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OBJECTIVES: Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain histogenesis. Most OFMTs have benign behavior, and many harbor gene fusions involving the PHD finger protein 1 (PHF1), such as EP400::PHF1, MEAF6::PHF1, EPC1::PHF1, and PHF1::TFE3. The PHF1::TFE3 fusion is unique because PHF1 is at 5' instead of residing at 3' in the other fusions. In this study, we describe 2 cases of OFMT harboring PHF1::TFE3 fusions and review 13 published cases. METHODS: Two cases of PHF1::TFE3-positive OFMT were investigated using RNA Next-Generation Sequencing and immunohistochemistry. RESULTS: Most (12/15) of the PHF1::TFE3 OFMTs we studied were located at proximal and distal extremities, with a multinodular growth pattern. Only 1 case (1/10) had a shell of bone at the periphery. Areas morphologically similar to sclerosing epithelioid fibrosarcoma or low-grade fibromyxoid sarcoma were found in 8 of 12 (66.7%) cases. Eleven cases (11/15 [73.3%]) were regarded as malignant based on more than 2/50 high-power field mitotic figures, increased cellularity, or the presence of necrosis. Among the 9 cases with follow-up data, 2 patients died of disease (with metastases), 1 patient is alive with metastases, and 1 patient had multiple local recurrences. CONCLUSIONS: Because PHF1 is located at 3' in all the PHF1 fusions in OFMTs except PHF1::TFE3, the different driver molecular alterations suggest that OFMTs with 3'-PHF1 fusions and OFMTs with PHF1::TFE3 are different tumors. Immunohistochemistry confirmed TFE3 expression in all PHF1::TFE3 OFMTs. Because PHF1::TFE3-positive OFMTs have increased mitotic figures and tumor cellularity, with a high rate of metastasis, using the name PHF1::TFE3 positive fibromyxoid sarcoma may be appropriate.

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One-dimensional (1D) van der Waals (vdW) heterotubes, where different kinds of 1D nanotubes coaxially nest inside each other, offer a flexible platform for promising applications. The various properties of these 1D heterotubes depend on their diameter. Here, we present a systematic theoretical investigation into the structural and electronic properties of two kinds of 1D transition-metal dichalcogenide (TMD) heterotubes. We demonstrate that the thermodynamic stability of 1D heterotubes is determined by their interlayer distance. Additionally, we establish that the band alignment transition changes from type I to type II in 1D TMD heterotubes. We identify two distinct transition mechanisms, originating from the exchange of either the valence band maximum or the conduction band minimum. According to an electrostatic model, the band alignment transition is attributed to the interlayer electric field effect, which depends on the heterotube diameter. The findings in this work provide valuable physical insights into the band alignment transition in 1D heterotubes and are instrumental for their potential applications in nanotechnology.

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Objectives: To summarize the clinical characteristics, outcomes and identify risk factors of Acinetobacter baumannii (AB) meningitis in children. Methods: This was a single-center, retrospective study. Children hospitalized between January 2016 and December 2021 who were diagnosed with AB meningitis were included. The clinical characteristics and outcomes were reviewed. Risk factors were determined using univariate analyses (chi-square and Mann-Whitney U tests). Results: Seventeen patients were included; 15 cases were secondary to neurosurgery, and two were neonates with primary bacterial meningitis. Common symptoms included fever, convulsions and nervous system abnormalities. Cerebrospinal fluid (CSF) tests typically showed increased white blood cell counts dominated by neutrophils, reduced glucose levels and elevated protein levels. Ten patients were successfully treated (successful treatment [ST] group); seven had failed treatment (failed treatment [FT] group). Univariate analyses revealed that mechanical ventilation, routine white cell counts in the peripheral blood, procalcitonin, protein in the CSF, septic shock and carbapenem-resistant AB (CRAB) differed significantly between the groups. Conclusion: AB meningitis in children has a high mortality rate. FT was associated with mechanical ventilation, septic shock, CRAB, lower peripheral leukocyte counts, higher protein levels in the CSF and procalcitonin. Larger studies are needed to identify independent risk factors for adverse outcomes.

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Pyrethroid are the primary insecticides used for controlling of Bactricera dorsalis, a highly destructive and invasive fruit pest. Field populations have developed serious resistance, especially to ß-cypermethrin. While mutations in the voltage-gated sodium channel (Vgsc) are a common mechanism of pyrethroid resistance, variations in BdVgsc associated with ß-cypermethrin resistance remain unclear. Here, we reported the resistance levels of five field populations from China, with resistance ratio ranging from 1.54 to 21.34-fold. Cloning the full length of BdVgsc revealed no specific or known amino acid mutations between the most resistant population and the susceptible strain. However, three types of partial intron retention (IRE4-5, IRE19-f and IREL-24) were identified in BdVgsc transcripts, with these intron retentions containing stop codons. The expression of IRE4-5 transcripts and total BdVgsc showed different trends across developmental stages and tissues. Exposure to ß-cypermethrin led to increased expression of IRE4-5. Comparison of genomic and transcriptional sequences reveled that IRE4-5 transcripts had two types (IRE4-5.5 T and IRE4-5.6 T) caused by genomic variations. Both field and congenic strains indicated that homozygotes for IRE4-5.5 T had lower IRE4-5 transcript levels than homozygotes for IRE4-5.6 T. However, congenic and field strains exhibited inconsistent results about the association of expression levels of IRE4-5 transcripts with sensitivity to ß-cypermethrin. In summary, this study is the first to identify intron retention transcripts in the Vgsc gene from B. dorsalis and to examine their expression patterns across different developmental stages, tissues, and strains with varying sensitivities to ß-cypermethrin. The potential role of the intron retentions of BdVgsc in insecticide toxicity is also discussed.

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Small molecule prodrugs self-assembled nano-delivery systems with tumor responsive linkages are emerging as an effective platform. However, the heterogeneity of tumor microenvironment may limit the anti-tumor effect of prodrug nanomedicines with a single response module. Here, we chose disulfide bond as the response module and branched chain alcohol as the self-assembly modification module to construct a single-responsive prodrug. We also constructed a double-responsive paclitaxel prodrug combining triglyceride and disulfide bond, taking into account of the highly expressed lipase and glutathione levels in tumor cells. The results showed that the anti-tumor effect of single-responsive branched chain alcohol modified prodrug nanoparticles was inferior to triglyceride prodrug nanoparticles with dual response modules. The triglyceride structure can not only serve as a self-assembly modification module, but also serve as a response module for intelligent drug release in tumor. Such dual roles will facilitate the efficient delivery of small molecule self-assembled prodrugs to tumor sites.

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Reproductive disorders in donkeys present a significant challenge to their health and welfare, impacting their roles in agriculture, conservation, and companionship. With the development of large-scale donkey farming in recent years, reproductive disorders have become a limiting factor for the expansion of the donkey population. In general, donkeys suffer from a similar array of diseases like horses, but little is known about the specificities of donkey reproductive disorders. This review synthesizes current knowledge on the pathogenesis, distribution, presentation, diagnosis, treatment, and prognosis of a diverse array of reproductive disorders affecting donkeys. There are similar infectious and non-infectious causes for infertility and pregnancy loss in jennies compared with mares, but a difference in disease susceptibility does exist, which may be attributed to genetic influence, pathogen specificity, the environment, and reproductive management practices. Diagnostic and treatment plans need to be tailored towards the particularities of donkey reproductive disorders to increase donkey populations and to enhance the standard of care for this species. Enhancing reproductive health in donkeys not only ensures their sustainable use but also promotes their welfare and longevity in diverse human-animal interactions.

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The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 inhibitor, SILA-123. This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC50 = 2.1 nM) and FLT3-ITD (IC50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC50 = 0.98 nM) and MV4-11 (IC50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.

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To develop a reliable sulfide (S2-) autotrophic denitrification (SAD) process under S2- and SO42- salinity stresses, the biofilm performance and microbial mechanisms were comparatively studied using different inocula of activated sludge (AS) and intertidal sediment (IS). Biofilm IS enriched more denitrification genes (0.34 %) and S2- oxidation genes (0.29 %) than those with AS. Higher denitrification performance was obtained under S2- (100 mg/L) and SO42- (5-15 g/L Na2SO4) stresses, but no significantly differences were observed under levels of 0-200 mg/L S2- and 30 g/L Na2SO4. Notably, biofilm samples in SAD systems with IS still had more S2- oxidation genes at high S2- levels of 100-200 mg/L and Na2SO4 level of 30 g/L. The key functional genus Thiobacillus accumulated well at 30 g/L Na2SO4, but was strongly inhibited at 200 mg/L S2-. The findings were advantage to SAD application under sulfide and salinity stresses.

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Coumarins, derived from the phenylpropanoid pathway, represent one of the primary metabolites found in angiosperms. The alignment of the tetrahydropyran (THP) and tetrahydrofuran (THF) rings with the lactone structure results in the formation of at least four types of complex coumarins. However, the mechanisms underlying the structural diversity of coumarin remain poorly understood. Here, we report the chromosome-level genome assembly of Notopterygium incisum, spanning 1.64 Gb, with a contig N50 value of 22.7 Mb and 60,021 annotated protein-coding genes. Additionally, we identified the key enzymes responsible for shaping the structural diversity of coumarins, including two p-coumaroyl CoA 2'-hydroxylases crucial for simple coumarins basic skeleton architecture, two UbiA prenyltransferases responsible for angular or linear coumarins biosynthesis, and five CYP736 cyclases involved in THP and THF ring formation. Notably, two bifunctional enzymes capable of catalyzing both demethylsuberosin and osthenol were identified for the first time. Evolutionary analysis implies that tandem and ectopic duplications of the CYP736 subfamily, specifically arising in the Apiaceae, contributed to the structural diversity of coumarins in N. incisum. Conclusively, this study proposes a parallel evolution scenario for the complex coumarin biosynthetic pathway among different angiosperms and provides essential synthetic biology elements for the heterologous industrial production of coumarins.

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Ten new drimane meroterpenoids talarines A-J (1-10), along with six known analogues (11-16), were isolated from desert soil-derived fungus Talaromyces pinophilus LD-7. Their 2D structures were elucidated by comprehensive interpretation of NMR and HRESIMS data. Electronic circular dichroism calculation was used to establish their absolute configurations. Compounds 2, 10, and 11 showed antiviral activities toward vesicular stomatitis virus with IC50 values of 18, 15, and 23 nM, respectively. The structure-bioactivity relationship indicated that chlorine substitution at C-5 contributed greatly to their antiviral activities. Finally, we identified a new halogenase outside the biosynthetic gene cluster, which was responsible for C-5 halogenation of the precursor isocoumarin 17 as a tailoring step in chlorinated meroterpenoids assembly.

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α-Terpineol, an alcoholic monoterpene with lilac-like aroma, possesses diverse biological activities and has found applications in the food, pharmaceutical, cosmetic, and agricultural industries. Our previous studies indicated that gene PdTP1 was highly expressed in Penicillium digitatum DSM 62840 during the biotransformation of limonene to α-terpineol, while its actual biological functions are not fully understood. Here, PdTP1 was functionally characterized with bioinformatics analysis, subcellular localization, transcriptional activation activity, overexpression, and RNA interference (RNAi) silencing and RNA-seq analysis. Results showed that PdTP1 protein contained a GAL4-like Zn2Cys6 DNA-binding domain and a fungal_trans domain, was located in the nucleus and cell membrane and presented transcriptional activation effect, suggesting that PdTP1 encoded a Zn2Cys6 type transcription factor. Overexpression of PdTP1 in P. digitatum promoted limonene biotransformation and increased α-terpineol production, and opposite results were observed after the silencing of PdTP1. Moreover, transcription factor PdTP1 was found to affect the growth of P. digitatum and participate in ionic stress and oxidative stress responses. RNA-seq data revealed that altering the PdTP1 expression influenced the expression of some genes related to terpene metabolism or biosynthesis, fungal growth, and stress responses. In summary, PdTP1, which encoded a Zn2Cys6 transcription factor, played important roles in improving the production of α-terpineol from limonene and regulating fungal growth and environmental stress responses.

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With the rapid advancement of the Internet of Things, network security has garnered increasing attention from researchers. Applying deep learning (DL) has significantly enhanced the performance of Network Intrusion Detection Systems (NIDSs). However, due to its complexity and "black box" problem, deploying DL-based NIDS models in practical scenarios poses several challenges, including model interpretability and being lightweight. Feature selection (FS) in DL models plays a crucial role in minimizing model parameters and decreasing computational overheads while enhancing NIDS performance. Hence, selecting effective features remains a pivotal concern for NIDSs. In light of this, this paper proposes an interpretable feature selection method for encrypted traffic intrusion detection based on SHAP and causality principles. This approach utilizes the results of model interpretation for feature selection to reduce feature count while ensuring model reliability. We evaluate and validate our proposed method on two public network traffic datasets, CICIDS2017 and NSL-KDD, employing both a CNN and a random forest (RF). Experimental results demonstrate superior performance achieved by our proposed method.

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BACKGROUND: Shengmai San Formula (SMS) is a traditional Chinese medicine (TCM) that has been used to treat wasting-thirst regarded as diabetes mellitus, which occurs disproportionately in obese patients. Therefore, we investigated whether SMS could be used to treat obesity, and explored possible mechanisms by which it might improve glucose and fat metabolism. METHODS: To investigate the effects of SMS on a high-fat diet (HFD)-induced obesity (DIO) model, we studied glucose metabolism via glucose tolerance testing (GTT) and insulin tolerance testing (ITT). Browning of white adipose tissue (WAT) was evaluated using H&E staining, along with browning-related gene and protein expression. Changes in bile acid (BA) levels in serum, liver, ileum, and inguinal white adipose tissue were detected by Ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). In addition, antimicrobial mixture (ABX) and fecal microbial transplantation (FMT) experiments were used to verify the role of gut flora in the effects produced by SMS on HFD-induced obesity model. RESULTS: SMS ameliorated diet-induced dyslipidemia in a dose-dependent manner and reduced glucose intolerance and insulin resistance in DIO mice, helping to restore energy metabolism homeostasis. SMS significantly altered the structure of intestinal microbiome composition, decreasing the abundance of Lactobacillus carrying bile salt hydrolase (BSH) enzymes and thereby increasing the level of conjugated BAs in the blood, ileum, and iWAT. Increased TCA content promoted the secretion of Slit3 from M2 macrophages in iWAT, which activates the protein kinase A/calmodulin-dependent protein kinase II (PKA/CaMKII) signaling pathway in sympathetic neurons via the roundabouts receptor 1(ROBO1). This pathway promotes the synthesis and release of norepinephrine (NE), inducing cyclic adenosine monophosphate (cAMP) release in adipose tissue that activates the cyclic adenosine monophosphate/protein kinase A/phosphorylated hormone-sensitive lipase (cAMP/PKA/pHSL) pathway and enhances WAT browning. ABX treatment eliminated SMS effects on glucose and lipid metabolism in DIO mice, whereas glucose and lipid metabolism in obese mice improved following SMS-FMT and increased the level of serum bile acids. CONCLUSION: SMS affects intestinal flora and bile acid composition in vivo and increased TCA promotes M2 macrophage polarization and Slit3 release in adipose tissue. This induces NE release and increases WAT browning in obese mice, which may be a mechanism by which SMS could be used to treat obesity.

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The world's largest green tide, caused by the nuisance green algae Ulva prolifera, has occurred in the southern Yellow Sea for 16 consecutive years. It is puzzling why the extensive floating green tide occurs exclusively in the southern Yellow Sea, rather than other waters. We speculate that the transition of U. prolifera from a sessile state to a surface-floating one is the underlying cause of the floating green tide. Here we founded that the floating of U. prolifera was attributed to detachment from substrata and appropriate desiccation. The convergence of unreasonable green algae disposal, geographical features and farming patterns of Porphyra (economic red algae) in Subei Shoal contributed to mass production of floating U. prolifera, resulting in the exclusive occurrence of the floating green tides. Inducing the natural inactivation of green algae to prevent the floating of U. prolifera may effectively mitigate the extensive Ulva bloom at zero cost.

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In this work, molecular geometric phase effects are studied using the idea of exact factorization (EF) (Abediet al2010Phys. Rev. Lett.105123002) and exact effective force (Liet al2022Phys. Rev. Lett.128113001). In particular, we performed dynamics simulations for a two-state vibronic coupling model, and interpreted the results in three different perspectives: the Born-Huang expansion, the exact time-dependent potential energy surface (TDPES) and the exact effective force. We find that (i) at particular moment, while the vanishing nuclear density that occurs periodically in space is conventionally attributed to destructive interference of the nuclear wave packet owing to the geometric phase, such phenomenon can be equally well interpreted through the energy perspective, as manifested in the exact TDPES in the EF scheme; (ii) when combined with trajectory-based classical dynamics, the exact effective force obtained through EF qualitatively reproduces the correct nuclear density, while the adiabatic force gives the wrong density, particularly in the interference region. Our results suggest that the exact effective force is a potential starting point for making approximations and improving trajectory-based computational methods towards an accurate description of geometric phase effects.

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OBJECTIVE: Oxidative stress is strongly associated with atopic dermatitis (AD), and increased antioxidant intake could potentially reduce the risk of or alleviate its symptoms. However, the argument is disputed. Therefore, we conducted a Mendelian randomization (MR) analysis to explore the causal relationship between dietary antioxidant vitamin intake and AD. METHODS: We applied MR analysis to examine the causative association between dietary antioxidant vitamin intake (vitamin C, vitamin E, carotene, and retinol) and AD. The genome-wide association study (GWAS) summary data for antioxidant vitamins intake and AD were obtained from the IEU OpenGWAS database and the UK biobank. Our study consisted of two major parts, MR analysis to detect the causal relationship between exposure and outcome, and sensitivity analysis as supplemental evidence to verify the robustness of the results. RESULT: The results revealed a suggestive causal relationship between vitamin E intake and AD (p = 0.038, OR 95% CI = 0.745-0.992). However, there was no causal relationship between the other three vitamins (vitamin C, carotene, and retinol) and AD (p = 0.507, OR 95% CI = 0.826-1.099) (p = 0.890, OR 95% CI = 0.864-1.184) (p = 0.492, OR 95% CI = 0.893-1.264). None of the single nucleotide polymorphisms (SNPs) were detected as heterogeneous and pleiotropy in the sensitivity analysis (p > 0.05). CONCLUSION: The analysis suggested that dietary intake of vitamin E may potentially lower the risk of AD. Conversely, intake of vitamin C, retinol, and carotene is not causally related to AD. Although vitamin E intake could be protective against AD, intake of dietary antioxidant vitamins to prevent or treat AD is not necessary.

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Chronic hepatitis B virus (HBV) infection is a global health problem that substantially increases the risk of developing liver disease. The development of a novel strategy to induce anti-HB seroconversion and achieve a long-lasting immune response against chronic HBV infection remains challenging. Here, we found that chronic HBV infection affected the signaling pathway involved in STING-mediated induction of host immune responses in dendritic cells (DCs) and then generated a lymph node-targeted nanovaccine that co-delivered hepatitis B surface antigen (HBsAg) and cyclic diguanylate monophosphate (c-di-GMP) (named the PP-SG nanovaccine). The feasibility and efficiency of the PP-SG nanovaccine for CHB treatment were evaluated in HBV-carrier mice. Serum samples were analyzed for HBsAg, anti-HBs, HBV DNA, and alanine aminotransferase levels, and liver samples were evaluated for HBV DNA and RNA and HBcAg, accompanied by an analysis of HBV-specific cellular and humoral immune responses during PP-SG nanovaccine treatment. The PP-SG nanovaccine increased antigen phagocytosis and DC maturation, efficiently and safely eliminated HBV, achieved a long-lasting immune response against HBV reinjection, and disrupted chronic HBV infection-induced immune tolerance, as characterized by the generation and multifunctionality of HBV-specific CD8+ T and CD4+ T cells and the downregulation of immune checkpoint molecules. HBV-carrier mice immunized with the PP-SG nanovaccine achieved partial anti-HBs seroconversion. The PP-SG nanovaccine can induce sufficient and persistent viral suppression and achieve anti-HBs seroconversion, rendering it a promising vaccine candidate for clinical chronic hepatitis B therapy.

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In the field of energy storage, supercapacitors have received extensive attention in recent years. However, achieving the expected electrochemical performance and energy density of supercapacitors is still a huge challenge. The design and synthesis of binder-free composite electrode with core-shell structure is an effective strategy to improve the electrochemical performance of supercapacitors. In this paper, a heterogeneous core-shell structured and binder-free electrode material MgCo2O4@Ni(OH)2 (MCO@NH) grown on nickel foam (NF) is prepared by a simple hydrothermal and oil bath method. The unique core-shell structure makes the MCO@NH have a large specific surface area, which provides abundant active sites for ion transport and storage, thereby improving the electrochemical performance. The MCO@NH/NF nanocomposite demonstrates a high specific capacitance (Cs) of 1583 F g-1 at 1 A/g. A solid-state asymmetric supercapacitor (ASC) assembled with MCO@NH/NF and active carbon (AC) exhibits excellent energy density (45 Wh kg-1 at 457.5 W kg-1) and outstanding capacitance (89.51 %) and coulombic efficiency (97.8 %) after 12,000 cycles, evidencing its good operation stability and potential practical applications. Therefore, the prepared core-shell MCO@NH/NF electrode can be a promising candidate for energy storage devices.

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BACKGROUND: Cardiovascular diseases (CVD) remain the leading cause of mortality globally, and the scarcity of scientific evidence regarding the impact of ketogenic diets on CVD risk factors necessitates urgent attention and redress. OBJECTIVES: This meta-analysis evaluates the impact of the ketogenic diet on CVD risk factors compared with control diets through randomized controlled trials (RCTs). METHODS: The study was registered in advance in the PROSPERO database (CRD42023491853). A systematic search was conducted across PubMed, Web of Science, EMBASE, and Cochrane Library to identify relevant RCTs. Fixed and random effects were employed to calculate the mean differences and 95% confidence intervals (CIs) for changes in CVD risk factors pre- and postketogenic diet intervention. RESULTS: A total of 27 RCTs with 1278 participants were analyzed. The ketogenic diet intervention presented increase in total cholesterol (mean differences: 0.36 mmol/L; 95% CI: 0.15, 0.57; I2: 85.1%), low-density lipoprotein cholesterol (mean differences: 0.35 mmol/L; 95% CI: 0.20, 0.50; I2: 73.9%) and high-density lipoprotein cholesterol (mean differences: 0.16 mmol/L; 95% CI: 0.09, 0.23; I2: 86.7%) concentrations. Reductions were observed in the triglyceride (mean differences: -0.20 mmol/L; 95% CI: -0.29, -0.11; I2: 72.2%), blood glucose (mean differences: -0.18 mmol/L; 95% CI: -0.33, -0.02; I2: 76.4%), blood insulin (mean differences: -8.32 pmol/L; 95% CI: -14.52, -2.12; I2: 81.5%), diastolic blood pressure (mean differences: -1.41 mmHg; 95% CI: -2.57, -0.26; I2: 49.1%), weight (mean differences: -2.59 kg; 95% CI: -3.90, -1.28; I2: 87.4%), and body mass index (mean differences: -1.59 kg/m2; 95% CI: -2.32, -0.86; I2: 84.5%) concentrations after implementing ketogenic diets. CONCLUSIONS: Although the ketogenic diet demonstrates benefits in terms of triglyceride, blood pressure, weight, and glycemic control, its impact on CVD risk factors, especially the elevated total cholesterol and low-density lipoprotein cholesterol concentrations, warrants a cautious approach.

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Neuroscience research has made immense progress over the last decade, but our understanding of the brain remains fragmented and piecemeal: the dream of probing an arbitrary brain region and automatically reading out the information encoded in its neural activity remains out of reach. In this work, we build towards a first foundation model for neural spiking data that can solve a diverse set of tasks across multiple brain areas. We introduce a novel self-supervised modeling approach for population activity in which the model alternates between masking out and reconstructing neural activity across different time steps, neurons, and brain regions. To evaluate our approach, we design unsupervised and supervised prediction tasks using the International Brain Laboratory repeated site dataset, which is comprised of Neuropixels recordings targeting the same brain locations across 48 animals and experimental sessions. The prediction tasks include single-neuron and region-level activity prediction, forward prediction, and behavior decoding. We demonstrate that our multi-task-masking (MtM) approach significantly improves the performance of current state-of-the-art population models and enables multi-task learning. We also show that by training on multiple animals, we can improve the generalization ability of the model to unseen animals, paving the way for a foundation model of the brain at single-cell, single-spike resolution. Project page and code: https://ibl-mtm.github.io/.