Mixed Lineage Kinase Domain-like Protein MLKL Breaks Down Myelin following Nerve Injury.

Successful regeneration of severed peripheral nerves requires the breakdown and subsequent clearance of myelin, tightly packed membrane sheaths of Schwann cells that protect nerve fibers and harbor nerve growth-inhibitory proteins. How Schwann cells initiate myelin breakdown in response to injury is still largely unknown. Here we report that, following sciatic nerve injury, MLKL, a pseudokinase known to rupture cell membranes during necroptotic cell death, is induced and targets the myelin sheath membrane of Schwann cells to promote myelin breakdown. The function of MLKL in disrupting myelin sheaths requires injury-induced phosphorylation of serine 441, an activation signal distinct from the necroptosis-inducing phosphorylation by RIP3 kinase. Mice with Mlkl specifically knocked out in Schwann cells showed delayed myelin sheath breakdown. Lack of MLKL reduced nerve regeneration following injury, whereas overexpression of MLKL accelerated myelin breakdown and promoted the regeneration of axons.

A phage nucleus-associated RNA-binding protein is required for jumbo phage infection.

Large-genome bacteriophages (jumbo phages) of the proposed family Chimalliviridae assemble a nucleus-like compartment bounded by a protein shell that protects the replicating phage genome from host-encoded restriction enzymes and DNA-targeting CRISPR-Cas nucleases. While the nuclear shell provides broad protection against host nucleases, it necessitates transport of mRNA out of the nucleus-like compartment for translation by host ribosomes, and transport of specific proteins into the nucleus-like compartment to support DNA replication and mRNA transcription. Here, we identify a conserved phage nuclear shell-associated protein that we term Chimallin C (ChmC), which adopts a nucleic acid-binding fold, binds RNA with high affinity in vitro, and binds phage mRNAs in infected cells. ChmC also forms phase-separated condensates with RNA in vitro. Targeted knockdown of ChmC using mRNA-targeting dCas13d results in accumulation of phage-encoded mRNAs in the phage nucleus, reduces phage protein production, and compromises virion assembly. Taken together, our data show that the conserved ChmC protein plays crucial roles in the viral life cycle, potentially by facilitating phage mRNA translocation through the nuclear shell to promote protein production and virion development.

FAM91A1-TBC1D23 complex structure reveals human genetic variations susceptible for PCH.

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.

Development and external validation of a predictive model for prolonged length of hospital stay in elderly patients undergoing lumbar fusion surgery: comparison of three predictive models.

PURPOSE: This study aimed to develop a predictive model for prolonged length of hospital stay (pLOS) in elderly patients undergoing lumbar fusion surgery, utilizing multivariate logistic regression, single classification and regression tree (hereafter, "classification tree") and random forest machine-learning algorithms. METHODS: This study was a retrospective review of a prospective Geriatric Lumbar Disease Database. The primary outcome measure was pLOS, which was defined as the LOS greater than the 75th percentile. All patients were grouped as pLOS group and non-pLOS. Three models (including logistic regression, single-classification tree and random forest algorithms) for predicting pLOS were developed using training dataset and internal validation using testing dataset. Finally, online tool based on our model was developed to assess its validity in the clinical setting (external validation). RESULTS: The development set included 1025 patients (mean [SD] age, 72.8 [5.6] years; 632 [61.7%] female), and the external validation set included 175 patients (73.2 [5.9] years; 97[55.4%] female). Multivariate logistic analyses revealed that older age (odds ratio [OR] 1.06, p < 0.001), higher BMI (OR 1.08, p = 0.002), number of fused segments (OR 1.41, p < 0.001), longer operative time (OR 1.02, p < 0.001), and diabetes (OR 1.05, p = 0.046) were independent risk factors for pLOS in elderly patients undergoing lumbar fusion surgery. The single-classification tree revealed that operative time ≥ 232 min, delayed ambulation, and BMI ≥ 30 kg/m2 as particularly influential predictors for pLOS. A random forest model was developed using the remaining 14 variables. Intraoperative EBL, operative time, delayed ambulation, age, number of fused segments, BMI, and RBC count were the most significant variables in the final model. The predictive ability of our three models was comparable, with no significant differences in AUC (0.73 vs. 0.71 vs. 0.70, respectively). The logistic regression model had a higher net benefit for clinical intervention than the other models. The nomogram was developed, and the C-index of external validation for PLOS was 0.69 (95% CI, 0.65-0.76). CONCLUSION: This investigation produced three predictive models for pLOS in elderly patients undergoing lumbar fusion surgery. The predictive ability of our three models was comparable. Logistic regression model had a higher net benefit for clinical intervention than the other models. Our predictive model could inform physicians about elderly patients with a high risk of pLOS after surgery.

The effectiveness of brief reminiscence-based psychosocial interventions for cancer patients: A systematic review and meta-analysis.

AIM: To determine the effectiveness of brief reminiscence-based psychosocial interventions in alleviating psychological distress in cancer patients. BACKGROUND: Cancer patients suffer tremendous psycho-spiritual pain, which affects their quality of life. Brief reminiscence-based psychosocial interventions have demonstrated positive effects on the mental health of cancer patients; however, the efficacy of these interventions has been inconsistent. DESIGN: A systematic review and meta-analysis. METHODS: This review was conducted and reported in accordance with the PRISMA 2020 checklist provided by the EQUATOR network. The Cochrane Library, Web of Science, PsycINFO, PubMed, Embase, CINAHL and Scopus databases were systematically searched from inception to 27 November 2022 to identify randomised controlled trials (RCTs) published in English. RESULTS: Twenty studies involving 1744 cancer participants were included. The meta-analysis showed statistically significant effects of brief reminiscence-based psychosocial interventions on hope, anxiety and depression at post-intervention. A separate analysis revealed that brief reminiscence-based psychosocial interventions had a sustainable effect on hope, spiritual well-being, anxiety and depression at 1 month after the intervention. However, no statistically significant effect on quality of life was found in our study either immediately after the intervention or at 1 month. CONCLUSIONS: Brief reminiscence-based psychosocial interventions can significantly reduce anxiety and depressive symptoms and improve hope and spiritual well-being in cancer patients. RELEVANCE TO CLINICAL PRACTICE: This study further supports that brief reminiscence-based psychosocial interventions should be incorporated into the routine care of cancer patients to address their psychosocial distress. PATIENT OR PUBLIC CONTRIBUTION: All authors of this article contributed to the study conception and design. All authors of the included studies provided original data for this paper.

CrMP-Sol database: classification, bioinformatic analyses and comparison of cancer-related membrane proteins and their water-soluble variant designs.

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.

RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation.

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 domain-like 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.

A prospective comparative study of the MNA-SF and GNRI nutritional screening tools in predicting infectious complications among elderly patients over 70 years undergoing posterior lumbar arthrodesis.

Malnutrition is a risk factor for postoperative infectious complications of elderly patients undergoing posterior lumbar arthrodesis. At present, there is no gold standard for nutrition screening tools. We analyzed the value of predicting infectious complications among elderly patients over 70 years undergoing posterior lumbar arthrodesis by comparing the MNA-SF and GNRI. Demographic data, anthropometric measurements, serum albumin, surgical data and the occurrence of infectious complications and LOS were collected. Mini Nutritional Assessment short form (MNA-SF), Geriatric Nutritional Risk Index (GNRI) were performed within 24 h before surgery. Multivariable logistic regression analyses were used to identify predictors of infectious complications. The discriminatory performances of GNRI and MNA-SF scores for the occurrence of infectious complications were determined by receiver operating characteristic curves (ROC) analyses and the area under the curve (AUC). The study included 252 patients with a median age of 76.82 ± 6.41 years (range 70-84 years), and 142 patients (56.3%) were female. There were no significant differences in infectious complications (p = 0.236) and LOS (p = 0.580) among different GNRI categories. 27.3% malnourished patients evaluated by the MNA-SF suffered from infectious complications and 10.1% patients at risk of malnourished had infectious complications. Those patients had statistically significant higher prevalence of infectious complications (p = 0.002) and longer LOS (p = 0.023) than well-nourished patients. Multivariable analysis revealed that preoperative malnutrition and at risk of malnourished by the MNA-SF was significantly associated with infections. The area under the curve (AUC) of MNA-SF was 0.754, which was significantly high than AUC of GNRI (0.623) (Delong's test, p = 0.033). This study demonstrated that MNA-SF is a simple and effective tool for predicting the risk of infectious complications in elderly patients undergoing posterior lumbar arthrodesis.

Comparative short-term outcomes of enhanced recovery after surgery (ERAS) program and non-ERAS traditional care in elderly patients undergoing lumbar arthrodesis: a retrospective study.

BACKGROUND: Enhanced recovery after surgery (ERAS) program is an evidence-based improvement over non-ERAS traditional care. The aim of the present study was to analyze the safety, feasibility, and efficacy of an ERAS program in patients over 70 years undergoing lumbar arthrodesis by comparison with non-ERAS traditional care. METHODS: During January 2018 to December 2018, patients enrolled received non-ERAS traditional care, while the ERAS program was implemented from January to December 2019. Demographic characteristics, comorbidities, surgical data and postoperative recovery parameters were collected from all patients. Postoperative pain scores were evaluated by visual analog scales (VAS). The clinical outcomes were length of stay (LOS), postoperative complications and postoperative pain scores. Compliance results were also collected. RESULT: A total of 127 patients were enrolled, including 67 patients in the non-ERAS traditional care group and 60 patients in the ERAS group. The demographic characteristics and comorbidities of the two groups showed no significant differences. The LOS of patients treated with ERAS program (13.6 ± 4.0 days) was significantly less than that of patients treated with non-ERAS traditional care (15.6 ± 3.9 days) (p = 0.034). Complication rate was 8.3% in the ERAS group versus 20.9% in the non-ERAS traditional care group (p = 0.048). VAS (back) in the ERAS group was significantly lower on postoperative day (POD) 1 and POD2. Postoperative recovery parameters were improved in the ERAS group. The overall compliance with the ERAS program was 94%. CONCLUSIONS: Based on our results, ERAS program is safer and more effective for elderly patients over 70 undergoing lumbar arthrodesis than non-ERAS traditional care.

The radiographic characteristics and developmental mechanism of the lumbar degenerative retrolisthesis under a high-grade PI.

BACKGROUND: When talking about backward displacement of the vertebra, it generally refers to the retrolisthesis under low pelvic incidence (PI). It is worth to mention that lumbar retrolisthesis could also occur under a high-grade PI. Little knowledge was known about the radiographic characteristics and developmental mechanism of the retrolisthesis under high PI. This study was designed to describe the radiographic features and to explore the developmental mechanism of this type of backward vertebral displacement. METHODS: A total of 887 consecutive subjects from our database were retrospectively reviewed. Degenerative lumbar retrolisthesis was found in 78 patients, including 54 patients with a relative low-grade PI (Group L) and 24 patients with a relative high-grade PI (Group H). 60 subjects without lumbar spondylolisthesis were randomly selected as the control group. Clinical and radiologic data were collected and compared between different groups. RESULTS: 91.4% of patients in Group H had the type 4 sagittal construction in terms of Roussouly classification, while 92.6% of patients in Group L had the type 1 sagittal construction. The distribution of retrolisthesis was found about two vertebrae higher with larger backward slope in Group H than Group L. Compared with the control, patients with retrolisthesis under high PI had significantly greater thoracolumbar kyphosis (TLK), PI, sacral slope, sagittal vertical axis, T1 pelvic angle and severer disc degeneration and facet arthritis. Logistic regression analysis showed TLK was the independent factor predicting the development of retrolisthesis under a high-grade PI. CONCLUSIONS: Retrolisthesis under a high-grade PI and type 4 sagittal construction had higher location and larger backward slope than retrolisthesis under a low-grade PI. Retrolisthesis under high PI might be primarily associated with the increased backward sliding forces at the hypertilted vertebra in large TLK segment and lumbar instability caused by disc degeneration and facet arthritis.

Different acute behaviors of pelvic incidence after long fusion to sacrum between elderly patients with severe and minor sagittal deformity: a retrospective radiographic study on 102 cases.

PURPOSE: To compare the acute behaviors of pelvic incidence (PI) between elderly adult spinal deformity (ASD) patients with severe and minor sagittal deformity based on SRS-Schwab classification and to identify the mechanism of the variability in PI after long fusion to S1. METHODS: Patients aged 60 years or above with available radiographs were included. The following parameters were measured pre- and postoperatively: Thoracic kyphosis, thoracolumbar kyphosis (TLK), lumbar lordosis (LL), PI, pelvic tilt, sacral slope, sagittal vertical axis (SVA), PI-LL and T1 pelvic angle (TPA). RESULTS: Forty-two patients were found with severe sagittal deformity were assigned to Group S, and 60 patients with minor sagittal deformity were assigned to Group M. Immediately after surgery, lumbar curve, TLK and PI-LL were obviously corrected in both groups, while LL, PI, SVA and TPA were significantly increased in Group S alone. PI was significantly increased from 42.6 ± 4.7° to 51.7 ± 6.0° in Group S (P = 0.002), but changed from 45.4 ± 10.2° to 46.3 ± 10.3° in Group M without statistical significance. Pearson correlation analysis showed changes in PI was significantly correlated with changes in SVA (r = 0.415, P = 0.011) in patients with PI increased more than 5°. CONCLUSION: PI spontaneously increases in elderly ASD patients with severe sagittal deformity after long fusion to sacrum, while is relative invariable in those with minor sagittal deformity. Variation in PI could be considered as a secondary change compensating for the spinal sagittal malalignment under long spinal fusion in elderly patients.

The extracellular loop of the auxiliary ß1-subunit is involved in the regulation of BKCa channel mechanosensitivity.

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 ß1-subunits could be detected yet the cells were mechanosensitive. Whether the ß1-subunit is involved in the regulation of BKCa mechanosensitivity is unclear. In the present study, ZERO-BK and ß1-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 ß1-subunits showed stretch sensitivity, but there was no mechanosensitivity in HEK293 cells transfected only with ZERO-BK. We also showed that expression of the ß1-subunit could increase mechanosensitivity of the STREX-type α-subunits (STREX-BK). To identify the domain in ß1-subunits responsible for affecting stretch sensitivity, we expressed ß1- LoopDel (chimeric ß1-subunits without the extracellular loop) or ß1- C TermDel (chimeric ß1-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 ß1-subunits virtually abolished the mechanosensitivity. These results suggest that the extracellular loop of the ß1-subunit is involved in the regulation of BKCa channel mechanosensitivity and that role is independent of STREX.

Psoas muscle index and psoas muscle density are associated with functional status in patients with degenerative lumbar spinal stenosis.

BACKGROUND: The factors affecting lumbar spinal function in patients with degenerative lumbar spinal stenosis (DLSS) are still unclear. OBJECTIVE: This study explored psoas major muscle morphology in patients with DLSS and its association with their functional status. METHODS: A retrospective study was conducted on 288 patients with DLSS and 260 control subjects. Psoas major muscle evaluation included three morphometric parameters at the L3/4 disc level: psoas major index (PMI), muscle attenuation, and psoas major morphological changes (MPM). The association between psoas major morphology and functional status was assessed using the Oswestry disability index (ODI). RESULTS: Both female and male patients with DLSS had a higher PMI and lower muscle attenuation. PMI and muscle attenuation were inversely correlated with age in the DLSS group. After multivariable analyses, the PMI and psoas major muscle attenuation were positively correlated with patients' functional status. CONCLUSION: The PMI and muscle attenuation were positively correlated with functional status in patients with DLSS. These findings have important implications for physiotherapy programs of postoperative rehabilitation and conservative management of DLSS.

Efficacy of using telecare services for community-dwelling people with diabetes: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the glycated hemoglobin (HbA1c), blood pressure, self-efficacy, and quality of life efficacy of using telecare services for community-dwelling people with diabetes. METHODS: Cochrane Library, Web of Science, PsycINFO, PubMed, EMBASE, CINAHL, and Scopus databases were systematically searched from their inception dates to June 22, 2023. Two evaluators independently selected and evaluated eligible studies. A protocol was registered in PROSPERO. RESULTS: An analysis of 17 studies that included 3586 subjects showed that telecare significantly improved the management of patients with diabetes. Compared to controls, intervention care had significant benefits regarding HbA1c (MD = -0.30, 95 % CI = -0.44 - -0.17, 16 studies), systolic blood pressure (MD = -2.45, 95 % CI = -4.53 - -0.36, P = 0.02), self-efficacy (MD = 0.36, 95 % CI = 0.04 - 0.67, P = 0.03) and quality of life (MD = 0.37, 95 % CI = 0.05 - 0.70, P = 0.02). However, diastolic blood pressure (MD = -1.37, 95 % CI = -3.34 - -0.61, P = 0.17) was not found to be significantly affected. CONCLUSIONS: Telecare is effective in improving self-management among community-dwelling people with diabetes, suggesting an effective means for them to achieve self-management.

TRIM25 predominately associates with anti-viral stress granules.

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.

The Role of Pelvic Compensation in Sagittal Balance and Imbalance: The Impact of Pelvic Compensation on Spinal Alignment and Clinical Outcomes Following Adult Spinal Deformity Surgery.

BACKGROUND AND OBJECTIVES: The Scoliosis Research Society (SRS)-Schwab system does not include a pelvic compensation (PC) subtype, potentially contributing to gaps in clinical characteristics and treatment strategy for deformity correction. It also remains uncertain as to whether PC has differing roles in sagittal balance (SB) or imbalance (SI) status. To compare radiological parameters and SRS-22r domains between patients with failed pelvic compensation (FPC) and successful pelvic compensation (SPC) based on preoperative SB and SI. METHODS: A total of 145 adult spinal deformity patients who received deformity correction were analyzed. Radiographic and clinical outcomes were collected for statistical analysis. Patients were classified into 4 groups based on the median value of PT/PI ratio (PTr) and the cutoff value of SB. Patients with low PTr and high PTr were defined as FPC and SPC, respectively. Radiographic and clinical characteristics of different groups were compared. RESULTS: Patients with SPC exhibited significantly greater improvements in lumbar lordosis, pelvic tilt, PTr, and T1 pelvic angle as compared to patients with FPC, irrespective of SB or SI. No apparent differences in any of SRS-22r domains were observed at follow-up when comparing the SB-FPC and SB-SPC patients. However, patients with SI-SPC exhibited significantly better function, self-image, satisfaction, and subtotal domains at follow-up relative to those with SI-FPC. When SI-FPC and SI-SPC patients were subdivided further based on the degree of PI-LL by adjusting for age, the postoperative function and self-image domains were significantly better in the group with overcorrection of PI-LL than undercorrection of PI-LL in SI-FPC patients. However, no differences in these SRS-22r scores were observed when comparing the subgroups in SI-SPC patients. CONCLUSION: Flexible pelvic rotation is associated with benefits to the correction of sagittal parameters, irrespective of preoperative SB or SI status. However, PC is only significantly associated with clinical outcomes under SI. Patients with SI-FPC exhibit poorer postoperative clinical outcomes, which should be recommended to minimize PI-LL.

Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.

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.

Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.

RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fu sed in s arcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic 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.

Correlation of psoas major muscle morphology with function and clinical symptoms in patients with symptomatic multilevel lumbar spinal stenosis.

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 < 0.001). In the univariable and multivariable analyses, a greater HU value was associated with a higher functional status as assessed by the ODI (p = 0.002), and a higher PMI was associated with less severe back pain as measured by the VAS score (p < 0.001). CONCLUSION: This study showed that muscle attenuation of psoas major positively correlated with the functional status and PMI negatively correlated with low back pain severity in patients diagnosed with SMLSS. Future prospective studies are needed to evaluate whether improvement in such muscle parameters through physiotherapy programs can alleviate the clinical symptoms and improve the functional status of patients with SMLSS.

Bibliometric analysis of research on neurodegenerative diseases and single-cell RNA sequencing: Opportunities and challenges.

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.