Age, sex, and APOE gene-specific associations between dynapenic obesity and dementia in a large cohort.

OBJECTIVE: To investigate the associations between dynapenic obesity and the risk of dementia, and the modifying effects of age, sex, and the APOE gene, using a large population-based cohort. METHODS: 279,884 participants aged 55 and above from the UK Biobank were included. The participants were classified into four categories based on body mass index and hand grip strength: healthy, obesity, dynapenia, and dynapenic obesity. The incident dementia was identified based on linked hospital records and death register data. Cox proportional hazards regression models were used to estimate the associations, followed by age-, sex-, and apolipoprotein E (APOE) gene-stratified analyses. RESULTS: During the median follow-up of 12.4 years, 5,170 (1.8%) participants developed dementia. Compared with the healthy group, participants with dynapenic obesity had 67% higher dementia risk (hazard ratio [HR]: 1.67, 95% confidence interval [CI]: 1.44-1.94). Compared with the healthy group, higher risks of dementia in participants with dynapenic obesity were respectively observed in male (HR: 2.03, 95% CI: 1.65-2.50), younger (<65 years, HR: 1.97, 95% CI: 1.55-2.50), and non-ε4-carrier (HR: 1.97, 95% CI: 1.60-2.44) (all P for interaction <0.05). In participants under 65 years and non-ε4-carrier, those with dynapenic obesity had the highest risk of dementia (HR: 2.63, 95% CI: 1.91-3.62), compared with the healthy group (P for second order interaction = 0.026). CONCLUSIONS: Dynapenic obesity is associated with increased risks of dementia, especially in participants under 65 years and non-ε4-carrier, suggesting the importance of managing dynapenic obesity in the prevention of cognition-related disorders.

Dietary patterns, metabolomics and frailty in a large cohort of 120 000 participants.

Objective: To examine the associations of dietary patterns with frailty and whether metabolic signatures (MSs) mediate these associations. Methods: We used UK Biobank data to examine (1) the associations of four dietary patterns (i.e., alternate Mediterranean diet [aMED], Recommended Food Score [RFS], Dietary Approaches to Stop Hypertension [DASH] and Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet) with frailty (measured by the frailty phenotype and the frailty index) using multivariable logistic regression (analytic sample 1: N = 124 261; mean age = 57.7 years), and (2) the mediating role of MSs (weighted sums of the metabolites selected from 168 plasma metabolites using the LASSO algorithm) in the above associations via mediation analysis (analytic sample 2: N = 26 270; mean age = 57.7 years). Results: Four dietary patterns were independently associated with frailty (all P < 0.001). For instance, compared to participants in the lowest tertile for RFS, those in the intermediate (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.74, 0.89) and highest (OR: 0.62; 95% CI: 0.56, 0.68) tertiles had a lower risk of frailty. We found that 98, 68, 123 and 75 metabolites were associated with aMED, RFS, DASH and MIND, respectively, including 16 common metabolites (e.g., fatty acids, lipoproteins, acetate and glycoprotein acetyls). The MSs based on these metabolites partially mediated the association of the four dietary patterns with frailty, with the mediation proportion ranging from 26.52% to 45.83%. The results were robust when using another frailty measure, the frailty index. Conclusions: The four dietary patterns were associated with frailty, and these associations were partially mediated by MSs. Adherence to healthy dietary patterns may potentially reduce frailty development by modulating metabolites.

How do the main components influence the VOCs emission characteristics and formation pathways during moso bamboo heat treatment?

Bamboo heat treatment will cause plenty of release of volatile organic compounds (VOCs) into the atmosphere which are important precursors for ozone (O3) formation. In this study, dewaxed bamboo was heat-treated at 180 °C for 2 h to investigate the emission characteristics and the formation pathways of VOCs during heat treatment by removing different main components. The results showed that aldehydes (22.61%-57.54%) and esters (14.64%-38.88%) are the primary VOCs released during heat treatment. These compounds mainly originate from the degradation of hemicellulose, lignin, cellulose, and the linkage bonds between them in bamboo. During the bamboo heat treatment, the degradation of CO, CH, and CO bonds in hemicellulose results in the release of 5-hydroxymethylfurfural, 3-furfural, and 1-(+)-ascorbic acid 2,6-dihexadecanoate. The breakage of benzene ring group and the CO and CH bonds of lignin leading to the emission of VOCs including m-Formylphenol, Vanillin, and Syringaldehyde. The degradation of aliphatic CH, CC, and CO bonds in the amorphous region of cellulose contributes to an enhanced release of alcohols, olefins, and alkanes. It is calculated that acids (28.92%-59.47%), esters (10.10%-22.03%) and aldehydes (17.88%-39.91%) released during heat treatment contributed more to Ozone Formation Potential (OFP).

Identification of novel pathways and immune profiles related to sarcopenia.

Introduction: Sarcopenia is a progressive deterioration of skeletal muscle mass strength and function. Methods: To uncover the underlying cellular and biological mechanisms, we studied the association between sarcopenia's three stages and the patient's ethnicity, identified a gene regulatory network based on motif enrichment in the upregulated gene set of sarcopenia, and compared the immunological landscape among sarcopenia stages. Results: We found that sarcopenia (S) was associated with GnRH, neurotrophin, Rap1, Ras, and p53 signaling pathways. Low muscle mass (LMM) patients showed activated pathways of VEGF signaling, B-cell receptor signaling, ErbB signaling, and T-cell receptor signaling. Low muscle mass and physical performance (LMM_LP) patients showed lower enrichment scores in B-cell receptor signaling, apoptosis, HIF-1 signaling, and the adaptive immune response pathways. Five common genes among DEGs and the elastic net regression model, TTC39DP, SLURP1, LCE1C, PTCD2P1, and OR7E109P, were expressed between S patients and healthy controls. SLURP1 and LCE1C showed the highest expression levels among sarcopenic Chinese descent than Caucasians and Afro-Caribbeans. Gene regulatory analysis of top upregulated genes in S patients yielded a top-scoring regulon containing GATA1, GATA2, and GATA3 as master regulators and nine predicted direct target genes. Two genes were associated with locomotion: POSTN and SLURP1. TTC39DP upregulation was associated with a better prognosis and stronger immune profile in S patients. The upregulation of SLURP1 and LCE1C was associated with a worse prognosis and weaker immune profile. Conclusion: This study provides new insight into sarcopenia's cellular and immunological prospects and evaluates the age and sarcopenia-related modifications of skeletal muscle.

Review of rehabilitation protocols for brachial plexus injury.

Brachial plexus injury (BPI) is one of the most serious peripheral nerve injuries, resulting in severe and persistent impairments of the upper limb and disability in adults and children alike. With the relatively mature early diagnosis and surgical technique of brachial plexus injury, the demand for rehabilitation treatment after brachial plexus injury is gradually increasing. Rehabilitation intervention can be beneficial to some extent during all stages of recovery, including the spontaneous recovery period, the postoperative period, and the sequelae period. However, due to the complex composition of the brachial plexus, location of injury, and the different causes, the treatment varies. A clear rehabilitation process has not been developed yet. Rehabilitation therapy that has been widely studied focusing on exercise therapy, sensory training, neuroelectromagnetic stimulation, neurotrophic factors, acupuncture and massage therapy, etc., while interventions like hydrotherapy, phototherapy, and neural stem cell therapy are less studied. In addition, rehabilitation methods in some special condition and group often neglected, such as postoperative edema, pain, and neonates. The purpose of this article is to explore the potential contributions of various methods to brachial plexus injury rehabilitation and to provide a concise overview of the interventions that have been shown to be beneficial. The key contribution of this article is to form relatively clear rehabilitation processes based on different periods and populations, which provides an important reference for the treatment of brachial plexus injuries.

Self-Assembly of Selenium-Doped Carbon Quantum Dots as Antioxidants for Hepatic Ischemia-Reperfusion Injury Management.

Hepatic ischemia-reperfusion injury (HIRI) is a critical complication after liver surgery that negatively affects surgical outcomes of patients with the end-stage liver-related disease. Reactive oxygen species (ROS) are responsible for the development of ischemia-reperfusion injury and eventually lead to hepatic dysfunction. Selenium-doped carbon quantum dots (Se-CQDs) with an excellent redox-responsive property can effectively scavenge ROS and protect cells from oxidation. However, the accumulation of Se-CQDs in the liver is extremely low. To address this concern, the fabrication of Se-CQDs-lecithin nanoparticles (Se-LEC NPs) is developed through self-assembly mainly driven by the noncovalent interactions. Lecithin acting as the self-assembly building block also makes a pivotal contribution to the therapeutic performance of Se-LEC NPs due to its capability to react with ROS. The fabricated Se-LEC NPs largely accumulate in the liver, effectively scavenge ROS and inhibit the release of inflammatory cytokines, thus exerting beneficial therapeutic efficacy on HIRI. This work may open a new avenue for the design of self-assembled Se-CQDs NPs for the treatment of HIRI and other ROS-related diseases.

Electrical stimulation therapy for peripheral nerve injury.

Peripheral nerve injury is common and frequently occurs in extremity trauma patients. The motor and sensory impairment caused by the injury will affect patients' daily life and social work. Surgical therapeutic approaches don't assure functional recovery, which may lead to neuronal atrophy and hinder accelerated regeneration. Rehabilitation is a necessary stage for patients to recover better. A meaningful role in non-pharmacological intervention is played by rehabilitation, through individualized electrical stimulation therapy. Clinical studies have shown that electrical stimulation enhances axon growth during nerve repair and accelerates sensorimotor recovery. According to different effects and parameters, electrical stimulation can be divided into neuromuscular, transcutaneous, and functional electrical stimulation. The therapeutic mechanism of electrical stimulation may be to reduce muscle atrophy and promote muscle reinnervation by increasing the expression of structural protective proteins and neurotrophic factors. Meanwhile, it can modulate sensory feedback and reduce neuralgia by inhibiting the descending pathway. However, there are not many summary clinical application parameters of electrical stimulation, and the long-term effectiveness and safety also need to be further explored. This article aims to explore application methodologies for effective electrical stimulation in the rehabilitation of peripheral nerve injury, with simultaneous consideration for fundamental principles of electrical stimulation and the latest technology. The highlight of this paper is to identify the most appropriate stimulation parameters (frequency, intensity, duration) to achieve efficacious electrical stimulation in the rehabilitation of peripheral nerve injury.

Coded phase-sensitive OTDR with delayed polarization multiplexing for a WFBG array.

Polarization fading degrades the performance of phase-sensitive optical time-domain reflectometry (φ-OTDR) seriously and has to be suppressed. A novel scheme is proposed in this paper to combat polarization fading, which features a quite simple transceiver structure by exploiting both polarization diversity through delayed polarization multiplexing and the aperiodic autocorrelation of pseudorandom binary sequence. The components of Jones matrix of a sensing fiber are then shown at those four peaks of aperiodic autocorrelation and can be obtained directly without complicated computation to give a polarization independent phase variation due to vibration. Moreover, the scheme does not require stringent match between the delayed time and the spacing between sensors. The proposed scheme is demonstrated through experiment on a weak fiber Bragg grating (WFBG) array, which shows a high crosstalk rejection ratio among sensors of more than 50 dB and a high dynamic range of more than 30 dB.

Role of prebiotics in enhancing the function of next-generation probiotics in gut microbiota.

With the development of high-throughput DNA sequencing and molecular analysis technologies, next-generation probiotics (NGPs) are increasingly gaining attention as live bacterial therapeutics for treatment of diseases. However, compared to traditional probiotics, NGPs are much more vulnerable to the harsh conditions in the human gastrointestinal tract, and their functional mechanisms in the gut are more complex. Prebiotics have been confirmed to play a critical role in improving the function and viability of traditional probiotics. Defined as substrates that are selectively utilized by host microorganisms conferring a health benefit, prebiotics are also important for NGPs. This review summarizes potential prebiotics for use with NGPs and clarifies their characteristics and functional mechanisms. Then we particularly focus on illustrating the protective effects of various prebiotics by enhancing the antioxidant capacity and their resistance to digestive fluids. We also elucidate the role of prebiotics in regulating anti-bacterial effects, intestinal barrier maintenance, and cross-feeding mechanisms of NPGs. With the expanding range of candidate NGPs and prebiotic substrates, more studies need to be conducted to comprehensively elucidate the interactions between prebiotics and NGPs outside and inside hosts, in order to boost their nutritional and healthcare applications.

Cognitive Function and Upper Limb Rehabilitation Training Post-Stroke Using a Digital Occupational Training System.

Stroke rehabilitation often requires frequent and intensive therapy to improve functional recovery. Virtual reality (VR) technology has shown the potential to meet these demands by providing engaging and motivating therapy options. The digital occupational training system is a VR application that utilizes cutting-edge technologies, including multi-touch screens, virtual reality, and human-computer interaction, to offer diverse training techniques for advanced cognitive capacity and hand-eye coordination abilities. The objective of this study was to assess the effectiveness of this program in enhancing cognitive function and upper extremity rehabilitation in stroke patients. The training and assessment consist of five cognitive modules covering perception, attention, memory, logical reasoning, and calculation, along with hand-eye coordination training. This research indicates that after eight weeks of training, the digital occupational training system can significantly improve cognitive function, daily living skills, attention, and self-care abilities in stroke patients. This software can be employed as a time-saving and clinically effective rehabilitation aid to complement traditional one-on-one occupational therapy sessions. In summary, the digital occupational training system shows promise and offers potential financial benefits as a tool to support the functional recovery of stroke patients.

Molecular classification of human papillomavirus-positive cervical cancers based on immune signature enrichment.

Background: Human papillomavirus-positive (HPV+) cervical cancers are highly heterogeneous in clinical and molecular characteristics. Thus, an investigation into their heterogeneous immunological profiles is meaningful in providing both biological and clinical insights into this disease. Methods: Based on the enrichment of 29 immune signatures, we discovered immune subtypes of HPV+ cervical cancers by hierarchical clustering. To explore whether this subtyping method is reproducible, we analyzed three bulk and one single cell transcriptomic datasets. We also compared clinical and molecular characteristics between the immune subtypes. Results: Clustering analysis identified two immune subtypes of HPV+ cervical cancers: Immunity-H and Immunity-L, consistent in the four datasets. In comparisons with Immunity-L, Immunity-H displayed stronger immunity, more stromal contents, lower tumor purity, proliferation potential, intratumor heterogeneity and stemness, higher tumor mutation burden, more neoantigens, lower levels of copy number alterations, lower DNA repair activity, as well as better overall survival prognosis. Certain genes, such as MUC17, PCLO, and GOLGB1, showed significantly higher mutation rates in Immunity-L than in Immunity-H. 16 proteins were significantly upregulated in Immunity-H vs. Immunity-L, including Caspase-7, PREX1, Lck, C-Raf, PI3K-p85, Syk, 14-3-3_epsilon, STAT5-α, GATA3, Src_pY416, NDRG1_pT346, Notch1, PDK1_pS241, Bim, NF-kB-p65_pS536, and p53. Pathway analysis identified numerous immune-related pathways more highly enriched in Immunity-H vs. Immunity-L, including cytokine-cytokine receptor interaction, natural killer cell-mediated cytotoxicity, antigen processing and presentation, T/B cell receptor signaling, chemokine signaling, supporting the stronger antitumor immunity in Immunity-H vs. Immunity-L. Conclusion: HPV+ cervical cancers are divided into two subgroups based on their immune signatures' enrichment. Both subgroups have markedly different tumor immunity, progression phenotypes, genomic features, and clinical outcomes. Our data offer novel perception in the tumor biology as well as clinical implications for HPV+ cervical cancer.

Carbonic anhydrase 14 protects the liver against the cytotoxicity of bile acids in a biliary bicarbonate umbrella-related manner.

AIMS: The "biliary bicarbonate umbrella" is considered a critical protective mechanism of cholangiocytes against bile acid cytotoxicity. Defects in its function are closely related to various chronic cholangiopathies. Carbonic anhydrase 14 (CAR14) is an important element of normal bicarbonate homeostasis and is highly expressed in liver tissues. This study aimed to explore the effects and mechanism of CAR14 on bile acid cytotoxicity in the liver. MAIN METHODS: In vitro, alterations in the whole transcriptome after Car14 gene silencing were assessed by RNA sequencing, and the expression changes in key factors in the "biliary bicarbonate umbrella" were verified by qRT-PCR and western blotting. In vivo, 7 days after bile duct ligation in Car14 gene knockout and wild-type mice, their serum liver function indicators, liver histopathology, hepatic bile acid composition, and whole hepatic proteomic changes were investigated. KEY FINDINGS: In vitro, the transcriptional alterations induced by Car14 silencing were mainly related to transmembrane transport, including ion exchangers and ion channels that are vital in the "biliary bicarbonate umbrella" such as AE2 and CFTR. In vivo, Car14 knockout induced more severe liver dysfunction, hepatic fibrosis and bile duct lesions, and resulted in increased hepatic bile acid levels and altered bile acid compositions in BDL mice. In response, the uptake and synthesis of bile acids in the liver of Car14 knockout mice were suppressed. SIGNIFICANCE: Our data revealed that CAR14 protects the liver against bile acid toxicity, which might provide a theoretical basis for clinical strategies to prevent or treat bile duct diseases.

Comparison of the efficacy and safety of sacral root magnetic stimulation with transcutaneous posterior tibial nerve stimulation in the treatment of neurogenic detrusor overactivity: an exploratory randomized controlled trial.

Background: Both repetitive sacral root magnetic stimulation (rSMS) and transcutaneous posterior tibial nerve stimulation (TTNS) have demonstrated clinical benefits for lower urinary tract dysfunction. However it still remains unclear that which method is more effective and safer to treat neurogenic detrusor overactivity (NDO). Methods: From December 2020 to December 2021, 50 patients (31 men and 19 women, aged 47.9±12.4 years) with NDO secondary to suprasacral spinal cord injury (SCI) were enrolled and randomly allocated to the rSMS or TTNS group based on a computer-generated random numbers table. The stimulation was applied continuously 5 times per week for 20 sessions. Urodynamic test was conducted at baseline and the day after the final 20th treatment session. The primary outcome was the individual change (Δ) in maximum cystometric capacity (MCC) from baseline to post-treatment. Secondary outcomes included changes (Δ) for the following parameters: volume at 1st involuntary detrusor contraction (1st IDCV), maximal detrusor pressure (Pdetmax), bladder compliance (BC), postvoid residual (PVR) volume, and bladder voiding efficiency (BVE). Additionally, adverse reactions including pain and skin irritation during stimulation were observed and recorded as safety outcomes. Results: Finally 47 patients completed the study (23 in rSMS and 24 in TTNS group). A per-protocol (PP) analysis was performed, and Mann-Whitney U test and unpaired t-test were used for statistical analysis. Compared with the efficacy of TTNS, rSMS showed statistically greater ΔMCC [median +43 mL (IQR, 22-62 mL) vs. +20 mL (IQR, 15-25 mL), P=0.001, with a between-group difference of +22 mL (95% CI: +7 to +35 mL)] and ΔBVE [median +10.0% (IQR, 3.8-15.7%) vs. +3.5% (IQR, 0.0-7.8%), P=0.003, with a between-group difference of +5.9% (95% CI: +1.2% to +9.7%)]. No significant differences were found in Δ1st IDCV (P=0.40), ΔPdetmax (P=0.67), ΔBC (P=0.79) and ΔPVR (P=0.92) between the two groups. Meanwhile, patients exhibited high tolerance to both protocols, and no adverse reactions were observed. Conclusions: RSMS may be more effective to improve urodynamics in the treatment for NDO than TTNS, cause it led to a statistical improvement in bladder capacity and voiding efficiency, without any side effects. RSMS is thus worthy of further clinical promotion. Trial Registration: Chinese Clinical Trial Registry ChiCTR2100050663.

Effect and Mechanism of Bifidobacterium animalis B94 in the Prevention and Treatment of Liver Injury in Rats.

Objective: To investigate the effect of Bifidobacterium animalis B94 on the prevention and treatment of liver injury in rats and to elucidate the underlying mechanism of this relationship. Methods: Specific pathogen-free (SPF) rats were selected as the healthy control group, liver injury group and B94 treatment group, with 6 rats in each group. After the model was established, the experimental animals were tested for serum liver function indicators, gut microbiota composition, metabolite composition, and histopathology. Results: The albumin/globulin ratio and serum TBA, alanine aminotransferase, aspartate aminotransferase, and indirect bilirubin levels in the B94 treatment group were significantly lower than those in the liver injury group. 16S rRNA analysis showed that the gut microbiota of the three groups of rats were significantly different. Metabolic profile analysis showed that there were significant differences in the gut metabolomes of the three groups. Haematoxylin-eosin staining of the intestinal mucosa and liver tissues showed that the degree of liver and intestinal tissue damage in the B94 treatment group was significantly lower than that in the liver injury group. Conclusion: Bifidobacterium animalis B94 can affect the process of liver injury in rats by improving liver function, reducing intestinal damage, and regulating gut microbiota and metabolite production.

Early physical therapy for a patient affected by coronavirus disease 2019 (COVID-19) on awake veno-venous extracorporeal membrane oxygenation: a case report.

Since December 8, 2019, an acute respiratory illness has spread rapidly in China, causing 3,097 people to die as of March 7, and it has become a global crisis. The common symptoms are fever, fatigue, dry cough, myalgia, and dyspnea. This case report presents a 36-year-old male who was diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected pneumonia on February 2, 2020. This patient received veno-venous extracorporeal membrane oxygenation (V-V ECMO) last for 10 days as salvage treatment as his condition became critical in the acute setting. As soon as his status became stable, he began to receive an early rehabilitation program performed by our rehabilitation team. After 43 days of treatment under the efforts of our teamwork, the patient was able to walk 800 meters, and then was discharged the next day. To our knowledge, this is the first report of early physical therapy for a patient with coronavirus disease 2019 (COVID-19) who was receiving extracorporeal membrane oxygenation (ECMO) whilst awake. This case indicates that early physical rehabilitation is safe and feasible and resulted in an expedited recovery using ECMO whilst awake. The goals for physiotherapy management include avoiding atelectasis, airway clearance, weaning and increasing the functional level. This report may contribute to the current literature on early physical therapy rehabilitation programs for awake ECMO patients.

Robust automated radiation therapy treatment planning using scenario-specific dose prediction and robust dose mimicking.

PURPOSE: We present a framework for robust automated treatment planning using machine learning, comprising scenario-specific dose prediction and robust dose mimicking. METHODS: The scenario dose prediction pipeline is divided into the prediction of nominal dose from input image and the prediction of scenario dose from nominal dose, each using a deep learning model with U-net architecture. By using a specially developed dose-volume histogram-based loss function, the predicted scenario doses are ensured sufficient target coverage despite the possibility of the training data being non-robust. Deliverable plans may then be created by solving a robust dose mimicking problem with the predictions as scenario-specific reference doses. RESULTS: Numerical experiments are performed using a data set of 52 intensity-modulated proton therapy plans for prostate patients. We show that the predicted scenario doses resemble their respective ground truth well, in particular while having target coverage comparable to that of the nominal scenario. The deliverable plans produced by the subsequent robust dose mimicking were showed to be robust against the same scenario set considered for prediction. CONCLUSIONS: We demonstrate the feasibility and merits of the proposed methodology for incorporating robustness into automated treatment planning algorithms.

Polysaccharide from Scutellaria barbata D. Don attenuates inflammatory response and microbial dysbiosis in ulcerative colitis mice.

This study aimed to evaluate the effect of polysaccharides from Scutellaria barbata D. Don (PSB) on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in C57BL/6 mice. PSB was isolated, and its chemical composition was preliminarily identified. The average molecular weight of PSB was 1.25 × 104 Da and it was mainly comprised of arabinose, galacturonic acid, galactose, glucose, and glucuronic acid in molar ratios of 1.00:2.09:4.52:4.73:4.90. PSB (25 and 50 mg/kg) and sulfasalazine (200 mg/kg) significantly relieved weight loss and symptoms and alleviated colonic pathological injury in mice with UC. In addition, PSB decreased the levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), IL-6, and IL-18 in the colon and suppressed DSS-induced activation of the nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. The improvement in the abundance of several bacterial genera, such as the Lachnospiraceae_NK4A136_group, Ruminococcus, Bacteroides, Parasutterella, and Eisenbergiella might be closely related to the reduction in the intestinal inflammatory response after PSB treatment. These results revealed that PSB could potentially be utilized to treat UC and other diseases associated with an imbalance in the intestinal flora.

Subtyping of Human Papillomavirus-Positive Cervical Cancers Based on the Expression Profiles of 50 Genes.

Background: Human papillomavirus-positive (HPV+) cervical cancers are highly heterogeneous in molecular and clinical features. However, the molecular classification of HPV+ cervical cancers remains insufficiently unexplored. Methods: Based on the expression profiles of 50 genes having the largest expression variations across the HPV+ cervical cancers in the TCGA-CESC dataset, we hierarchically clustered HPV+ cervical cancers to identify new subtypes. We further characterized molecular, phenotypic, and clinical features of these subtypes. Results: We identified two subtypes of HPV+ cervical cancers, namely HPV+G1 and HPV+G2. We demonstrated that this classification method was reproducible in two validation sets. Compared to HPV+G2, HPV+G1 displayed significantly higher immune infiltration level and stromal content, lower tumor purity, lower stemness scores and intratumor heterogeneity (ITH) scores, higher level of genomic instability, lower DNA methylation level, as well as better disease-free survival prognosis. The multivariate survival analysis suggests that the disease-free survival difference between both subtypes is independent of confounding variables, such as immune signature, stemness, and ITH. Pathway and gene ontology analysis confirmed the more active tumor immune microenvironment in HPV+G1 versus HPV+G2. Conclusions: HPV+ cervical cancers can be classified into two subtypes based on the expression profiles of the 50 genes with the largest expression variations across the HPV+ cervical cancers. Both subtypes have significantly different molecular, phenotypic, and clinical features. This new subtyping method captures the comprehensive heterogeneity in molecular and clinical characteristics of HPV+ cervical cancers and provides potential clinical implications for the diagnosis and treatment of this disease.

Probabilistic Pareto plan generation for semiautomated multicriteria radiation therapy treatment planning.

Objective.We propose a semiautomatic pipeline for radiation therapy treatment planning, combining ideas from machine learning-automated planning and multicriteria optimization (MCO).Approach.Using knowledge extracted from historically delivered plans, prediction models for spatial dose and dose statistics are trained and furthermore systematically modified to simulate changes in tradeoff priorities, creating a set of differently biased predictions. Based on the predictions, an MCO problem is subsequently constructed using previously developed dose mimicking functions, designed in such a way that its Pareto surface spans the range of clinically acceptable yet realistically achievable plans as exactly as possible. The result is an algorithm outputting a set of Pareto optimal plans, either fluence-based or machine parameter-based, which the user can navigate between in real time to make adjustments before a final deliverable plan is created.Main results.Numerical experiments performed on a dataset of prostate cancer patients show that one may often navigate to a better plan than one produced by a single-plan-output algorithm.Significance.We demonstrate the potential of merging MCO and a data-driven workflow to automate labor-intensive parts of the treatment planning process while maintaining a certain extent of manual control for the user.

A biocompatible two-photon absorbing fluorescent mitochondrial probe for deep in vivo bioimaging.

Mitochondria, key organelles which keep in tune with energy demands for eukaryotic cells, are firmly associated with neurological conditions and post-traumatic rehabilitation. In vivo fluorescence imaging of mitochondria, especially with deep tissue penetration, would open a window to investigate the actual context of the brain. However, the depth of traditional two-photon mitochondrial fluorescence imaging is still limited due to the poor biological compatibility or low two-photon absorption cross-sections. A biocompatible mitochondria-targeted two-photon fluorescent dye (FO2) with an excellent two-photon absorption cross-section (the maximum of 1184 GM at 790 nm) and low cellular toxicity was designed and synthesized to overcome this problem. With this dye, we reached an imaging depth of ca. 640 µm during mitochondrial imaging of cortical cells in live animals. FO2 could be an excellent mitochondrial probe for live animal neural imaging to investigate the function and dysfunction of mitochondria in the brain.