TRIM21 induces selective autophagic degradation of c-Myc and sensitizes regorafenib therapy in colorectal cancer.

Kirsten rat sarcoma virus (KRAS) mutation is associated with malignant tumor transformation and drug resistance. However, the development of clinically effective targeted therapies for KRAS-mutant cancer has proven to be a formidable challenge. Here, we report that tripartite motif-containing protein 21 (TRIM21) functions as a target of extracellular signal-regulated kinase 2 (ERK2) in KRAS-mutant colorectal cancer (CRC), contributing to regorafenib therapy resistance. Mechanistically, TRIM21 directly interacts with and ubiquitinates v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) at lysine 148 (K148) via K63-linkage, enabling c-Myc to be targeted to the autophagy machinery for degradation, ultimately resulting in the downregulation of enolase 2 expression and inhibition of glycolysis. However, mutant KRAS (KRAS/MT)-driven mitogen-activated protein kinase (MAPK) signaling leads to the phosphorylation of TRIM21 (p-TRIM21) at Threonine 396 (T396) by ERK2, disrupting the interaction between TRIM21 and c-Myc and thereby preventing c-Myc from targeting autophagy for degradation. This enhances glycolysis and contributes to regorafenib resistance. Clinically, high p-TRIM21 (T396) is associated with an unfavorable prognosis. Targeting TRIM21 to disrupt KRAS/MT-driven phosphorylation using the antidepressant vilazodone shows potential for enhancing the efficacy of regorafenib in treating KRAS-mutant CRC in preclinical models. These findings are instrumental for KRAS-mutant CRC treatment aiming at activating TRIM21-mediated selective autophagic degradation of c-Myc.

Flavin-Dependent Monooxygenase Kmy13 Mediates Formation of the Carbocyclic ansa System during Kendomycin B Biosynthesis.

Kendomycin B is distinguished from other ansamycins by its unique, fully carbogenic ansa scaffold. We show here that FAD-dependent monooxygenase Kmy13 is solely responsible for installing the rare ansa structural framework; in vivo gene disruption/complementation experiments and in vitro enzymatic assays are described in detail. Moreover, the compound with a ß-keto ester, kendolactone A (2), was confirmed as the natural substrate of Kmy13 and a bona fide biosynthetic intermediate en route to kendomycin B. Further structural prediction and biochemical assays have provided significant insights into the catalytic mechanism of Kmy13.

Increased bone mass but delayed mineralization: in vivo and in vitro study for zoledronate in bone regeneration.

BACKGROUND: Bisphosphonates (BPs) are widely used to inhibit excessive osteoclast activity. However, the potential to compromise bone defect healing has limited their broader application. To better understand the influence of BPs on bone regeneration, we established a bone grafting model with Zoledronate administration, aiming to deepen the understanding of bone remodeling and mineralization processes. METHODS: A bone grafting model was established in the distal femurs of male Sprague-Dawley rats. The experimental group received systemic administration of Zoledronate (ZOL, 0.2 mg/kg, administered twice). Histological analysis and immunohistochemistry (IHC) were employed to assess osteoblastic and macrophage activity, tartrate-resistant acid phosphatase (TRAP) staining was used to evaluate osteoclastogenesis. Mineralization was assessed through Micro-CT analysis, Raman spectroscopy, and back-scatter scanning electron microscopy (BSE-SEM). Additionally, the in vitro effects of ZOL on osteoblast and osteoclast activity were investigated to further elucidate its impact on bone regeneration. RESULTS: In vivo, the ZOL group showed increased bone mass, as observed in histological and radiological assessments. However, Micro-CT, Raman spectroscopy, and BSE-SEM detection revealed lower mineralization levels in ZOL group's regenerated bone. Acid-etched SEM analysis showed abnormal osteocyte characteristics in ZOL-group's regenerated bone. Simultaneously, elevated osteopontin (OPN), F4/80 expression along with reduced TRAP expressing was found in the grafting region of ZOL group. In vitro, ZOL did not negatively impact osteogenetic activity (ALP, BMP4, OCN expression) at the tested concentrations (0.02-0.5 g/ml) but significantly impaired mineralization and inhibited osteoclast formation, even at the lowest concentration. CONCLUSIONS: This study highlights a less recognized negative effect of ZOL on bone mineralization during bone regeneration. More research is needed to elucidate the underlying mechanism.

Asymmetric α-Allylation of Amino Acid Esters with Alkynes Enabled by Chiral Aldehyde/Palladium Combined Catalysis.

A highly efficient, atom-economical α-allylation reaction of NH2-unprotected amino acid esters and alkynes is achieved by chiral aldehyde/palladium combined catalysis. A diverse range of α,α-disubstituted nonproteinogenic α-amino acid esters are produced in 31-92% yields and 84-97% ee values. The allylation products are utilized for the synthesis of drug molecule BMS561392 and other chiral molecules possessing complex structures. Mechanistic investigations reveal that this reaction proceeds via a chiral aldehyde-/palladium-mediated triple cascade catalytic cycle.

Occlusal disharmony promotes anxiety-like behaviours by suppressing Sirt1.

BACKGROUND: Previous studies have indicated that occlusal disharmony (OD) can promote anxiety-like behaviours. However, the specific molecules involved in the development of anxiety-like behaviours and their underlying mechanisms remain unknown. METHODS: OD was produced by anterior crossbite of female mice. We measured the anxiety levels of mice in each group and screened the hippocampal mRNA expression profiles of mice in the control group and OD group. The role of target mRNA in OD-induced anxiety-like behaviours was evaluated and we preliminarily explored the possible downstream pathways. RESULTS: The results suggested that OD can induce and promote anxiety-like behaviours with/without chronic unpredictable mild stress. We found that Sirt1 was significantly downregulated within the hippocampus in OD mice. In addition, the downregulation of Sirt1 within the hippocampus in OD and control mice promoted anxiety-like behaviours, increased acetylated histone H3 expression and decreased Dnah12 transcription levels. In contrast, in OD mice subjected to an injection of resveratrol, there was a remission of anxiety-like behaviours and an upregulation of Sirt1 in the hippocampus, the effects of which were accompanied by decreased acetylated histone H3 expression and increased Dnah12 transcription levels. CONCLUSIONS: OD leads to increased sensitivity to chronic stress in mice, resulting in anxiety-like behaviours. During this process, Sirt1 acts as an effective factor in the regulation of OD-induced anxiety-like behaviours. CLINICAL RELEVANCE: OD, as a stressor, could induce anxiety-like behaviours. It investigates the impact of OD (a stressor) on the molecular genetic of the pathophysiology of major neuropsychiatric disorders.

Structural Insight Into the Function of DnaB Helicase in Bacterial DNA Replication.

In bacteria, chromosome replication is achieved by the coordinations of more than a dozen replisome enzymes. Replication initiation protein DnaA melts DNA duplex at replication origin (oriC) and forms a replication bubble, followed by loading of helicase DnaB with the help of loader protein DnaC. Then the DnaB helicase unwinds the dsDNA and supports the priming of DnaG and the polymerizing of DNA polymerase. The DnaB helicase functions as a platform coupling unwinding, priming, and polymerizing events. The multiple roles of DnaB helicase are underlined by its distinctive architecture and dynamics conformations. In this review, we will discuss the assembling of DnaB hexamer and the conformational changes upon binding of various partners, DnaB in states of closed dilated (CD), closed constricted (CC), closed helical (CH), and open helical (OH) are discussed. These multiple interfaces among DnaB and partners are potential targets for inhibitors design and novel peptide antibiotics development.

Surveillance of household foodborne disease outbreaks in Zhejiang Province, China, 2010-2022.

BACKGROUND: Foodborne diseases are a growing public health concern worldwide and households are a common setting. This study aimed to explore the epidemiological characteristics of household foodborne disease outbreaks in Zhejiang Province and propose targeted prevention and control measures. METHODS: Descriptive statistical methods were used to analyze household foodborne disease outbreak data collected from the Foodborne Disease Outbreaks Surveillance System in Zhejiang Province from 2010 to 2022. RESULTS: Household foodborne disease outbreaks showed an upward trend during the study period (Cox-Staurt trend test, p = 0.01563 < 0.05). These outbreaks mainly occurred from June to September, with 62.08% (352/567) of all reported outbreaks. The number of reported outbreaks varied in 11 prefectures, with a maximum of 100 and a minimum of only 7. Household foodborne disease outbreaks had a wide spectrum of etiologic factors. Mushroom toxins accounted for the largest proportion of all etiologies (43.39 %) and caused the highest proportion of hospitalization (54.18%) and death (78.26%). Such outbreaks are caused by accidently eating wild poisonous mushrooms. Bacterial infection (16.23%) was the second most common etiology, with Salmonella spp. and Vibrio parahaemolyticus being the primary pathogens. These outbreaks were caused by improper storage, improper processing or a combination of factors, and the foods involved were mainly aquatic animals, eggs and cooked meat. Other identified etiologies included plant toxins (9.52%), chemicals (7.23%), animal toxins (3.70%), and viruses (1.76%). Among the above-mentioned etiologies, mushroom toxins, bacteria, and animal toxins had seasonal characteristics. Analysis of regions and etiologies revealed that the proportion of various etiologies was different in 11 prefectures. Wild mushrooms (43.39%), aquatic animals (9.88%), and toxic plants (8.47%) were the top three foods involved in these outbreaks. The most common factors contributing to household foodborne disease outbreaks were inedibility and misuse (59.08%), followed by multiple factors (7.58%), improper storage (7.41%), and improper processing (7.41%). CONCLUSIONS: Household foodborne disease outbreaks were closely related to the lack of knowledge regarding foodborne disease prevention. Therefore, public health agencies should strengthen residents' surveillance and health education to improve food safety awareness and effectively reduce foodborne diseases in households. In addition, timely publicity and early warning by relevant government departments, the introduction of standards to control the contamination of pathogenic bacteria in raw materials, and strengthened supervision of the sale of substances that may cause health hazards, such as poisonous mushrooms and nitrites, will also help reduce such outbreaks.

Species-Specific Responses of Bloom-Forming Algae to the Ocean Warming and Acidification.

Macroalgal biomass blooms, including those causing the green and golden tides, have been rising along Chinese coasts, resulting in considerable social impacts and economic losses. To understand the links between the ongoing climate changes (ocean warming and acidification) and algal tide formation, the effects of temperature (20 and 24 °C), pCO2 concentration (Partial Pressure of Carbon Dioxide, 410 ppm and 1000 ppm) and their interaction on the growth of Ulva prolifera and Ulva lactuca (green tide forming species), as well as Sargassum horneri (golden tide forming species) were investigated. The results indicate that the concurrent rises in temperature and pCO2 level significantly boosted the growth and nutrient uptake rates of U. lactuca. For U. prolifera, the heightened growth and photosynthetic efficiency under higher CO2 conditions are likely due to the increased availability of inorganic carbon. In contrast, S. horneri exhibited negligible responsiveness to the individual and combined effects of the increased temperature and CO2 concentration. These outcomes indicate that the progressive climate changes, characterized by ocean warming and acidification, are likely to escalate the incidence of green tides caused by Ulva species, whereas they are not anticipated to precipitate golden tides.

Blocking α1 Adrenergic Receptor as a Novel Target for Treating Alzheimer's Disease.

While amyloidopathy and tauopathy have been recognized as hallmarks in Alzheimer's disease (AD) brain, recently, increasing lines of evidence have supported the pathological roles of cerebrovascular changes in the pathogenesis and progression of AD. Restoring or ameliorating the impaired cerebrovascular function during the early phase of the disease may yield benefits against the cognitive decline in AD. In the present study, we evaluated the potential therapeutic effects of nicergoline [NG, a well-known α1 adrenergic receptor (ADR) blocker and vasodilator] against AD through ameliorating vascular abnormalities. Our in vitro data revealed that NG could reverse ß-amyloid1-42 (Aß1-42)-induced PKC/ERK1/2 activation, the downstream pathway of α1-ADR activation, in α1-ADR-overexpressed N2a cells. NG also blocked Aß1-42- or phenylephrine-induced constrictions in isolated rat arteries. All these in vitro data may suggest ADR-dependent impacts of Aß on vascular function and the reversal effect of NG. In addition, the ameliorating impacts of NG treatment on cerebral vasoconstriction, vasoremodeling, and cognitive decline were investigated in vivo in a PSAPP transgenic AD mouse model. Consistent with in vitro findings, the chronic treatment of NG significantly ameliorated the cerebrovascular dysfunctions and Aß plaque depositions in the brain. Moreover, an improved cognitive performance was also observed. Taken together, our findings supported the beneficial effects of NG on AD through adrenergic-related mechanisms and highlighted the therapeutic potential of α1-adrenergic vasomodulators against AD pathologies.

Potassium diformate affects the growth and development of broilers by improving intestinal function and digestive enzyme activity.

Gut health of broiler chickens is essential for production performance. The present study aimed to evaluate the impact of dietary supplementation with potassium diformate (KDF) on growth performance and intestinal health in broiler chickens. A total of 180 Arbor Acres (AA) broiler chickens were randomly allocated into 3 treatments, with 6 replicates, containing 10 chicks in each replicate. The treatment groups were: control group (CON) was fed a basal diet; KDF-4 groups fed the basal diet with 4 g/kg KDF; KDF-8 groups fed the basal diet with 8 g/kg KDF. The experiment period lasted for 42 d. During the starter phase, the ADFI and F/G of broilers in KDF groups were lower (P < 0.05) compared to the CON group. Furthermore, the BW and ADG in KDF-4 group was improved (P<0.05). The treatment groups exhibited a significant increase (P < 0.05) in both ADG and ADFI during the grower and overall phase. Moreover, the F/G in KDF-4 group was lower (P < 0.05) compared to the CON and KDF-8 groups. The semi-eviscerated weight rate (SEWR), eviscerated carcass weight rate (ECWR), pectoral muscle rate (PMR), and leg muscle rate (LMR) of broilers were improved (P < 0.05) in KDF groups. The serum levels of glucose (GLU) and UREA (UA) were significantly higher (P < 0.05) in KDF-8 group. Additionally, the nutrient apparent utilization rate of dry matter (DM), energy (EE), and crude protein (CP) were improved (P < 0.05) in KDF-4 group. The villus height (VH) and villus height to crypt depth ratio (V/C) of duodenum, jejunum, and ileum were higher (P < 0.05) in KDF groups compared to the CON group, while crypt depth (CD) was significantly reduced (P < 0.05). The digestive enzyme activities of lipase (LIP), amylase (AMS), or trypsin (TPS) were significantly enhanced (P < 0.05) in the intestinal chyme, while the total bacterial count, Escherichia coli, Lactobacilli, Bifidobacteria, and Bacillus were reduced (P < 0.05) in the ileum. This study demonstrates that the inclusion of KDF in the diet of broilers leads to improvements in growth, slaughter performance, nutrient utilization rate, and maintenance of intestinal health.

The impact of sarcopenia on the incidence of postoperative outcomes following spine surgery: Systematic review and meta-analysis.

PURPOSE: Sarcopenia is considered to be an important predictor of adverse outcomes following spinal surgery, but the specific relationship between the two is not clear. The purpose of this meta-analysis is to systematically review all relevant studies to evaluate the impact of sarcopenia on spinal surgery outcomes. METHODS: We systematically searched PubMed, Embase and the Cochrane Library for relevant articles published on or before January 9, 2023. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was calculated in a random effects meta-analysis. The main outcome was the risk of adverse outcomes after spinal surgery, including adverse events and mortality. This systematic review and meta-analysis was conducted following the PRISMA guidelines to evaluate the impact of sarcopenia on spinal surgery outcomes. In addition, we also conducted a subgroup analysis and leave-one-out sensitivity analyses to explore the main sources of heterogeneity and the stability of the results. RESULTS: Twenty-four cohort studies, with a total of 243,453 participants, met the inclusion criteria. The meta-analysis showed that sarcopenia was significantly associated with adverse events (OR 1.63, 95% CI 1.17-2.27, P < 0.001) but was no significantly associated with mortality (OR 1.17, 95% CI 0.93-1.46, P = 0.180), infection (OR 2.24, 95% CI 0.95-5.26, P < 0.001), 30-day reoperation (OR 1.47, 95% CI 0.92-2.36, P = 0.413), deep vein thrombosis (OR 1.78, 95% CI 0.69-4.61, P = 0.234), postoperative home discharge (OR 0.60, 95% CI 0.26-1.37, P = 0.002) and blood transfusion (OR 3.28, 95% CI 0.74-14.64, P = 0.015). CONCLUSION: The current meta-analysis showed that patients with sarcopenia have an increased risk of adverse events and mortality after spinal surgery. However, these results must be carefully interpreted because the number of studies included is small and the studies are significantly different. These findings may help to increase the clinicians' awareness of the risks concerning patients with sarcopenia to improve their prognosis.

Biodegradation of 3-methylpyridine by an isolated strain, Gordonia rubripertincta ZJJ.

Methylpyridines are a class of highly toxic pyridine derivatives. In this study, a novel degrading bacterium was isolated for 3-methylpyridine (3-MP) degradation (Gordonia rubripertincta ZJJ, GenBank accession NO. OP430847.1; CCTCC M 2022975). The maximum specific degradation rate, half-saturation constant and inhibition constant were fitted to be 0.48 h-1, 88.3 mg L-1 and 924.0 mg L-1, respectively. During 3-MP biodegradation, the lost total organic carbon was transformed into CO2 (67.4 %) and biomass (32.6 %), and ammonia nitrogen was almost the sole inorganic species with a conversion rate of 36.3 %. Three metabolic pathways were possibly involved in 3-MP degradation: I) methyl oxidation followed by ring hydroxylation and hydrogenation; II) rupture of C=C and C-N bonds after ring reduction; III) initial ring hydroxylation. The study not only provides a novel strain for the high-efficient degradation of 3-MP, but also contributes to an in-depth understanding of 3-MP biotransformation.

Compound heterozygous mutations of NTNG2 cause intellectual disability via inhibition of the CaMKII signaling.

Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization. In this study, we identify compound heterozygous mutations of c.547delC, p.(Arg183Alafs∗186) and c.605G > A, p.(Trp202X) in NTNG2 causing a syndrome exhibiting developmental delay, intellectual disability, hypotonia, and facial dysmorphism. To elucidate the underlying cellular and molecular mechanisms, CRISPR-Cas9 technology is employed to generate a knock-in mouse model expressing the R183Afs and W202X mutations. We report that the Ntng2R183Afs/W202X mice exhibit hypotonia and impaired learning and memory. We find that the levels of CaMKII and p-GluA1Ser831 are decreased, and excitatory postsynaptic transmission and long-term potentiation are impaired. To increase the activity of CaMKII, the mutant mice receive intraperitoneal injections of DCP-LA, a CaMKII agonist, and show improved cognitive function. Together, our findings reveal molecular mechanisms of how NTNG2 deficiency leads to impairments of cognitive ability and synaptic plasticity.

Cleft Palate Induced by Augmented Fibroblast Growth Factor-9 Signaling in Cranial Neural Crest Cells in Mice.

Although enhanced fibroblast growth factor (FGF) signaling has been demonstrated to be crucial in many cases of syndromic cleft palate caused by tongue malposition in humans, animal models that recapitulate this phenotype are limited, and the precise mechanisms remain elusive. Mutations in FGF9 with the effect of either loss- or gain-of-function effects have been identified to be associated with cleft palate in humans. Here, we generated a mouse model with a transgenic Fgf9 allele specifically activated in cranial neural crest cells, aiming to elucidate the gain-of-function effects of Fgf9 in palatogenesis. We observed cleft palate with 100% penetrance in mutant mice. Further analysis demonstrated that no inherent defects in the morphogenic competence of palatal shelves could be found, but a passively lifted tongue prevented the elevation of palatal shelves, leading to the cleft palate. This tongue malposition was induced by posterior spatial confinement that was exerted by temporomandibular joint (TMJ) dysplasia characterized by a reduction in Sox9+ progenitors within the condyle and a structural decrease in the posterior dimension of the lower jaw. Our findings highlight the critical role of excessive FGF signaling in disrupting spatial coordination during palate development and suggest a potential association between palatal shelf elevation and early TMJ development.

Structural characterization and immune activity evaluation of a polysaccharide from Lyophyllum Decastes.

An innovative acidic hydrolysate fingerprinting workflow was proposed for the characterization of Lyophyllum Decastes polysaccharide (LDP) by ultra performance liquid chromatography-mass spectrometry (UPLC-MS). The crude polysaccharides were firstly separated and purified by using DE-52 column and the BRT GPC purification system, respectively. The molecular weight and monosaccharide content of homogeneous polysaccharides were ascertained by utilizing HPGPC and ion chromatography separately. Secondly, the linkage of LDP was identified by methylation analysis and 1D/2D NMR spectra. The UPLC-MS/MS was used to scan and identify the acidic hydrolysate products of LDP using the PGC column. The oligosaccharides were collected by chromatography and identified by mass spectrometry. Thirdly, the expression of IL-1ß, IL-6, iNOS, TNF-α and IFNAR-I was measured in order to assess the immunological activity of LDP. Besides, the targeted receptors identification of polysaccharides was performed by screening the expression of TLRs family protein. The results showed that oligosaccharide fragments with different molecular weights can be obtained by partial hydrolysis, which further verified that the structures of LDP polysaccharides was a 1-6-linked ß-glucan. Moreover, the LDP polysaccharide can up-regulate the content of IL-1ß, IL-6, iNOS, TNF-α and IFNAR-I and plays an important immunoregulation role through TLRs family.

Assessing the causal effects of Eubacterium and Rumphococcus on constipation: a Mendelian randomized study.

Background: Constipation is affected by a number of risk variables, including cardiovascular disease and growth factors. However, the impacts of gut flora on constipation incidence has not been shown. This work, Single-Variable Mendelian Randomization (SVMR) was utilized to estimate the causal relationship between the Eubacterium genus or Rumphococcus, and constipation. Methods: Data for constipation, Eubacterium genus and Rumphococcus were taken from the Integrated Epidemiology Unit (IEU) open GWAS database. Including 218,792 constipation samples, and there were 16,380,466 Single Nucleotide Polymorphisms (SNPs) for constipation. The ids of Eubacterium genus and Rumphococcus were sourced from MiBioGen database. The sample count for the Eubacterium genus was 17,380, with 656 SNPs. In addition, the sample size for Rumphococcus was 15,339, with 545 SNPs. The SVMR was performed to assess the risk of Eubacterium genus and Rumphococcus in constipation using weighted median, MR Egger, simple mode, inverse variance weighted (IVW), and weighted mode. Finally, we did a sensitivity analysis that included a heterogeneity, horizontal pleiotropy, and Leave-One-Out (LOO) test to examine the viability of the MR data. Results: The SVMR revealed that the Eubacterium genus and Rumphococcus were causally connected to constipation, with Rumphococcus (P = 0.042, OR = 1.074) as a hazardous factor and Eubacterium genus (P = 0.004, OR = 0.909) as a safety factor. Sensitivity tests then revealed the absence of variability between the constipation and the exposure factors (Eubacterium genus and Rumphococcus). Additionally, there were no other confounding factors and the examined SNPs could only influence constipation through the aforementioned exposure factors, respectively. As a result, the MR results were fairly robust. Conclusion: Our investigation verified the causal links between the Eubacterium genus or Rumphococcus, and constipation, with greater Rumphococcus expression increasing the likelihood of constipation and the opposite being true for the Eubacterium genus.

40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice.

The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR-aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.

Models for depression recognition and efficacy assessment based on clinical and sequencing data.

Major depression is a complex psychiatric disorder that includes genetic, neurological, and cognitive factors. Early detection and intervention can prevent progression, and help select the best treatment. Traditional clinical diagnosis tends to be subjective and misdiagnosed. Based on this, this study leverages clinical scale assessments and sequencing data to construct disease prediction models. Firstly, data undergoes preprocessing involving normalization and other requisite procedures. Feature engineering is then applied to curate subsets of features, culminating in the construction of a model through the implementation of machine learning and deep learning algorithms. In this study, 18 features with significant differences between patients and healthy controls were selected. The depression recognition model was constructed by deep learning with an accuracy of 87.26 % and an AUC of 91.56 %, which can effectively distinguish patients with depression from healthy controls. In addition, 33 features selected by recursive feature elimination method were used to construct a prognostic effect model of patients after 2 weeks of treatment, with an accuracy of 75.94 % and an AUC of 83.33 %. The results show that the deep learning algorithm based on clinical and sequencing data has good accuracy and provides an objective and accurate method for the diagnosis and pharmacodynamic prediction of depression. Furthermore, the selected differential features can serve as candidate biomarkers to provide valuable clues for diagnosis and efficacy prediction.

A Prediction Nomogram for Fractured Vertebra Recollapse After Posterior Reduction and Pedicle Screw Fixation in Thoracolumbar Fractures.

OBJECTIVE: This study aimed to establish a predictive nomogram model for recollapse of fractured vertebra after posterior pedicle screw fixation in thoracolumbar fractures (TLFs). METHODS: Patients undergoing posterior pedicle screw fixation for TLFs at our hospital between January 2016 and December 2021 were retrospectively reviewed. Patients were divided into 2 groups according to the presence or absence of recollapse of the fractured vertebra at the final follow-up. The predictors for fractured vertebra recollapse were identified by univariate and multivariable logistic regression analysis, and a nomogram model was developed. The prediction performance and internal validation were established. RESULTS: A total of 224 patients were included in this study. Of these, 46 (20.5%) patients developed recollapse of fractured vertebra. Age, thoracic and lumbar injury severity score, screw distribution in the fractured vertebra, and anterior vertebral height compression ratio were associated with vertebral recollapse. These predictors were used to construct a predictive nomogram. The area under the receiver operating characteristic curve of the nomogram model was 0.891. The concordance index was 0.891, and it was 0.877 with bootstrapping validation. The calibration curves and decision curve analysis also suggested that the nomogram model had excellent predictive performances for fractured vertebra recollapse. CONCLUSIONS: A clinical nomogram incorporating 4 variables was constructed to predict fractured vertebra recollapse after posterior pedicle screw fixation for TLFs. The nomogram demonstrated good calibration and discriminative abilities, which may help clinicians to make better treatment decisions.