Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse.

Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (Igf2) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.

Integrated Firefighting Textile with Temperature and Pressure Monitoring for Personal Defense.

Although electronic textiles that can detect external stimuli show great promise for fire rescue, existing firefighting clothing is still scarce for simultaneously integrating reliable early fire warning and real-time motion sensing, hardly providing intelligent personal protection under complex high-temperature conditions. Herein, we introduce an "all-in-one" hierarchically sandwiched fabric (HSF) sensor with a simultaneous temperature and pressure stimulus response for developing intelligent personal protection. A cross-arranged structure design has been proposed to tackle the serious mutual interference challenge during multimode sensing using two separate sets of core-sheath composite yarns and arrayed graphene-coated aerogels. The functional design of the HSF sensor not only possesses wide-range temperature sensing from 25 to 400 °C without pressure disturbance but also enables highly sensitive pressure response with good thermal adaptability (up to 400 °C) and wide pressure detection range (up to 120 kPa). As a proof of concept, we integrate large-scalable HSF sensors onto conventional firefighting clothing for passive/active fire warning and also detecting spatial pressure and temperature distribution when a firefighter is exposed to high-temperature flames, which may provide a useful design strategy for the application of intelligent firefighting protective clothing.

AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.

Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.

The value of computed tomography angiography in predicting the surgical effect and prognosis of severe traumatic brain injury.

It is difficult to predict the surgical effect and outcome of severe traumatic brain injury (TBI) before surgery. This study aims to approve an evaluation method of computed tomography angiography (CTA) to predict the effect of surgery and outcome in severe TBI. Between January 2010 and January 2020, we retrospectively reviewed 358 severe TBI patients who underwent CTA at admission and reexamination. CTA data were evaluated for the presence of cerebrovascular changes, including cerebrovascular shift (CS), cerebral vasospasm (CVS), large artery occlusion (LAO), and deep venous system occlusion (DVSO). Medical records were reviewed for baseline clinical characteristics and the relationship between CTA changes and outcomes. Cerebrovascular changes were identified in 247 (69.0%) of 358 severe TBI patients; only 25 (10.12%) of them had poor outcomes, and 162 (65.6%) patients had a good recovery. Eighty-three (23.18%) patients were diagnosed with CVS, 10 (12.05%) had a good outcome, 57 (68.67%) had severe disability and 16 (19.28%) had a poor outcome. There were twenty-six (7.3%) patients who had LAO and thirty-one (8.7%) patients who had DVSO; no patients had good recovery regardless of whether they had the operation or not. Cerebrovascular injuries and changes are frequent after severe TBI and correlate closely with prognosis. CTA is an important tool in evaluating the severity, predicting the operation effect and prognosis, and guiding therapy for severe TBI. Well-designed, multicenter, randomized controlled trials are needed to evaluate the value of CTA for severe TBI in the future.

Chemogenetic stimulation of intact corticospinal tract during rehabilitative training promotes circuit rewiring and functional recovery after stroke.

BACKGROUND: Neuromodulatory techniques have been proven to enhance functional recovery after stroke in patients and animals, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). However, the success and feasibility of these approaches were often variable, largely due to a lack of target specificity. OBJECTIVE: We explored the effects of specific chemogenetic stimulation of intact corticospinal tract during rehabilitative training on functional recovery after stroke in mice. METHODS: We developed a viral-based intersectional targeting approach that allows specific chemogentic activation of contralateral hindlimb corticospinal neurons (CSNs) in a photothrombotic stroke model. RESULTS: We demonstrated that specific chemogenetic activation of CSNs, when combined with daily rehabilitation training, leads to significant skilled motor functional recovery via promoting corticospinal tract (CST) axons midline crossing sprouting from intact to the denervated spinal hemicord, and rewiring new functional circuits by new synapse formation. Mechanistically, we revealed that combined chemogenetic stimulation of CSNs and daily rehabilitation training significantly enhanced the mTOR activity of CSNs. CONCLUSIONS: Our findings highlight the great potential of specific neural activation protocols in combination with motor training for the recovery of skilled motor functions after stroke.

STAR: A Web Server for Assisting Directed Protein Evolution with Machine Learning.

Protein engineering has made significant contributions to industries such as agriculture, food, and pharmaceuticals. In recent years, directed evolution combined with artificial intelligence has emerged as a cutting-edge R&D approach. However, the application of machine learning techniques can be challenging for those without relevant experience and coding skills. To address this issue, we have developed a web-based protein sequence recommendation system: STAR (Sequence recommendaTion via ARtificial intelligence). Our system utilizes Bayesian optimization as its backbone and includes a filtering step using a regression model to enhance the success rate of recommended sequences. Additionally, we have incorporated an in silico-directed evolution approach to expand the exploration of the protein space. The Web site can be accessed at https://www.FindProteinStar.com/.

Effects of ulinastatin therapy in deep vein thrombosis prevention after brain tumor surgery: A single-center randomized controlled trial.

BACKGROUND: Venous thromboembolism (VTE) is a common neurosurgical complication after brain tumor resection, and its prophylaxis has been widely studied. There are no effective drugs in the clinical management of venous thromboembolism, and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas. AIM: To explore whether ulinastatin (UTI) can prevent VTE after brain tumor resection. METHODS: The present research included patients who underwent brain tumor resection. Patients received UTIs (400,000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were the incidence of VTE, coagulation function, pulmonary emboli, liver function, renal function, and drug-related adverse effects. RESULTS: A total of 405 patients were evaluated between January 2019 and December 2021, and 361 of these were initially enrolled in the study to form intention-to-treat, which was given UTI (n = 180) or placebo (n = 181) treatment in a random manner. There were no statistically significant differences in baseline clinical data between the two groups. The incidence of VTE in the UTI group was remarkably improved compared with that in the placebo group. UTI can improve coagulation dysfunction, pulmonary emboli, liver function, and renal function. No significant difference was identified between the two groups in the side effects of UTI-induced diarrhea, vomiting, hospital stays, or hospitalization costs. The incidence of allergies was higher in the UTI group than in the placebo group. CONCLUSION: The findings from the present research indicated that UTI can decrease the incidence of VTE and clinical outcomes of patients after brain tumor resection and has fewer adverse reactions.

Early use of intravitreal triamcinolone to inhibit traumatic proliferative vitreoretinopathy: a randomised clinical trial.

AIMS: To evaluate the efficacy and safety of intravitreal triamcinolone acetonide (TA) injection at the end of emergency surgery for open globe injury (OGI) to suppress traumatic proliferative vitreoretinopathy (TPVR). METHODS: A single-centre, participant-masked, prospective, randomised controlled clinical trial. A total of 68 globe rupture patients with zone III were randomised to the control group (n=34) or the TA group (n=34) in 1:1 allocation ratio. Patients were treated with 0.1 mL TA in the TA group and 0.1 mL balanced salt solution in the control group at the end of emergency surgery. The primary outcome was the assessment of TPVR during vitrectomy 10±3 days later. Secondary outcomes included visual acuity (VA), retinal attachment rate, macular attachment rate, proliferative vitreoretinopathy (PVR) recurrent rate, side effects 6 months after vitrectomy. RESULTS: During vitrectomy, the TPVR grade of the control group was significantly more severe than the TA group (p=0.028). The TPVR score was significantly better in the TA group (9.30±0.82) than in the control group (6.44±1.06) (p=0.036). The final VA improved in 23 eyes (92%) in the TA group and in 14 eyes (63.64%) in the control group (p=0.008). The retinal attachment rates were 88% and 63.64% in the TA and control group, respectively (p=0.049). The two groups showed no significant difference in macular repositioning and PVR recurrent rate (p=0.215, 0.191). Temporary intraocular pressure elevation occurred in one eye in the TA group after emergency surgery. CONCLUSIONS: Early intravitreal TA injection for OGI effectively reduces TPVR, increases surgical success and improves visual prognosis.

FNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment.

Ischaemia of the heart and limbs attributable to compromised blood supply is a major cause of mortality and morbidity. The mechanisms of functional angiogenesis remain poorly understood, however. Here we show that FNIP1 plays a critical role in controlling skeletal muscle functional angiogenesis, a process pivotal for muscle revascularization during ischemia. Muscle FNIP1 expression is down-regulated by exercise. Genetic overexpression of FNIP1 in myofiber causes limited angiogenesis in mice, whereas its myofiber-specific ablation markedly promotes the formation of functional blood vessels. Interestingly, the increased muscle angiogenesis is independent of AMPK but due to enhanced macrophage recruitment in FNIP1-depleted muscles. Mechanistically, myofiber FNIP1 deficiency induces PGC-1α to activate chemokine gene transcription, thereby driving macrophage recruitment and muscle angiogenesis program. Furthermore, in a mouse hindlimb ischemia model of peripheral artery disease, the loss of myofiber FNIP1 significantly improved the recovery of blood flow. Thus, these results reveal a pivotal role of FNIP1 as a negative regulator of functional angiogenesis in muscle, offering insight into potential therapeutic strategies for ischemic diseases.

Controlling piezoresistance in single molecules through the isomerisation of bullvalenes.

Nanoscale electro-mechanical systems (NEMS) displaying piezoresistance offer unique measurement opportunities at the sub-cellular level, in detectors and sensors, and in emerging generations of integrated electronic devices. Here, we show a single-molecule NEMS piezoresistor that operates utilising constitutional and conformational isomerisation of individual diaryl-bullvalene molecules and can be switched at 850 Hz. Observations are made using scanning tunnelling microscopy break junction (STMBJ) techniques to characterise piezoresistance, combined with blinking (current-time) experiments that follow single-molecule reactions in real time. A kinetic Monte Carlo methodology (KMC) is developed to simulate isomerisation on the experimental timescale, parameterised using density-functional theory (DFT) combined with non-equilibrium Green's function (NEGF) calculations. Results indicate that piezoresistance is controlled by both constitutional and conformational isomerisation, occurring at rates that are either fast (equilibrium) or slow (non-equilibrium) compared to the experimental timescale. Two different types of STMBJ traces are observed, one typical of traditional experiments that are interpreted in terms of intramolecular isomerisation occurring on stable tipped-shaped metal-contact junctions, and another attributed to arise from junction‒interface restructuring induced by bullvalene isomerisation.

Controlled Decompression Alleviates Motor Dysfunction by Regulating Microglial Polarization via the HIF-1α Signaling Pathway in Intracranial Hypertension.

Decompressive craniectomy (DC) is a major form of surgery that is used to reduce intracranial hypertension (IH), the most frequent cause of death and disability following severe traumatic brain injury (sTBI) and stroke. Our previous research showed that controlled decompression (CDC) was more effective than rapid decompression (RDC) with regard to reducing the incidence of complications and improving outcomes after sTBI; however, the specific mechanisms involved have yet to be elucidated. In the present study, we investigated the effects of CDC in regulating inflammation after IH and attempted to identify the mechanisms involved. Analysis showed that CDC was more effective than RDC in alleviating motor dysfunction and neuronal death in a rat model of traumatic intracranial hypertension (TIH) created by epidural balloon pressurization. Moreover, RDC induced M1 microglia polarization and the release of pro-inflammatory cytokines. However, CDC treatment resulted in microglia primarily polarizing into the M2 phenotype and induced the significant release of anti-inflammatory cytokines. Mechanistically, the establishment of the TIH model led to the increased expression of hypoxia-inducible factor-1α (HIF-1α); CDC ameliorated cerebral hypoxia and reduced the expression of HIF-1α. In addition, 2-methoxyestradiol (2-ME2), a specific inhibitor of HIF-1α, significantly attenuated RDC-induced inflammation and improved motor function by promoting M1 to M2 phenotype transformation in microglial and enhancing the release of anti-inflammatory cytokines. However, dimethyloxaloylglycine (DMOG), an agonist of HIF-1α, abrogated the protective effects of CDC treatment by suppressing M2 microglia polarization and the release of anti-inflammatory cytokines. Collectively, our results indicated that CDC effectively alleviated IH-induced inflammation, neuronal death, and motor dysfunction by regulating HIF-1α-mediated microglial phenotype polarization. Our findings provide a better understanding of the mechanisms that underlie the protective effects of CDC and promote clinical translational research for HIF-1α in IH.

Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes.

Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Thermogenic stimulation selectively promotes mitochondrial proteostasis in mature white adipocytes via the mitochondrial protease LONP1. Disruption of LONP1-dependent proteolysis substantially impairs cold- or ß3 adrenergic agonist-induced white-to-beige identity switching of mature adipocytes. Mechanistically, LONP1 selectively degrades succinate dehydrogenase complex iron sulfur subunit B and ensures adequate intracellular succinate levels. This alters the histone methylation status on thermogenic genes and thereby enables adipocyte cell fate programming. Finally, augmented LONP1 expression raises succinate levels and corrects ageing-related impairments in white-to-beige adipocyte conversion and adipocyte thermogenic capacity. Together, these findings reveal that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and directs cell identity conversion during adipocyte thermogenic remodelling.

Quantitative Phosphoproteomics Reveals the Requirement of DYRK1-Mediated Phosphorylation of Ion Transport- and Cell Junction-Related Proteins for Notochord Lumenogenesis in Ascidian.

The dual-specificity tyrosine phosphorylation-regulated kinase (DYRK1) phosphorylates diverse substrates involved in various cellular processes. Here, we found that blocking the kinase activity of DYRK1 inhibited notochord development and lumenogenesis in ascidian Ciona savignyi. By performing phosphoproteomics in conjunction with notochord-specific proteomics, we identified 1065 notochord-specific phosphoproteins that were present during lumen inflation, of which 428 differentially phosphorylated proteins (DPPs) were identified after inhibition of DYRK1 kinase activity. These DPPs were significantly enriched in metal ion transmembrane transporter activity, protein transport and localization, and tight junction. We next analyzed the downregulated phosphoproteins and focused on those belonging to the solute carrier (SLC), Ras-related protein (RAB), and tight junction protein (TJP) families. In vivo phospho-deficient study showed that alanine mutations on the phosphosites of these proteins resulted in defects of lumenogenesis during Ciona notochord development, demonstrating the crucial roles of phosphorylation of transmembrane transport-, vesicle trafficking-, and tight junction-related proteins in lumen formation. Overall, our study provides a valuable data resource for investigating notochord lumenogenesis and uncovers the molecular mechanisms of DYRK1-mediated notochord development and lumen inflation.

Relative Bioavailability of Cadmium in Rice: Assessment, Modeling, and Application for Risk Assessment.

Rice consumption is the primary route of cadmium (Cd) exposure to the populations with rice as the staple food. To accurately assess the potential health risks of Cd exposure via rice consumption, determination of Cd relative bioavailability (RBA) in rice is necessary. However, large variations exist in Cd-RBA, hindering the application of source-specific Cd-RBA values to different rice samples. In this study, we collected 14 rice samples from Cd contaminated areas and determined both rice compositions and Cd-RBA using in vivo mouse bioassay. Total Cd concentration varied from 0.19 to 2.54 mg/kg in the 14 rice samples, while Cd-RBA in rice ranged from 42.10% to 76.29%. Cadmium-RBA in rice correlated positively with calcium (Ca) (R = 0.76) and amylose content (R = 0.75) but negatively with the concentrations of sulfur (R = -0.85), phosphorus (R = -0.73), phytic acid (R = -0.68), and crude protein (R = -0.53). Cd-RBA in rice can be predicted by Ca and phytic acid concentrations in a regression model (R2 = 0.80). Based on the total and bioavailable Cd concentrations in rice, weekly dietary Cd intake for adults was estimated to be 4.84-64.88 and 2.04-42.29 µg/kg bw/week, respectively. This work demonstrates the possibility of Cd-RBA prediction based on rice compositions and provides valuable suggestions for health risk assessment with consideration of Cd-RBA.

Silk fibroin based wearable electrochemical sensors with biomimetic enzyme-like activity constructed for durable and on-site health monitoring.

Flexible biomimetic sensors have encountered a bottleneck of sensitivity and durability, as the sensors must directly work within complex body fluid with ultra-trace biomarkers. In this work, a wearable electrochemical sensor on a modified silk fibroin substrate is developed using gold nanoparticles hosted into N-doped porous carbonizated silk fibroin (AuNPs@CSF) as active materials. Taking advantage of the inherent biocompatibility and flexibility of CSF, and the high stability and enzyme-like catalytic activity of AuNPs, AuNPs@CSF-based sensor exhibits durable stability and superior sensitivity to monitor H2O2 released from cancer cell (4T1) and glucose in sweat. The detection limits for H2O2 and glucose are low to be 1.88 µM and 23 µM respectively, and the sensor can be applied in succession within 30 days at room temperature. Further, physical cross-linking of polyurethane (PU) with SF well matches with the skin tissue mechanically and provides a flexible, robust and stable electrode-tissue interface. AuNPs@CSF is applied successfully for wearable electrochemical monitoring of glucose in human sweat.The present AuNPs@CSF will possess a potential application in clinical diagnosing of H2O2- or glucose-related diseases in future.

Microbial degradation mechanisms of surface petroleum contaminated seawater in a typical oil trading port.

Petroleum hydrocarbons are significant new persistent organic pollutants for marine oil spill risk areas. Oil trading ports, in turn, have become major bearers of the risk of offshore oil pollution. However, studies on the molecular mechanisms of microbial degradation of petroleum pollutants by natural seawater are limited. Here, an in situ microcosm study was conducted. Combined with metagenomics, differences in metabolic pathways and in the gene abundances of total petroleum hydrocarbons (TPH) are revealed under different conditions. About 88% degradation of TPH was shown after 3 weeks of treatment. The positive responders to TPH were concentrated in the genera Cycloclasticus, Marivita and Sulfitobacter of the orders Rhodobacterales and Thiotrichales. The genera Marivita, Roseobacter, Lentibacter and Glaciecola were key degradation species when mixing dispersants with oil, and all of the above are from the Proteobacteria phylum. The analysis showed that the biodegradability of aromatic compounds, polycyclic aromatic hydrocarbon and dioxin were enhanced after the oil spill, and genes with higher abundances of bphAa, bsdC, nahB, doxE and mhpD were found, but the photosynthesis-related mechanism was inhibited. The dispersant treatment effectively stimulated the microbial degradation of TPH and then accelerated the succession of microbial communities. Meanwhile, functions such as bacterial chemotaxis and carbon metabolism (cheA, fadeJ and fadE) were better developed, but the degradation of persistent organic pollutants such as polycyclic aromatic hydrocarbons was weakened. Our study provides insights into the metabolic pathways and specific functional genes for oil degradation by marine microorganisms and will help improve the application and practice of bioremediation.

Metformin enhances neural precursor cells migration and functional recovery after ischemic stroke in mice.

Resident neural precursor cells (NPCs) activation is a promising therapeutic strategy for brain repair. This strategy involves stimulating multiple stages of NPCs development, including proliferation, self-renewal, migration, and differentiation. Metformin, an FDA-approved diabetes drug, has been shown to promote the proliferation and differentiation of NPCs. However, it is still unclear whether metformin promotes the migration of NPCs. EVOS living cell imaging system was used for observing the migration for primary NPCs dynamically in vitro after metformin treatment. For in vivo study, a mouse model of ischemic stroke was established through middle cerebral artery occlusion (MCAO). To label the proliferating cell in subventricular zone, BrdU was injected intraperitoneally into the mice. After co-staining with BrdU and doublecortin (DCX), a marker for NPCs, the migration of Brdu and DCX double positive NPCs was detected along the rostral migratory stream (RMS) and around the infarct area using frozen brain sections. Finally, the rotarod test, corner test and beam walking were performed to evaluate the motor functions of the mice after stroke in different groups. The results showed that metformin enhanced NPCs migration in vivo and in vitro by promoting F-actin assembly and lamellipodia formation. What's more, metformin treatment also significantly reduced the infarct volume and alleviated functional dysfunction after stroke. Mechanistically, metformin promoted NPCs migration via up-regulating the CDC42 expression. Taken together, metformin represents an optimal candidate agent for neural repair that is capable of not only expanding the adult NPC population but also subsequently driving them toward the destination for neuronal differentiation.

Ancestral glycoprotein hormone and its cognate receptor present in primitive chordate ascidian: Molecular identification and functional characterization.

The glycoprotein hormone (GPH) system is fundamentally significant in regulating the physiology of chordates, such as thyroid activity and gonadal function. However, the knowledge of the GPH system in the primitive chordate ascidian species is largely lacking. Here, we reported an ancestral GPH system in the ascidian (Styela clava), which consists of GPH α subunit (Sc-GPA2), GPH ß subunit (Sc-GPB5), and the cognate leucine-rich repeat-containing G protein-coupled receptor (Sc-GPHR). Comparative structure analysis revealed that distinct from vertebrate GPH ß subunits, Sc-GPB5 was less conserved, showing an atypical N-terminal sequence with a type II transmembrane domain instead of a typical signal peptide. By investigating the presence of recombinant Sc-GPA2 and Sc-GPB5 in cell lysates and culture media of HEK293T cells, we confirmed that these two subunits could be secreted out of the cells via distinct secretory pathways. The deglycosylation experiments demonstrated that N-linked glycosylation only occurred on the conserved cysteine residue (N78) of Sc-GPA2, whereas Sc-GPB5 was non-glycosylated. Although Sc-GPB5 exhibited distinct topology and biochemical properties in contrast to its chordate counterparts, it could still interact with Sc-GPA2 to form a heterodimer. The Sc-GPHR was then confirmed to be activated by tethered Sc-GPA2/GPB5 heterodimer on the Gs-cAMP pathway, suggesting that Sc-GPA2/GPB5 heterodimer-initiated Gs-cAMP signaling pathway is evolutionarily conserved in chordates. Furthermore, in situ hybridization and RT-PCR results revealed the co-expression patterns of Sc-GPA2 and Sc-GPB5 with Sc-GPHR transcripts, respectively in ascidian larvae and adults, highlighting the potential functions of Sc-GPA2/GPB5 heterodimer as an autocrine/paracrine neurohormone in regulating metamorphosis of larvae and physiological functions of adults. Our study systematically investigated the GPA2/GPB5-GPHR system in ascidian for the first time, which offers insights into understanding the function and evolution of the GPH system within the chordate lineage.

Development and Validation of Nomogram-Based Prediction of Chronic Subdural Hematoma Recurrence after Initial Burr-Hole Surgery.

AIM: To establish, and validate a practical nomogram to predict recurrence of chronic subdural hematoma (CSDH) in patients after initial burr-hole surgery. MATERIAL AND METHODS: The prediction model was developed from a training set of 272 patients with CSDH who had undergone standard burr hole with irrigation surgery. A separate external validation cohort comprising 112 patients who underwent the same operation was also included. Least absolute shrinkage and selection operator (LASSO) regression was adopted to minimize the high dimension of data and predictor selection. Binary logistic regression was used to develop the present model. Subsequently, a nomogram was established as the ultimate representation of the prediction model. Area under the curve (AUC) was used to identify the discrimination of the designed predictive nomogram. The calibration plot was used to verify the goodness-of-fit of the nomogram. Finally, Decision curve analysis (DCA) was employed to appraise the clinical applicability of the present nomogram. RESULTS: A total of 3 independent variables were filtered by LASSO analysis from the 22 candidate factors. The AUC of the training and validation sets were 0.833 (95%CI: 0.774-0.894) and 0.817 (95%CI: 0.711-0.922), respectively, which indicated a good discrimination ability. The calibration charts showed that the prediction probability and the actual probability fitted well. The DCA of the prediction model indicated an excellent clinical efficacy. CONCLUSION: The proposed nomogram can quantitatively and conveniently predict the recurrence rate of CSDH after burr hole with irrigation surgery. Besides it can facilitate customized treatment adjustment and follow-up of patients who are at a high-risk of recurrence.

Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice.

The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.