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Abstract Background Morphometric analysis of the psoas major muscle has shown utility in predicting postoperative morbidity in various surgical fields, but its usefulness in predicting complications in elderly patients undergoing multilevel lumbar fusion surgery has not been studied. The study aimed to investigate if psoas major parameters are independent risk factors of early postoperative complication among elderly patients. Methods Patients who underwent multilevel lumbar fusion for degenerative lumbar spinal stenosis (DLSS) were included. The psoas major was measured at the lumbar 3/4 intervertebral disc level in three ways on computed tomography image: psoas muscle mass index, mean muscle attenuation, and morphologic change of the psoas major. Early complications were graded using the Clavien-Dindo classification system and the Comprehensive complication index (CCI). A CCI ≥ 26.2 indicated severe complications. Logistic regression was performed to identify independent risk factors. Results This retrospective study reviewed 108 patients (mean age 70.9 years, female to male ratio 1.8:1). Complications were observed in 72.2% of patients, with allogeneic blood transfusion being the most frequent (66.7%), followed by wound infection, acute heart failure (2.8% each). Severe complications occurred in 13.9% of patients. After multivariable regression analysis, those in the lowest psoas muscle attenuation tertile had higher odds of experiencing early postoperative complications (OR: 3.327, 95% CI 1.134–9.763, p = 0.029) and severe complications (OR: 6.964, 95% CI 1.928–25.160, p = 0.003). Conclusion The psoas muscle attenuation can be used as a predictor of early postoperative complications in elderly patients undergoing multilevel lumbar fusion surgery for DLSS.

Abstract Mutations in the Cockayne Syndrome group B (CSB) gene cause cancer in mice, but premature aging and severe neurodevelopmental defects in humans. CSB, a member of the SWI/SNF family of chromatin remodelers, plays diverse roles in regulating gene expression and transcription-coupled nucleotide excision repair (TC-NER); however, these functions do not explain the distinct phenotypic differences observed between CSB-deficient mice and humans. During investigating Cockayne Syndrome-associated genome instability, we uncover an intrinsic mechanism that involves elongating RNA polymerase II (RNAPII) undergoing transient pauses at internal T-runs where CSB is required to propel RNAPII forward. Consequently, CSB deficiency retards RNAPII elongation in these regions, and when coupled with G-rich sequences upstream, exacerbates genome instability by promoting R-loop formation. These R-loop prone motifs are notably abundant in relatively long genes related to neuronal functions in the human genome, but less prevalent in the mouse genome. These findings provide mechanistic insights into differential impacts of CSB deficiency on mice versus humans and suggest that the manifestation of the Cockayne Syndrome phenotype in humans results from the progressive evolution of mammalian genomes.

Abstract RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.

Abstract Stress granules (SGs) are induced by various environmental stressors, resulting in their compositional and functional heterogeneity. SGs play a crucial role in the antiviral process, owing to their potent translational repressive effects and ability to trigger signal transduction; however, it is poorly understood how these antiviral SGs differ from SGs induced by other environmental stressors. Here we identify that TRIM25, a known driver of the ubiquitination-dependent antiviral innate immune response, is a potent and critical marker of the antiviral SGs. TRIM25 undergoes liquid-liquid phase separation (LLPS) and co-condenses with the SG core protein G3BP1 in a dsRNA-dependent manner. The co-condensation of TRIM25 and G3BP1 results in a significant enhancement of TRIM25’s ubiquitination activity towards multiple antiviral proteins, which are mainly located in SGs. This co-condensation is critical in activating the RIG-I signaling pathway, thus restraining RNA virus infection. Our studies provide a conceptual framework for better understanding the heterogeneity of stress granule components and their response to distinct environmental stressors.

Abstract Membrane proteins are critical mediators for tumor progression and present enormous therapeutic potentials. Although gene profiling can identify their cancer-specific signatures, systematic correlations between protein functions and tumor-related mechanisms are still unclear. We present here the CrMP-Sol database ( https://bio-gateway.aigene.org.cn/g/CrMP ), which aims to breach the gap between the two. Machine learning was used to extract key functional descriptions for protein visualization in the 3D-space, where spatial distributions provide function-based predictive connections between proteins and cancer types. CrMP-Sol also presents QTY-enabled water-soluble designs to facilitate native membrane protein studies despite natural hydrophobicity. Five examples with varying transmembrane helices in different categories were used to demonstrate the feasibility. Native and redesigned proteins exhibited highly similar characteristics, predicted structures and binding pockets, and slightly different docking poses against known ligands, although task-specific designs are still required for proteins more susceptible to internal hydrogen bond formations. The database can accelerate therapeutic developments and biotechnological applications of cancer-related membrane proteins.

Summary: Neurodegeneration, characterized by the progressive deterioration in neuronal structure or function, presents an elusive mechanism. The use of single-cell RNA sequencing (scRNA-seq) technology in the clinic is becoming increasingly prevalent in recent decades. This technology offers unparalleled cell-level insights into neurodegenerative diseases, establishing itself as a potent tool for elucidating these diseases underlying mechanisms. Here, we made a deep investigation for scRNA-seq research in neurodegenerative diseases using bibliometric analysis from 2009 to 2022. We observed a robust upward trajectory in the number of publications on this subject. The United States stood out as the principal contributor to this expanding field. Specifically, the University of California System exhibited notable research prowess in this field. Alzheimer disease and Parkinson disease were the diseases most frequently investigated. Key research hotspots include the creation of a molecular brain atlas and identification of vulnerable neuronal subpopulations and potential therapeutic targets at the transcriptomic level.

Abstract Objective This study was performed to quantify the morphological characteristics of the psoas major muscle in patients with symptomatic multilevel degenerative lumbar spinal stenosis (SMLSS) and assess the correlations of these morphological characteristics with function and clinical symptoms. Methods One hundred fourteen patients diagnosed with SMLSS (≥ 3 segments) were included. The patients’ presenting symptoms were assessed with the Oswestry Disability Index (ODI), and visual analogue scale (VAS) scores were recorded. The morphology of the psoas major was evaluated at the L3/4 intervertebral disc level in three ways: by measuring (i) the psoas muscle mass index (PMI); (ii) the mean muscle attenuation (Hounsfield units, HU); and (iii) the morphologic change of the psoas major (mean ratios of the short axis to the long axis of the bilateral psoas major). Results Men had a higher PMI than women (p = 0.001). Patients with severe disability had a significantly lower PMI (p = 0.002) and muscle attenuation (p = 0.001). The PMI and muscle attenuation were significantly higher in the patients with no or mild back pain (both p

Abstract Many factors may trigger intervertebral disc (IVD) structural failure (intervertebral disc degeneration (IDD) and endplate changes), including inflammation, infection, dysbiosis, and the downstream effects of chemical factors. Of these, microbial diversity in the IVD and elsewhere in the body has been considered as one of the potential reasons for disc structural failure. The exact relationships between microbial colonization and IVD structural failure are not well understood. This meta‐analysis aimed to investigate the impact of microbial colonization and its location (such as skin, IVD, muscle, soft tissues, and blood) on IVD structural failure and corresponding low back pain (LBP) if any. We searched four online databases for potential studies. The potential relationships between microbial colonization in different sample sources (such as skin, IVD, muscle, soft tissues, and blood) and IDD and endplate change were considered as primary outcomes. Odds ratio (OR) and 95% confidence intervals (CI) for direct comparisons were reported. Grading of Recommendations Assessment, Development and Evaluation (GRADE) scale was used to assess the quality of evidence. Twenty‐five cohort studies met the selection criteria. Overall pooled prevalence of microbial colonization in 2419 patients with LBP was 33.2% (23.6%–43.6%). The pooled prevalence of microbial colonization in 2901 samples was 29.6% (21.0%–38.9%). Compared with the patients without endplate change, the patients with endplate changes had higher rates of microbial colonization of disc (OR = 2.83; 95% CI = 1.93–4.14; I2 = 37.6%; p = 0.108). The primary pathogen was Cutibacterium acnes which was present in 22.2% of cases (95% CI = 13.3%–32.5%; I2 = 96.6%; p = 0.000). This meta‐analysis and systematic review found low‐quality grade evidence for an association between microbial colonization of disc with endplate changes. The primary pathogen was C. acnes. Due to lack of enough high‐quality studies and methodological limitations of this review, further studies are required to improve our understanding of the potential relationships and mechanisms of microbiota, dysbiosis, IVD colonization and IVD structural failure.

Abstract Background To achieve the proper sagittal alignment, previous studies have developed different assessment systems for adult degenerative scoliosis (ADS) which could help the spine surgeon in making treatment strategies. The purpose of our study is to evaluate whether Roussouly classification or global alignment and proportion (GAP) score is more appropriate in the prediction of mechanical complications after surgical treatment of ADS. Methods ADS patients who received long segmental fusion in the treatment during the period from December 2016 to December 2018 were evaluated in this study. Basic information and radiologic measurements were collected for analysis. Patients were divided into two groups according to occurrence or absence of mechanical complications for comparison. Mechanical complications included proximal junctional kyphosis (PJK), proximal junctional failure (PJF). GAP categories divided GAP score into proportioned spinopelvic position, moderately disproportioned position, and severely disproportioned position according to the cut-off values. The correlation between evaluation systems and mechanical complications was analyzed through a logistic regression model via stepwise backward elimination based on the Wald statistics. Receiver operator characteristic (ROC) curve was used to determine the predictability of the evaluation systems in the occurrence of mechanical complications and calculate their cut-off value. Area under the curve (AUC) was used to evaluate the validity of the thresholds. Results A total of 80 patients were included in this study. There were 41 patients in mechanical complication group and 39 patients in no mechanical complication group. GAP score (P = 0.008) and GAP categories (P = 0.007) were positively correlated with mechanical complications; Roussouly score was negatively correlated with mechanical complications (P = 0.034); GAP score was positively correlated with PJK (P = 0.021); Roussouly score was negatively correlated with implant-related complications (P = 0.018); GAP categories were correlated with implant loosening (P = 0.023). Results of ROC showed that GAP score was more effective in predicting PJK (AUC = 0.863) and PJF (AUC = 0.724) than Roussouly score; GAP categories (AUC = 0.561) was more effective than GAP score (AUC = 0.555) in predicting implant-related complications. Conclusions Roussouly classification could only be a rough estimate of optimal spinopelvic alignment. Quantitative parameters in GAP score made it more effective in predicting mechanical complications, PJK and PJF than Roussouly classification.

Biotin is an essential enzyme cofactor and two pathways for the generation of the biotin precursor pimeloyl-ACP are known. Here, the authors identify and characterize a third pathway for biotin precursor synthesis involving BioZ and they also present the Agrobacterium tumefaciens BioZ crystal structure.

Abstract Background Degenerative disorders of the lumbar spine decrease the mobility and quality of life of elderly patients. Lumbar fusion surgery is the primary method of treating degenerative lumbar spine disorders; however, the surgical stress response associated with major surgery has been linked to pathophysiological changes in the elderly, resulting in undesirable postoperative morbidity, complications, pain, fatigue, and extended convalescence. In the present study, we aimed to determine whether enhanced recovery after surgery significantly improved satisfaction and outcomes in elderly patients (> 65 years old) with short-level lumbar fusion. Methods The study enrolled lumbar disc herniation or lumbar spinal stenosis patients if they were over the age of 65 years old underwent lumbar fusion at one or two levels. Data including demographic, comorbidity, and surgical information were collected from electronic medical records. Enhanced recovery after surgery interventions was categorized as preoperative, intraoperative, and postoperative. We also evaluated primary outcome, surgical complication, length of stay, postoperative pain scores, and 30-day readmission rates. Results A total of 192 patients were included, 96 in the enhanced recovery after surgery group and 96 case-matched patients in the non- enhanced recovery after surgery group. There were no statistically significant intergroup differences in regards to demographics, comorbidities, American Society of Anaesthesiologists grade, or the number of fusion levels. There were also no differences between mean surgery time of intraoperative blood loss between the enhanced recovery after surgery and non- enhanced recovery after surgery groups. In addition, the mean preoperative Japanese Orthopaedic Association score, visual analog score for the back and legs, and Oswestry Disability Index score were not significantly different between the two groups. Overall, enhanced recovery after surgery pathway compliance was 92.1%. There were no significant differences in the number of complications or the mortality rates between the enhanced recovery after surgery and non-enhanced recovery after surgery groups. Furthermore, the mean postoperative Japanese Orthopaedic Association score, Visual analog score for the back and legs, Oswestry Disability Index score, and readmission rates score revealed no significant differences between the groups at 30-day follow-up point. However, we observed a statistically significant decrease in length of stay in the enhanced recovery after surgery group (12.30 ± 3.03 of enhanced recovery after surgery group versus 15.50 ± 1.88 in non- enhanced recovery after surgery group, p = 0). Multivariable linear regression showed that comorbidities (p = 0.023) and implementation of enhanced recovery after surgery program (p = 0.002) were correlated with prolonged length of stay. Multivariable logistic regression showed that no characteristics were associated with complications. Conclusions This report describes the first enhanced recovery after surgery protocol used in elderly patients after short-level lumbar fusion surgery. Our enhanced recovery after surgery program is safe and could help decrease length of stay in elderly patients with short-level lumbar fusion.

Summary: Biotin is an indispensable cofactor in the three domains of life. The unusual virulence factor BioJ of Francisella catalyzes the formation of pimeloyl-ACP, an intermediate in biotin synthesis. Here, we report the 1.58 Å crystal structure of BioJ, the enzymatic activity of which is determined with the in vitro reconstituted reaction and biotin bioassay in vivo. Unlike the paradigm BioH, BioJ displays an atypical α/β-hydrolase fold. A structurally conserved catalytic triad (S151, D248, and H278) of BioJ is functionally defined. A proposed model for BioJ catalysis involves two basic residues-rich cavities, of which cavity-1, rather than cavity-2, binds to the ACP moiety of its physiological substrate, pimeloyl-ACP methyl ester. In summary, this finding provides molecular insights into the BioJ gatekeeper of biotin synthesis. : Biological Sciences; Microbiology; Structural Biology Subject Areas: Biological Sciences, Microbiology, Structural Biology

As an informative electroencephalogram (EEG) signal, steady-state visual evoked potential (SSVEP) stands out from many paradigms for application in wireless wearable devices. However, its data are usually enormous, occupy too many bandwidth sources and require immense power when transmitted in the raw data form, so it is necessary to compress the signal. This paper proposes a personalized EEG compression and reconstruction algorithm for the SSVEP application. In the algorithm, to realize personalization, a primary artificial neural network (ANN) model is first pre-trained with the open benchmark database towards BCI application (BETA). Then, an adaptive ANN model is generated with incremental learning for each subject to compress their individual data. Additionally, a personalized, non-uniform quantization method is proposed to reduce the errors caused by compression. The recognition accuracy only decreases by 3.79% when the compression rate is 12.7 times, and is tested on BETA. The proposed algorithm can reduce signal loss by from 50.43% to 81.08% in the accuracy test compared to the case without ANN and uniform quantization.

Heart sounds play an important role in the initial screening of heart diseases. However, the accurate diagnosis with heart sound signals requires doctors to have many years of clinical experience and relevant professional knowledge. In this study, we proposed an end-to-end lightweight neural network model that does not require heart sound segmentation and has very few parameters. We segmented the original heart sound signal and performed a short-time Fourier transform (STFT) to obtain the frequency domain features. These features were sent to the improved two-dimensional convolutional neural network (CNN) model for features learning and classification. Considering the imbalance of positive and negative samples, we introduced FocalLoss as the loss function, verified our network model with multiple random verifications, and, hence, obtained a better classification result. Our main purpose is to design a lightweight network structure that is easy for hardware implementation. Compared with the results of the latest literature, our model only uses 4.29 K parameters, which is 1/10 of the size of the state-of-the-art work.

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced Apoe-/- mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages. [ABSTRACT FROM AUTHOR]

Pontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, a subunit of the FAM91A1 complex, have been found in patients with PCH-like symptoms; however, definitive evidence that the mutations are causal is still lacking. Here, we show that depletion of FAM91A1 results in developmental defects in zebrafish similar to that of TBC1D23, an established PCH gene. FAM91A1 and TBC1D23 directly interact with each other and cooperate to regulate endosome-to-Golgi trafficking of KIAA0319L, a protein known to regulate axonal growth. Crystal structure of the FAM91A1-TBC1D23 complex reveals that TBC1D23 binds to a conserved surface on FAM91A1 by assuming a Z-shaped conformation. More importantly, the interaction between FAM91A1 and TBC1D23 can be used to predict the risk of certain TBC1D23-associated mutations to PCH. Collectively, our study provides a molecular basis for the interaction between TBC1D23 and FAM91A1 and suggests that disrupted endosomal trafficking underlies multiple PCH subtypes. [ABSTRACT FROM AUTHOR]

The wastewater produced during tertiary oil recovery often contains a large amount of hydrolyzed polyacrylamide (HPAM), which is difficult to treat using conventional biological methods because of its high molecular weight and viscosity. Electrochemical methods are considered to be effective for the treatment of refractory wastewater. In this study, the electrochemical degradation of HPAM using several anode materials was investigated. The results show that the highest HPAM removal efficiency was obtained when iron was used as the anode. The effects of the reaction time, voltage, current density, electrode distance, initial pH, and temperature on the efficiency of HPAM removal were investigated using single-factor experiments, and the HPAM removal rate was found to depend most strongly on the reaction time, voltage, and initial pH. Based on these results, Box–Behnken design was used to optimize the electrochemical treatment of HPAM, and the optimal conditions for HPAM removal were determined to be the following: voltage = 7.6 V, pH = 4.7, and reaction time = 10.5 min. The optimal conditions were tested experimentally, and the HPAM removal efficiency was found to be 98.4%, which fell within the 95% confidence interval of the model results. Analysis of the degradation mechanism showed that HPAM removal occurred mainly via electro-coagulation, with a contribution rate of 83%, together with electro-oxidation, and that the degradation intermediates included ammonia and ethers. Therefore, this electrochemical technique is effective for treatment of wastewater containing HPAM. [ABSTRACT FROM AUTHOR]

Demyelination in the central nervous system (CNS) underlies many human diseases, including multiple sclerosis (MS). We report here the findings of our study of the CNS demyelination process using immune-induced [experimental autoimmune encephalomyelitis (EAE)] and chemical-induced [cuprizone (CPZ)] mouse models of demyelination. We found that necroptosis, a receptor-interacting protein 3 (RIP3) kinase and its substrate mixed lineage kinase domainlike protein (MLKL)-dependent cell death program, played no role in the demyelination process, whereas the MLKL-dependent, RIP3-independent function of MLKL in the demyelination process initially discovered in the peripheral nervous system in response to nerve injury, also functions in demyelination in the CNS in these models. Moreover, a receptor-interacting protein 1 (RIP1) kinase inhibitor, RIPA-56, blocked disease progression in the EAE-induced model but showed no effect in the CPZ-induced model. It does so most likely at a step of monocyte elevation downstream of T cell activation and myelin-specific antibody generation, although upstream of breakdown of the blood-brain barrier. RIP1-kinase dead knock-in mice shared a similar result as mice treated with the RIP1 inhibitor. These results indicate that RIP1 kinase inhibitor is a potential therapeutic agent for immune-mediated demyelination diseases that works by prevention of monocyte elevation, a function previously unknown for RIP1 kinase. [ABSTRACT FROM AUTHOR]

The large conductance Ca2+-activated potassium (BKCa) channel is activated by stretch. The stress-regulated exon (STREX) in α-subunits is known to affect the mechanosensitivity of BKCa channels. However, in human colonic smooth muscle cells (HCoSMCs), we found that the α-subunits without STREX (ZERO-BK) and β¹-subunits could be detected yet the cells were mechanosensitive. Whether the β¹-subunit is involved in the regulation of BKCa mechanosensitivity is unclear. In the present study, ZERO-BK and β¹-subunits were individually expressed or coexpressed in HEK293 cells and cell-attached patch-clamp techniques were used to measure BKCa currents defining mechanosensitivity. Single-channel patch-clamp recordings from HEK293 cells cotransfected with ZERO-BK and β¹-subunits showed stretch sensitivity, but there was no mechanosensitivity in HEK293 cells transfected only with ZERO-BK. We also showed that expression of the β¹-subunit could increase mechanosensitivity of the STREX-type α-subunits (STREX-BK). To identify the domain in β¹-subunits responsible for affecting stretch sensitivity, we expressed β¹-LoopDel (chimeric β¹-subunits without the extracellular loop) or β¹-C TermDel (chimeric β¹-subunits without COOH terminus) with ZERO-BK in HEK293 cells. The data showed that deletion of the extracellular loop but not the COOH terminus of β¹-subunits virtually abolished the mechanosensitivity. These results suggest that the extracellular loop of the β¹-subunit is involved in the regulation of BKCa channel mechanosensitivity and that role is independent of STREX. [ABSTRACT FROM AUTHOR]