing skin adverse reactions to radiotherapy. Methods: Mice were irradiated at 15 ​Gy, targeting the head and neck region. After a 14-day interval, living cells were extracted from both wild-type (WT) mice and irradiated mice for single-cell RNA sequencing (scRNA-seq). The scRNA-seq data, retrieved from the GEO database (GSE201447), underwent stringent quality control using the Seurat (v4.3.0) R package. Cell type annotation relied on previously reported typical markers and CellMarker 2.0. Differentially expressed genes were calculated to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Cell-cell interactions were evaluated using the Cellchat R package. Results: The application of single-cell RNA sequencing (scRNA-seq) enabled a comprehensive characterization of the intricate cellular composition of both wild-type (WT) and irradiated mice skin. Remarkably, cells within irradiated mice skin exhibited a significant alteration in the intensity of cell-cell interactions compared to their wild-type counterparts. This change in interaction intensity was observed across various cell types, including fibroblast cells, endothelial cells, and dendritic cells. Importantly, these ''interacting cells'' shared common signaling pathways, notably the upregulation of the IL-17 pathway following irradiation. Conclusions: The modification of intercellular communication induced by irradiation primarily involves fibroblast cells, endothelial cells, and various types of immune cells. This investigation provides a novel perspective on potential targets and holds promise for enhancing the clinical management of IRIAD.

Abstract Background Lip infantile hemangiomas tend to show less volumetric regression and are more susceptible to visible sequelae in the involuted stage. Some of them still require surgical management after propranolol therapy. This study aimed to evaluate the efficacy and safety of the Stepwise, Multi-Incisional, and Single-Stage (SMISS) approach applied to lip reduction for those with involuted lip hemangiomas. Methods A retrospective review was performed to evaluate patients with lip hemangioma who received previous propranolol treatment and underwent the aforementioned procedure. Demographic characteristics, lesion morphology, and medical history were reviewed. The Visual Analog Scale was applied to assess the postoperative appearance. Complications within 12 months postoperatively were recorded. Results A total of 18 patients with lip hemangioma were eligible. All patients received oral propranolol therapy before surgery, with treatment duration ranging from 6.0 to 23.0 months. Their age at surgery ranged from 2.5 to 9.0 years. The median Visual Analog Scale scores were 8.0, ranging from 4.0 to 10.0. No severe complications were reported. Conclusions This modified technique based on the SMISS approach has proven reliable and effective in improving the aesthetic outcome for involuted lip infantile hemangiomas. Practical surgical techniques still play an important part in the propranolol era.

Identifying an integrative framework that could appropriately delineate underlying mechanisms and individual risk/protective factors for human health has remained elusive. Evolutionary mismatch theory provides a comprehensive, integrative model for understanding the underlying causes and mechanisms of a wide range of modern health and well-being problems, ranging from obesity to depression. Despite growing interest regarding its importance though, no psychometrically-sound measure of evolutionary mismatch yet exists to facilitate research and intervention. To construct such a scale, aimed at gauging individual differences in the extent to which people's modern lifestyles are mismatched with ancestral conditions, we conducted four studies (a pilot study, followed by 3 main studies, with a final sample of 1901 participants across the main studies). Results from exploratory and confirmatory factor analyses have produced a 36-item evolutionary mismatched lifestyle scale (EMLS) with 7 subdomains of mismatched behaviours (e.g., diet, physical activity, relationships, social media use) that is psychometrically sound. Further, the EMLS is associated with physical, mental and subjective health. We explore the potential of the EMLS as a tool for examining interpersonal and cultural variations in health and wellbeing, while also discussing the limitations of the scale and future directions in relation to further psychometric examinations.

Abstract Embryonic stem cells (ESCs) exhibit unique attributes of boundless self-renewal and pluripotency, making them invaluable for fundamental investigations and clinical endeavors. Previous examinations of microgravity effects on ESC self-renewal and differentiation have predominantly maintained a descriptive nature, constrained by limited experimental opportunities and techniques. In this investigation, we present compelling evidence derived from murine and human ESCs, demonstrating that simulated microgravity (SMG)-induced stress significantly impacts self-renewal and pluripotency through a previously unidentified conserved mechanism. Specifically, SMG induces the upregulation of heat shock protein genes, subsequently enhancing the expression of core pluripotency factors and activating the Wnt and/or LIF/STAT3 signaling pathways, thereby fostering ESC self-renewal. Notably, heightened Wnt pathway activity, facilitated by Tbx3 upregulation, prompts mesoendodermal differentiation in both murine and human ESCs under SMG conditions. Recognizing potential disparities between terrestrial SMG simulations and authentic microgravity, forthcoming space flight experiments are imperative to validate the impact of reduced gravity on ESC self-renewal and differentiation mechanisms.

Abstract Background Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1 expression. We designed this study to further explore the influence of P5C on T cell metabolism, and produced an antibody for targeting P5C to restore the functions of T cells. Method We co-immunoprecipated SHP1 from T cells and analyzed the proteins that were bound to it using liquid chromatography mass spectrometry (LC/MS-MS). The influence of P5C on T cells metabolism was also detected by LC/MS-MS. Seahorse XF96 analyzer was further used to identify the effect of P5C on T cells glycolysis. We subsequently designed and produced an antibody for targeting P5C by monoclonal technique and verified its effectiveness to restore the function of T cells in vitro and in vivo. Result PKM2 and LDHB bind SHP1 in T cells, and P5C could increase the levels of p-PKM2 while having no effect on the levels of PKM2 and LDHB. We further found that P5C influences T cell energy metabolism and carbohydrate metabolism. P5C also inhibits the activity of PKM2 and decreases the content of intracellular lactic acid while increasing the activity of LDH. Using seahorse XF96 analyzer, we confirmed that P5C remarkably inhibits glycolysis in T cells. We produced an antibody for targeting P5C by monoclonal technique and verified that the antibody could oppose the influence of P5C to restore the process of glycolysis and function in T cells. Meanwhile, the antibody also inhibits the growth of prostate tumors in an animal model. Conclusion Our study revealed that P5C inhibits the process of glycolysis in T cells by targeting SHP1/PKM2/LDHB complexes. Moreover, it is important that the antibody for targeting P5C could restore the function of T cells and inhibit the growth of prostate tumors.

Abstract Background In some patients with nonischemic cardiomyopathy (NICM), left ventricular (LV) function improves with medical assistance, resulting in left ventricular reverse remodeling (LVRR). However, predictors of LVRR are not fully understood. The left atrium (LA) has been reported as a prognostic predictor in patients with heart failure (HF). The present study aimed to evaluate clinical predictors of LVRR related to LA function on cardiac magnetic resonance (CMR). Methods A total of 103 patients with reduced left ventricular ejection fraction (LVEF) were enrolled in this retrospective study between September 2015 and July 2021. CMR parameters, including strain data, were measured in all patients. Echocardiographic data obtained approximately 2 years after enrollment were analyzed to assess LVRR. Results LVRR occurred in 46 patients (44.7%) during follow-up. The value of LA conduit strain was higher in the LVRR group than in the non-LVRR group (6.6 [interquartile range (IQR): 5.6–9.3]% versus 5.0 [IQR: 3.0-6.2]%; p 6.2% compared to those with ⩽6.2%. (log-rank test, p = 0.019). Conclusions LA conduit strain derived from CMR is an independent predictor of LVRR in patients with NICM.

Abstract Epidemiological studies have reported a positive association between chronic inflammation and cancer risk. However, the causal association between chronic inflammation and breast cancer (BC) risk remains unclear. Here, we performed a Mendelian randomization study to investigate the etiological role of chronic inflammation in BC risk. We acquired data regarding C-reactive protein (CRP), interleukin (IL)-1a, IL-1b, and IL-6 expression and BC related to single nucleotide polymorphisms (SNPs) from two larger consortia (the genome-wide association studies and the Breast Cancer Association Consortium). Next, we conducted the two-sample Mendelian randomization study to investigate the relationship of the abovementioned inflammatory factors with the incidence of BC. We found that genetically predicted CRP, IL-6, and IL-1a levels did not increase BC incidence (odds ratio (OR)CRP 1.06, 95% confidence interval (CI) 0.98–1.12, P = 0.2059, ORIL-6 1.05, 95% CI 0.95–1.16, P = 0.3297 and ORIL-1a 1.01, 95% CI 0.99–1.03, P = 0.2167). However, in subgroup analysis, genetically predicted IL-1b levels increased ER + BC incidence (OR 1.15, 95% CI 1.03–1.27, P = 0.0088). Our study suggested that genetically predicted IL-1b levels were found to increase ER + BC susceptibility. However, due to the support of only one SNP, heterogeneity and pleiotropy tests cannot be performed, which deserves further research.

In this paper, a novel ultrawideband phased array is presented based on exponential curve modified dipoles. A tightly-coupled exponential curve modified dipole arm is used to extend the operating bandwidth with a simple coplanar strip structure, which avoids the use of additional complex impedance conversion networks and reduces the processing difficulty and cost. The problematic common-mode resonance is moved out of the required operating bandwidth by the shorting pin. A wide angle impedance matching layer is used to improve beam scanning ability of the array. The proposed antenna array achieves 8.5:1 (2.06-17.6 GHz) bandwidth at broadside, with a scanning range of ±45° from 2.06-17.6 GHz (8.5:1 bandwidth) in the E-plane and ±45° from 2.2-17.6 GHz (8:1 bandwidth) in the H-plane, subject to active VSWR < 3. A $6\times6$ prototype was fabricated and measured with good agreement in measured and simulated results, which verify the ultrawideband performance of proposed array.

Ischemic heart failure rates rise despite decreased acute myocardial infarction (MI) mortality. Excessive myofibroblast activation post-MI leads to adverse remodeling. LIM kinases (LIMK1 and LIMK2) regulate cytoskeleton homeostasis and are pro-fibrotic markers in atrial fibrillation. However, their roles and mechanisms in postinfarction fibrosis and ventricular remodeling remain unclear. This study found that the expression of LIMKs elevated in the border zone (BZ) in mice MI models. LIMK1/2 double knockout (DKO) restrained pathological remodeling and reduced mortality by suppressing myofibroblast activation. By using adeno-associated virus (AAV) with a periostin promoter to overexpress LIMK1 or LIMK2, this study found that myofibroblast-specific LIMK2 overexpression diminished these effects in DKO mice, while LIMK1 did not. LIMK2 kinase activity was critical for myofibroblast proliferation by using AAV overexpressing mutant LIMK2 lack of kinase activity. According to phosphoproteome analysis, functional rescue experiments, co-immunoprecipitation, and protein-protein docking, LIMK2 led to the phosphorylation of β-catenin at Ser 552. LIMK2 nuclear translocation also played a role in myofibroblast proliferation after MI with the help of AAV overexpressing mutant LIMK2 without nuclear location signal. Chromatin immunoprecipitation sequencing identified that LIMK2 bound to Lrp6 promoter region in TGF-β treated cardiac fibroblasts, positively regulating Wnt signaling via Wnt receptor internalization. This study demonstrated that LIMK2 promoted myofibroblast proliferation and adverse cardiac remodeling after MI, by enhancing phospho-β-catenin (Ser552) and Lrp6 signaling. This suggested that LIMK2 could be a target for the treatment of postinfarction injury.

We apply a classical mathematical problem, the moment problem, with its related mathematical achievements, to the study of the parton distribution function (PDF) in hadron physics, and propose a strategy to sieve the moments of the PDF by exploiting its properties such as continuity, unimodality, and symmetry. Through an error-inclusive sifting process, we refine three sets of PDF moments from Lattice QCD. This refinement significantly reduces the errors, particularly for higher order moments, and locates the peak of PDF simultaneously. As our strategy is universally applicable to PDF moments from any method, we strongly advocate its integration into all PDF moment calculations.

Abstract Renal inflammation is a pivotal mechanism underlying the pathophysiology of diabetic nephropathy (DN). The Src homology phosphatase 2 (SHP2) has been demonstrated to be linked to diabetes-induced inflammation, yet its roles and explicit molecular mechanisms in DN remain unexplored. Here, we report that SHP2 activity is upregulated in both DN patients and db/db mice. In addition, pharmacological inhibition of SHP2 with its specific inhibitor PHPS1 alleviates DN in db/db mice and attenuates renal inflammation. In vitro, PHPS1 administration prevents inflammatory responses in HK-2 cells stimulated by high glucose (HG). Mechanistically, PHPS1 represses HG-induced activation of the proinflammatory ERK/NF-κB signaling pathway, and these inhibitory effects are blocked in the presence of an ERK specific inhibitor, hence demonstrating that PHPS1 suppresses ERK/NF-κB pathway-mediated inflammation. Moreover, PHPS1 retards ERK/NF-κB pathway activation in db/db mice, and histologically, SHP2 activity is positively correlated with ERK/NF-κB activation in DN patients. Taken together, these findings identify SHP2 as a potential therapeutic target and show that its pharmacological inhibition might be a promising strategy to mitigate DN. Video Abstract

Abstract Background Radiotherapy is widely used in treating cervical cancer patients, however, radioresistance unavoidably occurs and seriously affects the treatment effect. It is well known that hypoxia plays an important role in promoting radioresistance in tumor microenvironment, yet our understanding of the effect of small extracellular vesicles miRNA on cervical cancer radiosensitivity in hypoxic environment is still limited. Methods Small extracellular vesicles extracted from hypoxic and normoxic cultured cervical cancer cells were evaluated for their effects on radioresistance. miR-152-3p was found to be a potential effector in hypoxia-derived extracellular vesicles by searching the GEO database. Its downstream substrate was confirmed by double luciferase report, which was KLF15. The role of miR-152-3p and KLF15 in regulating cervical cancer radioresistance was detected by cell activity assays. The findings were confirmed in vivo by animal models. The expression of miR-152-3p was quantified by qRT-PCR and its prognostic significance was evaluated. Results Hypoxic environment promoted the secretion of small extracellular vesicles, and reduced the apoptosis and DNA damage caused by radiation, accompanied by increased expression of small extracellular vesicles miR-152-3p from hypoxic cervical cancer cells. Furthermore, small extracellular vesicles miR-152-3p promoted Hela xenograft growth and reduced the radiosensitivity vivo. Mechanism studies revealed that KLF15 protein was the downstream target of miR-152-3p in regulating radioresistance. Conclusion Our findings suggest that small extracellular vesicles miR-152-3p affects the therapeutic effect of radiotherapy and holds potential as a biomarker or therapeutic target for cervical cancer prognosis and improving radiotherapy.

Abstract Background Fibrosis-5 (FIB-5) index is a marker of liver fibrosis and has been shown to have a good prognostic value for patients with acute heart failure (AHF), and C-reactive protein (CRP) has inflammatory properties and predicts adverse prognosis in patients with HF. However, the long-term prognostic value of FIB-5 index combined with CRP in patients with acute decompensated HF (ADHF) is yet unclear. Methods This retrospective study included 1153 patients with ADHF hospitalized from January 2018 to May 2022.The FIB-5 index was calculated as (albumin [g/L]×0.3 + PLT count [109/L]×0.05)−(ALP [U/L]×0.014 + AST to ALT ratio×6 + 14). Patients were stratified into the following four groups according to the median value of FIB-5 index (=-2.11) and CRP (= 4.5): Group 1 had a high FIB-5 index (FIB-5 index >-2.11) and a low CRP (CRP ≤ 4.5); Group 2 had both low FIB-5 index and low CRP; Group 3 had both high FIB-5 index and high CRP; Group 4 had a low FIB-5 index (FIB-5 index ≤-2.11) and a high CRP (CRP > 4.5). The endpoint was major adverse cardiac and cerebral events (MACCEs). Multivariate Cox analysis was used to evaluate the association of the combination with the development of MACCEs. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analysis were used to compare the accuracy of the combination with a single prognostic factor for predicting the risk of MACCEs. Results During the mean follow-up period of 584 ± 12 days, 488 (42.3%) patients had MACCEs. Kaplan–Meier analysis revealed that the incidence of MACCEs was different in the four groups (P

Abstract LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated cardiomyopathy(LMNA-DCM) is one of the more common laminopathy which characterized by progressive heart failure and arrhythmia. However, the mutation features of LMNA-DCM are yet to be elucidated. Herein we described a dilated cardiomyopathy family carrying novel variant c.467G > C(p.Arg156Pro) of LMNA as heterozygous pathogenic variant identified by whole-exome sequencing. With the help of Alphafold2, we predicted mutant protein structure and found an interrupted α-helix region in lamin A/C. In the analysis of 49 confirmed pathogenic missense of laminopathies, Chi-square test showed the DCM phenotype was related to the α-helix region mutation (p

Alternative splicing is an essential regulatory mechanism for development and pathogenesis. Through alternative splicing one gene can encode multiple isoforms and be translated into proteins with different functions. Therefore, this diversity is an important dimension to understand the molecular mechanism governing embryo development. Isoform expression in preimplantation embryos has been extensively investigated, leading to the discovery of new isoforms. However, the dynamics of isoform switching of different types of transcripts throughout the development remains unexplored. Here, using single-cell direct isoform sequencing in over 100 single blastomeres from the mouse oocyte to blastocyst stage, we quantified isoform expression and found that 3-prime partial transcripts lacking stop codons are highly accumulated in oocytes and zygotes. These transcripts are not transcription by-products and might play a role in maternal to zygote transition (MZT) process. Long-read sequencing also enabled us to determine the expression of transposable elements (TEs) at specific loci. In this way, we identified 3,894 TE loci that exhibited dynamic changes along the preimplantation development, likely regulating the expression of adjacent genes. Our work provides novel insights into the transcriptional regulation of early embryo development.

BackgroundParkinson’s disease (PD) symptoms deteriorate with disease progression. Although deep brain stimulation (DBS) can effectively improve the motor signs of PD patients, it is not yet known whether DBS surgery, which is an invasive treatment modality, may change the progression of PD.ObjectiveThe aim of this work was to compare the effect of DBS with that of drug treatment on the progression of PD.MethodsA total of 77 patients with PD with the Hoehn and Yahr scale (HY) stage of 2.5 or 3 were included, and were divided into 34 in the drug therapy alone group (Drug-G) and 43 in the DBS therapy group (DBS-G). All patients were subjected to a follow-up of 2 years, and disease severity was assessed by the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III), the Montreal Cognitive Assessment (MOCA), the Hamilton Anxiety Scale (HAMA), and the Hamilton Depression Scale (HAMD) scores. In addition, the quality of life of patients and the burden on their family were assessed by the 39-item PD questionnaire (PDQ-39) scores, daily levodopa equivalent dose (LED), patient’s annual treatment-related costs, and the Zarit Caregiver Burden Scale (ZCBS) score. The changes in relevant scale scores between the two groups were compared at each follow-up stage.ResultsThe UPDRS-III score of the patients in the “off” state increased from year to year in both groups, and the degree of increase of this score was greater in the DBS-G than in the Drug-G group. The MOCA score in both groups began to decline in the 2nd year of follow-up, and the decline was greater in the Drug-G than in the DBS-G group. DBS treatment did not affect patients’ psychiatric disorders. The PDQ39, LED, costs, and ZCBS were negatively correlated with the follow-up time in patients in the DBS-G group, and positively correlated with the follow-up time in patients in the Drug-G.ConclusionPD is progressive regardless of treatment. The findings from this follow-up study suggest that the disease progression of patients in DBS-G may be slightly faster compared to the drug-G, but the advantages of DBS are also evident. Indeed, DBS better improves patient’s motor signs and quality of life and reduces the family burden. In addition, DBS has less impact on patients in terms of cognitive and mental effects.

Background: Gastric ulcers (GUs) are prevalent digestive disorders worldwide. Wuzhuyu Decoction (WZYT) is a traditional Chinese medicine that has been employed for centuries to alleviate digestive ailments like indigestion and vomiting. This study aims to explore the potential effects and underlying mechanisms of WZYT on alcohol induced gastric ulcer treatment.Methods: We employed macroscopic assessment to evaluate the gastric ulcer index (UI), while the enzyme-linked immunosorbent assay (ELISA) was utilized for detecting biochemical indicators. Pathological tissue analysis involved hematoxylin-eosin (H&E) staining and Periodic Acid-Schiff (PAS) staining to assess gastric tissue damage. Additionally, the integration of network analysis and metabolomics facilitated the prediction of potential targets. Validation was conducted using Western blotting.Results: The research revealed that WZYT treatment significantly reduced the gastric ulcer index (UI) and regulation of alcohol-induced biochemical indicators levels. Additionally, improvements were observed in pathological tissue. Network analysis results indicated that 62 compounds contained in WZYT modulate alcohol-induced gastric ulcers by regulating 183 genes. The serum metabolomics indicated significant changes in the content of 19 metabolites after WZYT treatment. Two pivotal targets, heme oxygenase 1 (HMOX1) and albumin (ALB), are believed to assume a significant role in the treatment of gastric ulcers by the construction of “compounds-target-metabolite” networks. Western blot analysis confirmed that WZYT has the capacity to elevate the expression of HMOX1 and ALB targets.Conclusion: The integration of network analysis and metabolomics provides a scientific basis to propel the clinical use of WZYT for GUs. Our study provides a theoretical basis for the use of Wuzhuyu decoction in the treatment of gastric ulcers.

The bump-on-tail (BOT) instability is generally caused by a beam of energetic particles existing in relatively cold background plasma. The employment of second-stage wave-driven module in the variable specific impulse magnetoplasma rocket (VASIMR) yields the production of energetic ions, which could drive the BOT instability. The present work explores this possibility for the first time via numerical simulations based on the experimental data on the VASIMR, i.e., referring to VX-50. It is found that the BOT instability does exist even in the plume region away from antenna. The results indicate that velocity space diffusion provides a stabilizing effect on the nonlinear evolution of waves, while dissipation in the bulk plasma essentially impedes it. To show the practical values implied by these computations, the influences of this BOT instability on the power coupling and thrust are investigated particularly. These findings are valuable for VASIMR, as well as other plasma thrusters that yield energetic particles inside relatively cold background plasma, to suppress BOT instability and thus increase the power coupling efficiency and thrust performance.

Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6–72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.

Abstract Correctly capturing the spatial‐temporal correlation of traffic sequences will benefit to make accurate predictions of the future traffic states. In the paper, the methods of enhancing road spatial and temporal information representation are proposed. Firstly, the parameter matrix of each road is constructed to represent the road‐specific traffic patterns for the graph convolution neural network and the recurrent neural network. Then, the node embedding, and matrix factorization are used to reduce the scale of the parameter matrix. Secondly, the node embedding‐based Data Adaptive Graph Generation model was introduced to infer the indirect relationship of each node, and the gating mechanism is designed to control the weights of the direct spatial information and the indirect spatial information. Thirdly, to enhance the traffic sequence representation, the time tag and peak tag for the sequences are designed at each sampling moment. At last, the Enhanced Road Information Representation in Graph Recurrent Network (En‐GRN) is proposed to predict traffic speed, and the prediction performance is tested on SZ‐taxi and Los‐loop dataset. The experimental results show that the presented works are effective for improving traffic prediction accuracy.

The symbiotic nitrogen fixation between rhizobia and peanuts offers an advantage in reducing nitrogen fertilizer inputs, decreasing the incidence rate of peanuts, and enhancing soil fertility. Inoculating rhizobia agent is an effective pathway to improve both the quality and yield of peanuts, contributing to food security and promoting sustainable agricultural practices. This study conducted a one-year field experiment in a subtropical humid monsoon climate area in Southeast China to investigate the effects of rhizobia agents on the growth and crop yield of four peanut varieties (i.e., Taihua No.4, No.6, No.8, and No.10). Our research showed that inoculation with rhizobia agent can increase the plant height, lateral branch length, fresh root weight, and leaf area of the four peanut varieties. Meanwhile, inoculation with a rhizobia agent can significantly (p < 0.05) increase the ~50% number of root nodules. Especially for the early-maturing and drought-resistant variety, Taihua No.4 exhibited the highest number of nodules and peanut fruits per plant in the pod-setting stage after inoculation with rhizobia agent, i.e., 24.5 and 18.0, respectively. Under the conventional fertilization conditions (N-P2O5-K2O 15-15-15, 450 kg/hm2), Taihua No.4 and No.6 inoculated with rhizobia agent achieved higher yield increase rates of 11.0% and 11.6% compared to other peanut varieties. This study indicated that the Taihua No.4 and No.6 are the most suitable peanut varieties for rhizobia inoculation and promotion, with enormous potential for yield increase. Meanwhile, optimizing rhizobia inoculation techniques and evaluating soil health status, economic benefits of peanuts, and applicable regions should be explored in the future.

Saline-alkali land is an important component of terrestrial ecosystems and may serve as a carbon sink but its net contribution to the overall terrestrial carbon sink is unknown. Using methods recommended by the IPCC, this study evaluates the impacts of interconverting saline-alkali and non-saline-alkali land on terrestrial carbon stocks by measuring two major carbon pools (soil organic carbon and vegetation carbon) in the saline-alkali land of China’s Songnen Plain. Distinct phases in the evolution of the region’s terrestrial carbon stock were delineated, factors contributing to transitions between phases were identified, and the effects of changes in the saline-alkali land carbon stock on the overall terrestrial carbon sink were estimated. Between 2005 and 2020, the region’s saline-alkali land carbon stock initially increased, then declined, and finally increased again. However, the overall terrestrial carbon stock decreased by 0.5 Tg (1 Tg = 1012 g), indicating that the increase in the saline-alkali land carbon stock was due primarily to expansion of the saline-alkali land area. The conversion of non-saline-alkali land to saline-alkali land was a carbon-emitting process; consequently, in areas undergoing saline-alkali land change, the lower carbon density bound was equal to the carbon density of unconverted saline-alkali land and the upper bound was equal to the carbon density of unconverted non-saline-alkali land. In general, changes in the carbon stock of saline-alkali land correlated negatively with changes in the overall terrestrial carbon stock. The conversion of saline-alkali land into grassland and cropland through biochar improvement and the planting of saline-tolerant crops (Leymus chinensis, salt-tolerant rice) has a positive effect on promoting the enhancement of terrestrial carbon stocks.

Land-use change is an important factor affecting terrestrial carbon balance, and it is crucial to explore the response of terrestrial carbon stocks to land-use change, especially in the Songnen Plain, which faces a fierce conflict between the rapid growth of production activities and ecosystem degradation. In this study, we measured soil organic carbon and vegetation biocarbon stocks in the Songnen Plain based on IPCC-recommended methodologies, and explored the characteristics of carbon stock changes in land-use trajectories, land-use drivers, and specific land-use change scenarios (cropland cultivation, returning cropland to forests, the expansion of land for construction, deforestation, greening, and land degradation). The results showed that soil organic carbon stock in the Songnen Plain decreased by 1.63 × 105 t, and vegetation biocarbon stock increased by 2.10 × 107 t from 2005 to 2020. Human factors and natural factors jointly contributed to the land-use change, but the extent of the role of human factors was greater than that of natural factors. The increase in land-use trajectory led to the decrease in soil organic carbon stock and the increase in vegetation biocarbon stock. There was no difference in the effects of human-induced and natural-induced land-use changes on vegetation biocarbon stocks, but the effects on soil organic carbon stocks were diametrically opposite, increasing by 43.27 t/km2 and decreasing by 182.02 t/km2, respectively. The reclamation of arable land, returning cropland to forests, and greening led to a net increase in terrestrial carbon stocks (+813,291.84 t), whereas land degradation, deforestation, and land-use expansion led to a decrease in terrestrial carbon stocks (−460,710.2 t). The results of this study can provide a reference for the adjustment of land-use structure and the increase in terrestrial carbon stock in the Songnen Plain.

Mulch is an important measure for improving agricultural productivity in many semiarid regions of the world. However, the impacts of various mulching materials on soil hydrothermal characteristics, enzyme activity, and potato yield in fields have not been comprehensively explored. Thus, a two-growing-season field experiment (2020–2021) with four treatments (SSM, straw strip mulching; PMP, plastic film mulching with large ridge; PMF, double ridge-furrow with full film mulching; and CK, no mulching with conventional planting as the control) was conducted to analyze soil hydrothermal and soil enzyme activities and potato yield on the semiarid Loess Plateau of Northwest China. The results indicated that mulching practices had a positive effect on the soil moisture, with SSM, PMP, and PMF increasing by 7.3%, 9.2%, and 9.2%, respectively, compared to CK. Plastic film mulching significantly increased the soil temperature by 1.3 °C, and straw mulching reduced the soil temperature by 0.7 °C in the 0–30 cm soil layers of the whole growth period. On average, SSM, PMP, and PMF increased soil urease activity in 0–40 cm soil layers by 14.2%, 2.8%, and 2.7%, respectively, and enhanced soil sucrase activity by 19.2%, 8.6%, and 5.7%, respectively, compared with CK. Plastic film mulching increased soil catalase activity by 9.6%, while SSM decreased by 10.1%. Mulching treatments significantly increased tuber yield and water use efficiency based on dry tuber yield (WUE), and SSM, PMP, and PMF increased tuber yield by 18.6%, 31.9%, and 29.7%, enhanced WUE by 50%, 50%, and 57.0% over CK. The correlation analysis revealed that soil moisture was the main factor influencing tuber yield (r = 0.95**). Mulching could improve the soil hydrothermal environment, regulate soil enzyme activities, and promote yield increase. As a sustainable protective mulching measure, straw strip mulching is conducive to improving the ecological environment of farmland and the sustainable development of regional organic agriculture.

Abstract Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.

With the widespread adoption of ultrasound guidance, Seldinger puncture techniques, and intracardiac electrical positioning technology for the placement of peripherally inserted central catheters in recent years, an increasing number of medical staff and patients now accept peripheral placement of totally implantable venous access devices (TIVADs) in the upper arm. This approach has the advantage of completely avoiding the risks of hemothorax, pneumothorax, and neck and chest scarring. Medical specialties presently engaged in this study in China include internal medicine, surgery, anesthesiology, and interventional departments. However, command over implantation techniques, treatment of complications, and proper use and maintenance of TIVAD remain uneven among different medical units. Moreover, currently, there are no established quality control standards for implantation techniques or specifications for handling complications. Thus, this expert consensus is proposed to improve the success rate of TIVAD implantation via the upper-arm approach, reduce complication rates, and ensure patient safety. This consensus elaborates on the technical indications and contraindications, procedures and technical points, treatment of complications, and the use and maintenance of upper-arm TIVAD, thus providing a practical reference for medical staff.

Abstract Stroke usually causes prolonged or lifelong disability, owing to the permanent loss of infarcted tissue. Although a variety of stem cell transplantation has been explored to improve neuronal defect behavior by enhancing neuroplasticity, it remains unknown whether the infarcted tissue can be reconstructed. We here cultured human cerebral organoids derived from human pluripotent stem cells (hPSCs) and transplanted them into the junction of the infarct core and the peri-infarct zone of NOD-SCID mice subjected to stroke. Months later, we found that the grafted organoids survived well in the infarcted core, differentiated into target neurons, repaired infarcted tissue, sent axons to distant brain targets, and integrated into the host neural circuit and thereby eliminated sensorimotor defect behaviors of stroke mice, whereas transplantation of dissociated single cells from organoids failed to repair the infarcted tissue. Our study offers a new strategy for reconstructing infarcted tissue via organoids transplantation thereby reversing stroke-induced disability.

Abstract Several groups of bacteria have complex life cycles involving cellular differentiation and multicellular structures. For example, actinobacteria of the genus Streptomyces form multicellular vegetative hyphae, aerial hyphae, and spores. However, similar life cycles have not yet been described for archaea. Here, we show that several haloarchaea of the family Halobacteriaceae display a life cycle resembling that of Streptomyces bacteria. Strain YIM 93972 (isolated from a salt marsh) undergoes cellular differentiation into mycelia and spores. Other closely related strains are also able to form mycelia, and comparative genomic analyses point to gene signatures (apparent gain or loss of certain genes) that are shared by members of this clade within the Halobacteriaceae. Genomic, transcriptomic and proteomic analyses of non-differentiating mutants suggest that a Cdc48-family ATPase might be involved in cellular differentiation in strain YIM 93972. Additionally, a gene encoding a putative oligopeptide transporter from YIM 93972 can restore the ability to form hyphae in a Streptomyces coelicolor mutant that carries a deletion in a homologous gene cluster (bldKA-bldKE), suggesting functional equivalence. We propose strain YIM 93972 as representative of a new species in a new genus within the family Halobacteriaceae, for which the name Actinoarchaeum halophilum gen. nov., sp. nov. is herewith proposed. Our demonstration of a complex life cycle in a group of haloarchaea adds a new dimension to our understanding of the biological diversity and environmental adaptation of archaea.

ABSTRACT Avian pathogenic Escherichia coli (APEC) leads to economic losses in poultry industry and is also a threat to human health. Various strategies were used for searching virulence factors, while little is known about the mechanism by which APEC survives in host or is eliminated by host. Thus, chicken colibacillosis model was constructed by intraperitoneally injecting E. coli O78 in this study, then the protein dynamic expression of spleen was characterized at different post-infection times by quantitative proteome. Comparative analysis showed that E. coli induced significant dysregulation at 72 h post infection in spleen tissue. Transcriptomic method was further used to assess the changes of dysregulated proteins at 72 h post infection at the mRNA level. Total 278 protein groups (5.7%) and 2,443 genes (24.4%) were dysregulated, respectively. The upregulated proteins and genes were consistently enriched in phagosome and lysosome pathways, indicating E. coli infection activates phagosome maturation pathway. The matured phagolysosome might kill the invasive E. coli. This study illuminated the genetic dysregulation in chicken spleen at the protein and mRNA levels after E. coli infecting and identified candidate genes for host response to APEC infection.

Radiation resistance has always been one of the main obstacles to tumor radiotherapy. Therefore, understanding the mechanisms underlying radiotherapy resistance is a focus of research. In this study, we induced two radiation-resistant cell lines to mimic the radiation resistance of NSCLC and investigated the mechanisms of radiotherapy resistance. Cell radiosensitivity was analyzed by single-cell gel electrophoresis, colony formation and tumor sphere formation assays. A wound healing assay was used to analyze cell migration. Western blotting and siRNA were used to identify the potential mechanism. In animal model experiments, xenograft tumors were used to verify the difference between radiotherapy-resistant and nonresistant NSCLC models after radiotherapy. Our results showed that NSCLC radiation-resistant cells exhibited more radioresistance and migratory abilities under low-dose irradiation. The expression of LIMK2 and p-CFL1 were upregulated in NSCLC radiation-resistant cells. Knockdown of LIMK2 significantly enhanced the radiosensitivity of NSCLC-resistant cells. In vivo, low-dose radiotherapy suppressed tumor growth, induced apoptosis and upregulated the expression of LIMK2 in xenograft tumors. However, radiotherapy had little effect on the NSCLC radiation resistance model. In conclusion, NSCLC radiation-resistant cells exhibit more radioresistance and migratory ability under low-dose irradiation. Strikingly, knockdown of LIMK2 enhanced the radiosensitivity of NSCLC-resistant cells.

Antimicrobial resistance has brought great burden to global public health. Alternative strategies are needed to reduce the development of drug resistance. Herein, we have developed an effective synergistic antibacterial strategy combining low–temperature photothermal therapy (LT–PTT) with antibiotic therapy, improving the bactericidal efficiency to avoid antimicrobial resistance. Copper sulfide templated with bovine serum albumin (CuS–BSA) nanoparticles were selected as the photothermal agent, and co–loaded into the hydrogel (Gel) with mupirocin. The Gel could slow down the release rate of CuS–BSA and mupirocin, thereby prolonging the effective drug reaction time. More importantly, when applying near–infrared laser irradiation, the antibacterial activity of the platform could be enhanced greatly by LT–PTT effect of CuS–BSA nanoparticles. In vitro and in vivo results both confirmed that the antibacterial efficacy of the synergistic therapeutic strategy was improved greatly with complete bacterial removal. Overall, this platform has posed a potential strategy to reduce the development of drug resistance and improve patient compliance.

In this paper, the strength development of a pure steel slag (SS) system with various concentrations of N,N,N′,N′-Tetrakis-(2-hydroxyethyl) ethylenediamine (THEED) was investigated. The hydration kinetics, pore structure and microstructure of SS pastes with and without THEED were characterized to underscore the working mechanism of THEED. Results show that THEED additions significantly increase the 3, 7 and 28 days compressive strength of hardened SS pastes. The enhancement effect increases with the dosage of THEED. At a concentration of 2000 ppm, THEED increased the compressive strength by 733%, 665%, and 545% at 3, 7 and 28 days, respectively. It is confirmed that THEED additions improve the hydration degree of SS by accelerating hydration of the aluminum phase (C3A, PDF-38-1429; C12A7, PDF-48-1882) and C2F,( PDF 38-0408) to generate Mc (PDF-41-0219) and Pa (PDF-30-0222) in the presence of CaCO3. Also, the hydration degree of silicates is increased by THEED. In this way, THEED additions refine the pore structure of hardened SS paste by increasing the pore volume with a diameter below 300 nm to achieve enhancement. The chelating effect of THEED results in promoting dissolution of SS, which provides the driving force for accelerating SS hydration.

Intrauterine adhesion (IUA), also referred to as Asherman Syndrome (AS), results from uterine trauma in both pregnant and nonpregnant women. The IUA damages the endometrial bottom layer, causing partial or complete occlusion of the uterine cavity. This leads to irregular menstruation, infertility, or repeated abortions. Transcervical adhesion electroreception (TCRA) is frequently used to treat IUA, which greatly lowers the prevalence of adhesions and increases pregnancy rates. Although surgery aims to disentangle the adhesive tissue, it can exacerbate the development of IUA when the degree of adhesion is severer. Therefore, it is critical to develop innovative therapeutic approaches for the prevention of IUA. Endometrial fibrosis is the essence of IUA, and studies have found that the use of different types of mesenchymal stem cells (MSCs) can reduce the risk of endometrial fibrosis and increase the possibility of pregnancy. Recent research has suggested that exosomes derived from MSCs can overcome the limitations of MSCs, such as immunogenicity and tumorigenicity risks, thereby providing new directions for IUA treatment. Moreover, the hydrogel drug delivery system can significantly ameliorate the recurrence rate of adhesions and the intrauterine pregnancy rate of patients, and its potential mechanism in the treatment of IUA has also been studied. It has been shown that the combination of two or more therapeutic schemes has broader application prospects; therefore, this article reviews the pathophysiology of IUA and current treatment strategies, focusing on exosomes combined with hydrogels in the treatment of IUA. Although the use of exosomes and hydrogels has certain challenges in treating IUA, they still provide new promising directions in this field.

Abstract Background Cancer cells often exhibit large‐scale genomic variations, such as circular extrachromosomal DNA (ecDNA) and structural variants (SVs), which have been highly correlated with the initiation and progression of cancer. Currently, no adequate method exists to unveil how these variations regulate gene expression in heterogeneous cancer cell populations at a single‐cell resolution. Methods Here, we developed a single‐cell multi‐omics sequencing method, scGTP‐seq, to analyse ecDNA and SVs using long‐read sequencing technologies. Results and Conclusions We demonstrated that our method can efficiently detect ecDNA and SVs and illustrated how these variations affect transcriptomic changes in various cell lines. Finally, we applied and validated this method in a clinical sample of hepatocellular carcinoma (HCC), demonstrating a feasible way to monitor the evolution of ecDNA and SVs during cancer progression.

BackgroundCerebral palsy (CP), a complex syndrome with multiple etiologies, is characterized by a range of movement disorders within the hypokinetic and hyperkinetic spectrum (dystonia or choreoathetosis). CP is often accompanied by neurological and psychiatric signs, such as spasticity, ataxia, and cognitive disorders. Although current treatment options for CP include pharmacological interventions, rehabilitation programs, and spasticity relief surgery, their effectiveness remains limited. Deep brain stimulation (DBS) has demonstrated significant effectiveness in managing dyskinesia; however, its potential therapeutic effect on CP remains determined.MethodsWe present a case of a 44-year-old Asian female who was born as a twin with neonatal ischemic–hypoxic encephalopathy due to prolonged labor and delivery. She was diagnosed with CP at the age of 1 year. The patient exhibited delayed development compared to her peers and presented with various symptoms, including slurred speech, broad-based gait, horseshoe inversion of the right lower extremity, involuntary shaking of the upper extremities bilaterally, and hypotonia and showed no improvement with levodopa therapy. Two years ago, she developed progressive head tremors, which worsened during periods of tension and improved during sleep. As medical treatments proved ineffective and there were no contraindications to surgery, we performed bilateral globus pallidus interna DBS (GPi-DBS) to alleviate her motor dysfunction.ResultsFollowing a 6-month follow-up, the patient demonstrated significant improvements in motor symptoms, including head and limb tremors and dystonia. In addition, significant improvement was observed in her overall psychological well-being, as evidenced by reduced anxiety and depression levels.ConclusionDBS is an effective treatment for dyskinesia symptoms associated with CP in adults. Moreover, its effectiveness may continue to increase over time.

The present study examined longitudinal relations between adverse environment (at the community and family level), life history (LH) profile (conceptualized as a suite of behavioral and physical traits with converging adaptive functions), and crystalized intelligence (mathematics and vocabulary test scores) using data on 1,185 Chinese adolescents obtained from the China Family Panel Studies survey. Multilevel structural equation modeling indicates that early familial environmental harshness was negatively associated with slow LH profiles and crystalized intelligence, slow LH profiles were positively associated with crystallized intelligence, and early community-level environmental harshness strengthened the positive association between slow LH and crystalized cognitive abilities. The results underscore the importance of the childhood environment in fostering individual LH and cognitive development.

BackgroundDespite encouraging results from immunotherapy combined with targeted therapy for hepatocellular carcinoma (HCC), the prognosis remains poor. Chemokines and their receptors are an essential component in the development of HCC, but their significance in HCC have not yet been fully elucidated. We aimed to establish chemokine-related prognostic signature and investigate the association between the genes and tumor immune microenvironment (TIME).Methods342 HCC patients have screened from the TCGA cohort. A prognostic signature was developed using least absolute shrinkage and selection operator regression and Cox proportional risk regression analysis. External validation was performed using the LIHC-JP cohort deployed from the ICGC database. Single-cell RNA sequencing (scRNA-seq) data from the GEO database. Two nomograms were developed to estimate the outcome of HCC patients. RT-qPCR was used to validate the differences in the expression of genes contained in the signature.ResultsThe prognostic signature containing two chemokines-(CCL14, CCL20) and one chemokine receptor-(CCR3) was successfully established. The HCC patients were stratified into high- and low-risk groups according to their median risk scores. We found that patients in the low-risk group had better outcomes than those in the high-risk group. The results of univariate and multivariate Cox regression analyses suggested that this prognostic signature could be considered an independent risk factor for the outcome of HCC patients. We discovered significant differences in the infiltration of various immune cell subtypes, tumor mutation burden, biological pathways, the expression of immune activation or suppression genes, and the sensitivity of different groups to chemotherapy agents and small molecule-targeted drugs in the high- and low-risk groups. Subsequently, single-cell analysis results showed that the higher expression of CCL20 was associated with HCC metastasis. The RT-qPCR results demonstrated remarkable discrepancies in the expression of CCL14, CCL20, and CCR3 between HCC and its paired adjacent non-tumor tissues.ConclusionIn this study, a novel prognostic biomarker explored in depth the association between the prognostic model and TIME was developed and verified. These results may be applied in the future to improve the efficacy of immunotherapy or targeted therapy for HCC.

An improved straw mulching model may be a sustainable agricultural production technology due to its improvements in soil water and the fertilizer environment by the recycling of waste straw resources. A four-year field experiment was conducted in a randomized block design on the Loess Plateau of northwestern China in 2015–2019, which aimed to study the effects of straw strip mulching (SSM) and conventional flat planting without mulching (CK) on soil water storage, water consumption characteristics, water use efficiency, precipitation use efficiency, winter wheat growth, economic benefits, and nutrient benefits. The results obtained for the four years showed that the SSM treatment improved soil water storage in the 0–180 cm soil layer over the whole growth period, which was especially obvious in the 0–60 cm soil layer at the jointing and blooming stages. Compared with CK, SSM increased the contribution rate of precipitation to total evapotranspiration and increased it quite significantly by 20.4 percentage points in the earlier growth period. SSM significantly reduced soil water storage consumption in the 0–180 cm soil layer and ultimately reduced evapotranspiration by 11.2 mm during the whole period. In the 0–180 cm soil layer, SSM decreased evapotranspiration by 33.1 mm from the sowing to the jointing stages, but increased it by 19.5 mm from the jointing to the blooming stages. In addition, SSM improved the water use efficiency of grain yield by 21.6% and improved the precipitation use efficiency of grain yield by 18.6%, and it ultimately increased grain yield by 16.5% through improving spike number by 9.5% and kernel number per spike by 8.9%. SSM improved the water use efficiency of biomass yield by 13.5% and the precipitation use efficiency of biomass yield by 9.9%, and it ultimately increased biomass yield by 8.7% and plant height by 6.5%. Furthermore, SSM increased net income by 413 CNY ha–1 and the total amount of straw returned to the field after harvest by 8 876–9 619 kg ha–1. After returning straw to the field, SSM significantly increased the soil nutrient contents, which could significantly reduce the burden of fertilization by farmers after a few years. Therefore, straw strip mulching technology could probably be a sustainable and potentially useful practice, which could save water and increase efficiency in rainfed winter wheat production.

Abstract Background Circulating fibrinogen-to-albumin ratio (FAR) has been proposed as a novel inflammatory biomarker and a cardiovascular disease risk predictor. However, its prognostic value in patients with acute decompensated heart failure (ADHF) and different glycemic metabolic states remains ambiguous. Methods A total of 1031 hospitalized patients with ADHF from January 2018 to May 2021 were included in the study. The primary endpoints were the major adverse cardiac and cerebral events (MACCEs). Patients were categorized into high-level FAR (FAR-H) and low-level FAR (FAR-L) groups based on the optimal cut-off value of FAR obtained from restricted cubic spline function analysis. The Kaplan–Meier plots and three multivariate-adjusted Cox proportional hazard models were used to determine the association between FAR and the risk of developing MACCEs in patients with ADHF at different glycemic metabolic states. Results MACCEs occurred in 483 (46.8%) patients during a median follow-up time of 520 days. The optimal FAR cut-off value was 0.079. Upon analyzing the Kaplan–Meier plots, the incidence of MACCEs was significantly different between the FAR groups in all patients and patients with diabetes mellitus (p 0.05). Conclusions Elevated FAR was independently associated with poor prognosis in patients with ADHF and DM and thus could be used as a risk stratification tool and a potential therapeutic target in the future.

Abstract Background Deinococcus radiodurans (D. radiodurans) is best known for its extreme resistance to diverse environmental stress factors, including ionizing radiation (IR), ultraviolet (UV) irradiation, oxidative stress, and high temperatures. Robust DNA repair system and antioxidant system have been demonstrated to contribute to extreme resistance in D. radiodurans. However, practically all studies on the mechanism underlying D. radiodurans’s extraordinary resistance relied on the treated strain during the post-treatment recovery lag phase to identify the key elements involved. The direct gene or protein changes of D. radiodurans after stress have not yet been characterized. Results In this study, we performed a proteomics profiling on D. radiodurans right after the heavy ion irradiation treatment, to discover the altered proteins that were quickly responsive to IR in D. radiodurans. Our study found that D. radiodurans shown exceptional resistance to 12C6+ heavy ion irradiation, in contrast to Escherichia coli (E.coli) strains. By using iTRAQ (Isobaric Tags for Relative and Absolute Quantitation)-based quantitative mass spectrometry analysis, the kinetics of proteome changes induced by various dosages of 12C6+ heavy ion irradiation were mapped. The results revealed that 452 proteins were differentially expressed under heavy ion irradiation, with the majority of proteins being upregulated, indicating the upregulation of functional categories of translation, TCA cycle (Tricarboxylic Acid cycle), and antioxidation regulation under heavy ion irradiation. Conclusions This study shows how D. radiodurans reacts to exposure to 12C6+ heavy ion irradiation in terms of its overall protein expression profile. Most importantly, comparing the proteome profiling of D. radiodurans directly after heavy ion irradiation with research on the post-irradiation recovery phase would potentially provide a better understanding of mechanisms underlying the extreme radioresistance in D. radiodurans.

Abstract Background and aims The therapeutic efficacy of single-dose mesenchymal stromal cell (MSC) therapy for heart failure (HF) remains inconsistent. This study aimed to investigate whether infusion with two-dose human umbilical cord MSC (hUCMSCs) could be therapeutically superior to single-dose therapy in a rat model of dilated cardiomyopathy (DCM) and explored the underlying mechanisms. Methods Male Sprague–Dawley rats were intraperitoneally injected with doxorubicin (DOX) to establish a DCM model and randomized to intravenously receive single-dose or two-dose hUCMSCs at an interval of 14 days. Their left ventricular (LV) systolic and diastolic functions were analyzed by echocardiography. The percentages of Th1, Th2, Th17, and Treg cells in the heart, spleen, lymph nodes, and peripheral blood and the levels of serum cytokines in individual rats were analyzed by flow cytometry and cytometric bead assay, respectively. The degrees of cardiac fibrosis and cardiomyocyte apoptosis were examined by histology. The importance of indoleamine 2,3-dioxygenase (IDO), an activator of Treg differentiation, in the therapeutic effect of hUCMSCs on inflammation and heart function of rats was determined after induction of IDO over-expression (IDO-OE) using IFN-γ (1 ng/ml) and TNF-α (10 ng/ml) stimulation or silencing (IDO-KD) using small interfering RNA (siRNA) technology. Results Compared with the single dose, two-dose hUCMSCs were more effective in improving LV performance, attenuating cardiac dilation, reducing cardiomyocyte apoptosis and cardiac fibrosis. Two-dose hUCMSC therapy significantly increased Treg number in the heart and peripheral blood, accompanied by increased cardiac IDO expression. Compared with the control hUCMSCs, IDO-OE hUCMSCs significantly enhanced Treg and Th2 cell responses and decreased systemic Th17 cell responses and Th1 cell numbers in the mediastinal lymph nodes. Treatment with IDO-OE hUCMSCs significantly improved LV remodeling and dysfunction. However, treatment with IDO-KD hUCMSCs had opposite effects in rats. Conclusions Administration of two-dose hUCMSCs has better therapeutic effects than single-dose therapy for inhibiting myocardial inflammation to improve LV function in DCM rats. These effects are associated with upregulating IDO expression and its systemic anti-inflammatory activities.

Abstract Aldolase A (ALDOA) is an enzyme that plays an important role in glycolysis and gluconeogenesis, which is closely related to tumor metabolism. In this study, the overall roles of ALDOA in pan-cancer have been investigated from several aspects using databases and online analysis tools. Using the ONCOMINE database, the expression of ALDOA in various cancers was analyzed. The prognostic role of ALDOA was explored by PrognoScan, GEPIA, and Kaplan–Meier Plotter. The immune-related role of ALDOA and its downstream substrates was decided by TIMER, cBioPortal and String. Our data indicate that ALDOA expression level in lung adenocarcinoma, liver hepatocellular carcinoma, head and neck squamous cell carcinoma is higher than that in normal tissues. Increased expression of ALDOA often indicates a poor prognosis for patients. The correlation between ALDOA and immune infiltration among different tumors is very different. We also investigate the relationship between ALDOA and its upstream/downstream proteins. Our results showed that ALDOA could be used as a biomarker for the tumor prognosis, and could be correlated with the infiltrating levels of macrophages, CD4+ T cells and CD8+ T cells.

Hereditary cholestatic liver disease caused by a class of autosomal gene mutations results in jaundice, which involves the abnormality of the synthesis, secretion, and other disorders of bile acids metabolism. Due to the existence of a variety of gene mutations, the clinical manifestations of children are also diverse. There is no unified standard for diagnosis and single detection method, which seriously hinders the development of clinical treatment. Therefore, the mutated genes of hereditary intrahepatic cholestasis were systematically described in this review.

ObjectiveInfantile hemangioma (IH), the most common infantile vascular neoplasm, is uniquely characterized by rapid proliferation followed by slow spontaneous involution lasting for years. In IH lesions, perivascular cells are the most dynamic cell subset during the transition from the proliferation phase to the involution phase, and we aimed to systematically study this kind of cell.Methods and resultsCD146-selective microbeads were used to isolate IH-derived mural-like cells (HemMCs). Mesenchymal markers of HemMCs were detected by flow cytometry, and the multilineage differentiation potential of HemMCs was detected by specific staining after conditioned culture. CD146-selected nonendothelial cells from IH samples showed characteristics of mesenchymal stem cells with distinct angiogenesis-promoting effects detected by transcriptome sequencing. HemMCs spontaneously differentiated into adipocytes 2 weeks after implantation into immunodeficient mice, and almost all HemMCs had differentiated into adipocytes within 4 weeks. HemMCs could not be induced to differentiate into endothelial cells in vitro. However, 2 weeks after implantation in vivo, HemMCs in combination with human umbilical vein endothelial cells (HUVECs) formed GLUT1+ IH-like blood vessels, which spontaneously involuted into adipose tissue 4 weeks after implantation.ConclusionsIn conclusion, we identified a specific cell subset that not only showed behavior consistent with the evolution of IH but also recapitulated the unique course of IH. Thus, we speculate that proangiogenic HemMCs may be a potential target for the construction of hemangioma animal models and the study of IH pathogenesis.

Summary: Stroke is a leading cause of adult disability worldwide, and better drugs are needed to promote functional recovery after stroke. Growing evidence suggests the critical role of network excitability during the repair phase for stroke recovery. Here, we show that β-hydroxybutyrate (β-HB), an essential ketone body (KB) component, is positively correlated with improved outcomes in patients with stroke and promotes functional recovery in rodents with stroke during the repair phase. These beneficial effects of β-HB depend on HDAC2/HDAC3-GABA transporter 1 (GAT-1) signaling-mediated enhancement of excitability and phasic GABA inhibition in the peri-infarct cortex and structural and functional plasticity in the ipsilateral cortex, the contralateral cortex, and the corticospinal tract. Together with available clinical approaches to elevate KB levels, our results offer a clinically translatable means to promote stroke recovery. Furthermore, GAT-1 can serve as a pharmacological target for developing drugs to promote functional recovery after stroke.

To investigate the flavor characteristics of peanuts grown in Jiangsu, China, ten local varieties were selected. The amino acids, 5′-nucleotides and volatile substances were detected, and the flavor and odor characteristics of these varieties were estimated using an electronic tongue and nose. The results showed that the fat and protein contents of ten peanut varieties changed significantly (p < 0.05), and may have been negatively correlated with those of the Taihua 6 variety—in particular, having the highest protein content and the lowest fat content. The amino acid contents of the peanuts were 20.08 g/100 g (Taihua 4)–27.18 g/100 g (Taihua 6). Taihua 6 also contained the highest bitter (10.41 g/100 g) and sweet (6.06 g/100 g) amino acids, and Taihua 10 had the highest monosodium glutamate-like amino acids (7.61 g/100 g). The content of 5′-nucleotides ranged from 0.08 mg/g (Taihua 9725) to 0.14 mg/g (Taihua 0122–601). Additionally, 5′-cytidylate monophosphate (5′-CMP) and 5′-adenosine monophosphate (5′-AMP) were the major 5′-nucleotides detected in the peanuts. A total of 42 kinds of volatile flavor compounds were detected, with both Taihua 4 and 6 showing the most (18 kinds) and the highest content being in Taihua 4 (7.46%). Both Taihua 9725 and 9922 exhibited the fewest kinds (nine kinds) of volatile components, and the lowest content was in Taihua 9725 (3.15%). Formic acid hexyl ester was the most abundant volatile substance in peanuts, and the highest level (3.63%) was detected in Taihua 7506. The electronic tongue and nose indicated that the greatest taste difference among the ten varieties of peanuts was mainly related to sourness, and Taihua 4 and Taihua 9922 had special taste characteristics. On the other hand, the greatest smell difference among the ten varieties of peanuts was mostly for methane and sulfur organic substances, and Taihua 0605-2 had a special and strong smell characteristic. In conclusion, the content and composition differences of the flavor substances of ten peanut varieties were responsible for their divergences in taste and smell. These results will provide guidelines for the further use (freshly consumed or processed) of these ten peanut varieties.

We assessed the effectiveness of land optimization for controlling non-point source (NPS) pollution by combining a multi-objective dynamic planning approach with the application of the Land Use and its Effects at Small regional extents model and the Soil and Water Assessment Tool. The combined modeling approach showed substantial ability to reduce NPS pollution in Shitoukoumen Reservoir, Changchun City, China, reducing the annual total loads of nitrogen and phosphorus in the study area by 8.7 and 10.12%, respectively. The total nitrogen load decreased significantly and stabilized at less than 8 kg/hm2 from a peak level of over 15 kg/hm2. Higher total phosphorus loads before land use optimization were concentrated in the central parts of the study area, with the highest values exceeding 2.3 kg/hm2, and tended to spread outward but resolved at 1.5 kg/hm2 after optimization. The results showed that from a macro-perspective, optimization of the spatial distribution and quantitative composition of land use can effectively control NPS pollution. The study also demonstrates the potential effectiveness of the coupled multi-model methodology for mitigating NPS in the future.