Interactions between mild depressive symptoms and amyloid pathology on the trajectory of neurodegeneration, cognitive decline, and risk of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) was driven by the interplay between modifiable environmental factors and ß-amyloid (Aß) pathology. We aimed to investigate the interaction effects of mild depressive symptoms (MDS) with Aß on AD development. METHODS: Longitudinal data of 1746 non-demented adults (mean age = 73 years, female = 53 %, maximum = 10 years) were derived from the Alzheimer's Disease Neuroimaging Initiative cohort. MDS was separately defined by the baseline status, longitudinal latent class, and average intensity during follow-up. Amyloid-positive (A+) status was determined based on cerebrospinal fluid levels of ß-amyloid. Regression models were employed to analyze the interactive effects of MDS with A+ on cognitive decline, neurodegeneration, and AD incidence. RESULTS: Individuals with both A+ status and MDS at baseline experienced the fastest neurodegeneration (p < 0.01), cognitive decline (p < 0.05), and a higher risk of developing AD (HR = 5.23, p < 0.001). Furthermore, A+ participants with the trajectory of increasing depressive symptoms demonstrated more pronounced neurodegeneration (p < 0.001), cognitive decline (p < 0.01), and elevated risk of AD (HR = 10.45, p < 0.001). Finally, A+ status in combination with a higher average intensity of depressive symptoms was associated with faster brain atrophy (p < 0.01) and brain metabolism decline (p < 0.05), cognitive decline (p < 0.05), and higher AD risk (HR = 13.99, p < 0.001). CONCLUSION: These findings emphasized that the MDS-Aß interaction relationship should be considered in risk stratification, prediction, and early management of neurodegeneration and cognitive decline in the pre-dementia stage.

Injectable polypeptide-polysaccharide depot for preventing postoperative tumor recurrence by concurrent in situ chemotherapy and brachytherapy.

Chemotherapy and radiotherapy in combination with sequence regimens are recognized as the current major strategy for suppressing postoperative tumor recurrence. However, systemic side effects and poor in-field cooperation of the two therapies seriously impair the therapeutic efficacy of patients. The combination of brachytherapy and chemotherapy through innovative biomaterials has proven to be an important strategy to achieve synergistic effects of radiotherapy and chemotherapy in-time and in-field. However, for postoperative chemoradiotherapy, as far as we know, there are few relevant reports. Herein, an injectable pH-responsive polypeptide-polysaccharide depot for concurrent in situ chemotherapy and brachytherapy was developed by encapsulating vincristine into iodine-125 radionuclide labeled hydrogel. This depot hydrogel was prepared by dynamic covalent bonds of Schiff base between aldehydeated hyaluronic acid and polyethylene glycol-polytyrosine. Therefore, this hydrogel enables smart response to tumor acidic microenvironment, rapid release of the encapsulated vincristine and an enhanced uptake effect by tumor cells, which significantly reduces IC50 of vincristine for the anaplasia Wilms' tumor cells in vitro. This depot hydrogel shows excellent stability and biocompatibility, and maintains for 14 days after in situ injection in a postoperative model of anaplasia Wilms' tumor. After injection at the cavity of tumor excision, responsively-released vincristine and the radioactive iodine-125 exerted excellent killing effects on residual tumor cells, inhibiting tumor relapse and liver metastasis of the recurrent tumor. Hence, this study proposes an effective therapeutic strategy for inhibiting anaplasia Wilms' tumor recurrence, which provides a new approach for concurrent postoperative chemo-radiotherapy and a desirable guidance in regimen execution of pediatric refractory tumors.

Comparisons of clinical characteristics, treatments, and outcomes among different pathological subtypes of chondrosarcoma in the spine.

INTRODUCTION: Spinal chondrosarcoma exhibits higher invasiveness and a worse prognosis compared to chondrosarcoma in the extremities. The prognosis and therapeutic plan vary greatly among different pathological subtypes of chondrosarcoma. This study aimed to analyze the differences in clinical characteristics, molecular features, therapeutic effects, and prognostic factors among the subtypes of chondrosarcoma in the spine. METHODS: A retrospective review was conducted on 205 patients with spinal chondrosarcoma. The clinical features and immunohistochemical (IHC) markers were compared among the pathological subtypes of chondrosarcoma grade 1, grade 2, grade 3, mesenchymal chondrosarcoma (MCS), dedifferentiated chondrosarcoma (DCS), and clear cell chondrosarcoma (CCCS). Chondrosarcoma grade 1/2/3 are collectively referred to as conventional chondrosarcoma (CCS) for multivariate survival analysis. Univariate and multivariate analyses were performed to investigate independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS) in patients with spinal chondrosarcoma. Furthermore, independent prognostic factors for OS and RFS were identified in CCS and MCS. RESULTS: MCS patients were younger than the other subtypes. Patients with chondrosarcoma grade 1/2 had better OS than those with chondrosarcoma grade 3, MCS and DCS, while only chondrosarcoma grade 1 patients showed better RFS than chondrosarcoma grade 2/3, MCS and DCS patients. Ki-67 index was higher in chondrosarcoma grade 3, MCS and DCS than chondrosarcoma grade 1/2. The comparison of IHC markers further highlighted the overexpression of P53/MDM2 in MCS and DCS. Gross total resection, including en-bloc and piecemeal resection, significantly improved OS and RFS for CCS patients, while only en-bloc resection significantly improved the prognosis of MCS patients. Chemotherapy appeared to be important for the OS of MCS patients. CONCLUSION: P53/MDM2 pathway was upregulated in MCS and DCS compared to chondrosarcoma grade 1/2. Radical tumor resection is crucial for the treatment of spinal chondrosarcoma, while MCS patients require further comprehensive treatments perioperatively.

Clinical features and mechanisms of neck myoclonus in narcolepsy.

STUDY OBJECTIVES: The purpose of this study was to investigate the effects of neck myoclonus (NM) on sleep quality and daytime sleepiness in patients with narcolepsy (NT) and to further explore possible underlying mechanisms. METHODS: We included 72 patients with narcolepsy type 1 (NT1), 34 patients with narcolepsy type 2 (NT2) and 33 healthy controls. Patients underwent questionnaires, lumbar puncture procedure, polysomnography, and multiple sleep latency test (MSLT). Healthy controls underwent polysomnography and questionnaires. Orexin-A levels in the cerebrospinal fluid (CSF) were analyzed by radioimmunoassay. Three catecholamines, including dopamine, norepinephrine and epinephrine, in the CSF were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: Both the NT1 and NT2 groups displayed a higher level of NM incidence rate and index compared to the control group in PSG. NT1 displayed greater MSLT REM--NM incidence rate and index than NT2. NM were often associated with arousal or awakening and body movements, which had a prominent influence on sleep quality in both narcoleptic patients and controls. There was a positive correlation between the NM index and the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale (SSS) and Ullanlinna Narcolepsy Scale (UNS) scores in NT1 patients. In MSLT of NT1 patients, REM-NM index were positively correlated with the CSF dopamine levels, and there were elevated dopamine levels but reduced orexin-A levels in patients with REM-NM. CONCLUSION: NM incidence rate and index were high in patients with narcolepsy, which had a huge effect on sleep quality and aggravated daytime sleepiness. NM should be considered pathological and viewed as a new sleep-related movement disorder. Orexin-A and dopamine may be involved in the development of NM.

Bioaccessibility and bioavailability of exogenous and endogenous toxic substances in traditional Chinese medicine and their significance in risk assessment.

Scientific risk assessment of exogenous and endogenous toxic substances in traditional Chinese medicine (TCM) is of great significance. The present review comprises a comprehensive summary of progress in the health risk assessment of harmful exogenous substances in TCMs. Such substances include heavy metals, pesticide residues, biotoxins, and endogenous toxic components involving pyrrolizidine alkaloids. The review also discusses the strengths and weaknesses of various bioaccessibility and bioavailability models, and their applications in risk assessment. Future avenues of risk assessment research are highlighted, including further exploration of risk assessment parameters, innovation of bioaccessibility and bioavailability techniques, enhancement of probabilistic risk assessment combined with bioavailability, improvement of cumulative risk assessment strategies, and formulation of strategies for reducing relative bioavailability (RBA) values in TCMs. Such efforts represent an attempt to develop a risk assessment system that is capable of evaluating the exogenous and endogenous toxic substances in TCMs to ensure its safe use in clinics, and to promote the sustainable development of the TCM industry.

Revisiting the impact of temperature on ground-level ozone: A causal inference approach.

It has been widely acknowledged that high temperatures and heatwaves promote ozone concentration, worsening the ambient air quality. However, temperature can impact ozone via multiple pathways, and quantifying each path is challenging due to environmental confounders. In this study, we frame the problem as a treatment-outcome issue and utilize a machine learning-aided causal inference technique to disentangle the impact of temperature on ozone formation. Our approach reveals that failing to account for the covariations of solar radiation and other meteorological factors leads to an overestimation of the O3-temperature response. Through process evaluation, we find that temperature influences local ozone formation mainly by accelerating chemical reactions and enhancing precursor production and changing boundary layer heights. The O3 response to temperature via enhancing soil NOx and changing relative humidity and wind field is however observable. A better appreciation of O3-temperature response is critical for improving air quality regulation in the warming future.

Spatial regulation of NMN supplementation on brain lipid metabolism upon subacute and sub-chronic PM exposure in C57BL/6 mice.

BACKGROUND: Atmospheric particulate matter (PM) exposure-induced neuroinflammation is critical in mediating nervous system impairment. However, effective intervention is yet to be developed. RESULTS: In this study, we examine the effect of ß-nicotinamide mononucleotide (NMN) supplementation on nervous system damage upon PM exposure and the mechanism of spatial regulation of lipid metabolism. 120 C57BL/6 male mice were exposed to real ambient PM for 11 days (subacute) or 16 weeks (sub-chronic). NMN supplementation boosted the level of nicotinamide adenine dinucleotide (NAD+) in the mouse brain by 2.04 times. This augmentation effectively reduced neuroinflammation, as evidenced by a marked decrease in activated microglia levels across various brain regions, ranging from 29.29 to 85.96%. Whole brain lipidomics analysis revealed that NMN intervention resulted in an less increased levels of ceramide (Cer) and lysophospholipid in the brain following subacute PM exposure, and reversed triglyceride (TG) and glycerophospholipids (GP) following sub-chronic PM exposure, which conferred mice with anti-neuroinflammation response, improved immune function, and enhanced membrane stability. In addition, we demonstrated that the hippocampus and hypothalamus might be the most sensitive brain regions in response to PM exposure and NMN supplementation. Particularly, the alteration of TG (60:10, 56:2, 60:7), diacylglycerol (DG, 42:6), and lysophosphatidylcholine (LPC, 18:3) are the most profound, which correlated with the changes in functional annotation and perturbation of pathways including oxidative stress, inflammation, and membrane instability unveiled by spatial transcriptomic analysis. CONCLUSIONS: This study demonstrates that NMN intervention effectively reduces neuroinflammation in the hippocampus and hypothalamus after PM exposure by modulating spatial lipid metabolism. Strategies targeting the improvement of lipid homeostasis may provide significant protection against brain injury associated with air pollutant exposure.

Bio-inspired fabrication of chitosan/PEO/Ti3C2Tx 2D MXene nanosheets supported palladium composite nanofiber catalysts via electrospinning.

In this study, novel chitosan/polyethylene oxide/Ti3C2Tx 2D MXene nanosheets (CS/PEO/Ti3C2Tx) nanofibers were successfully prepared by a continuous electrospinning process. During the electrospinning process, induced by the syringe tip capillary effects and electric field force, the Ti3C2Tx nanosheets were aligned along the direction of the nanofiber formation to occur a highly oriented structure. This well-ordered arrangement of the inorganic Ti3C2Tx nanosheets within the organic polymer matrix nanofiber was similar with nacre-like 'brick-and-motar' structure to some extent, resulting in a marked increase in thermal stability and mechanical properties of the resultant CS/PEO/Ti3C2Tx nanofiber. As 4 wt% of Ti3C2Tx nanosheets loaded, the highest tensile strength of the CS/PEO/Ti3C2Tx nanofiber mats was achieved as 31.7 MPa, about two times that of neat CS/PEO nanofibers. Uniformly dispersed Pd nanoparticles in size of about 1.6 nm have been successfully immobilized on the composite nanofiber with a solution impregnation process. With a loading as low as 0.2 mol% of Pd, the resultant Pd@CS/PEO/Ti3C2Tx composite nanofiber catalysts were highly active for both Heck and Sonogashira coupling reactions with broad reactants application scope, and could be recycled 15 runs without significant loss of activities.

Characterization of Runella zeae D-mannose 2-epimerase and its expression in Bacillus subtilis for D-mannose production from D-glucose.

D-Mannose 2-epimerase (MEase) catalyzes the bioconversion between D-glucose and D-mannose. It is an important potential biocatalyst for large-scale production of D-mannose, a functional monosaccharide used in pharmaceutical and food industries. In this study, a new microbial MEase was characterized from Runella zeae DSM 19591. The enzyme was purified by one-step nickel-affinity chromatography and determined to be a dimeric protein with two identical subunits of approximately 86.1 kDa by gel filtration. The enzyme showed the highest activity at pH 8.0 and 40 °C, with a specific activity of 2.99 U/mg on D-glucose and 3.71 U/mg on D-mannose. The melting temperature (Tm) was 49.4 °C and the half-life was 115.14 and 3.23 h at 35 and 40 °C, respectively. The purified enzyme (1 U/mL) produced 115.7 g/L of D-mannose from 500 g/L of D-glucose for 48 h, with a conversion ratio of 23.14 %. It was successfully expressed in Bacillus subtilis WB600 via pP43NMK as the vector. The highest fermentation activity was 10.58 U/mL after fed-batch cultivation for 28 h, and the whole cells of recombinant B. subtilis produced 114.0 g/L of D-mannose from 500 g/L of D-glucose, with a conversion ratio of 22.8 %.

The clinical symptoms and psychological status of biofeedback electrical stimulation combined with pelvic floor muscle training during the treatment of mild stress urinary incontinence after holmium laser enucleation of the prostate.

Introduction：To study the clinical symptoms and psychological status of biofeedback electrical stimulation combined with pelvic floor muscle training during the treatment of mild stress urinary incontinence (SUI) after holmium laser enucleation of the prostate (HoLEP). Methods：Group A was treated by biofeedback and electrical stimulation; Group B was treated by pelvic floor muscle training; and Group C was treated by biofeedback and electrical stimulation combined with pelvic floor muscle training. Patients in the 3 groups had follow-up evaluations every 8, 16, and 24 weeks. Clinical symptoms of urinary incontinence were assessed using the 24-hour urinary pad test, the Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI-SF); and psychological status was evaluated using the modified Hospital Anxiety Depression Scale (HADS). Results：The results of ICIQ-UI-SF showed that there were differences within and between the three groups at 8 weeks, 16 weeks, and 24 weeks (P<0.05). The results of the 24-hour pad tests were similar (P<0.05), except for no difference between Group B and Group C at 8 weeks(P＞0.05). In the study with the score of HADS > 35, the differences among the three groups were statistically significant(P<0.05). There was no significant difference among the three groups at 0 and 8 weeks (P>0.05). There were differences in the results between Group C and the other two groups at 16 and 24 weeks of treatment (P<0.05) .For patients with HADS < 35 at week 0, the results were basically the same except for the difference between groups at week 8. HADS of all patients were no statistical difference (P > 0.05). Conclusions：Biofeedback electrical stimulation combined with pelvic floor muscle training is an efficient non-surgical combination therapy for the symptoms of SUI after HoLEP for BPH. In addition, the recovery of the patient's psychological state does not coincide with the recovery of urinary incontinence; therefore, we propose that patients still need additional psychological treatment after SUI disappears.

Crystal structure and structure-guided tunnel engineering in a bacterial ß-1,4-galactosyltransferase.

Lacto-N-neotetraose (LNnT), a representative oligosaccharide found in human milk, has been previously examined for its beneficial traits. However, the LNnT titer is limited by the efficient glycosyltransferase pathway, particularly with respect to the catalysis of rate-limiting steps. As data on the crystal structure of the key enzyme required for synthesizing LNnT are lacking, the synthesis of LNnT remains an uncertainty. Here, for the first time we report the three-dimensional structure of a bacterial ß-1,4-galactosyltransferase, Aaß4GalT, and analyze the critical role played by residues in its catalytic efficacy. Guided by structural insights, we engineered this enzyme to enhance its catalytic efficiency using structure-guided tunnel engineering. The mutant enzyme L5 (K155M/H156D/F157W/K185M/Q216V) so produced, showed a 50-fold enhancement in catalytic activity. Crystal structure analysis revealed that the mechanism underlying the improvement in activity was of the swing door type. The closed conformation formed by dense hydrophobic packing with Q216V-K155M widened and permitted substrate entry. Our results show that altering the tunnel conformation helped appropriately accommodate the substrate for catalysis and provide a structural basis for the modification of other glycosyltransferases.

A case of Bartonella vinsonii endocarditis.

The diagnosis of Bartonella is challenging due to its rarity and negative culture results. Once the diagnosis is delayed and proper treatment is not given, it can develop into infective endocarditis, which can be fatal. We reported a 60-year-old female patient who had recurrent fever for 5 months. After receiving ineffective treatment at the local hospital, she sought medical attention at our hospital. Laboratory blood indicators testing and imaging indicated infective endocarditis, and metagenomic Next Generation Sequencing (m-NGS) testing confirmed the diagnosis of Bartonella vinsonii infection. After surgical treatment and the combination of doxycycline and ceftriaxone sodium for anti-infective therapy, the patient recovered. Valuing the combination of multiple auxiliary diagnostic methods and improving the application of m-NGS in the detection of unknown pathogens can compensate for the current limitations in the diagnosis of Bartonella. Early diagnosis and treatment are extremely important for Bartonella endocarditis.

An IGHG1 variant exhibits polarized prevalence and confers enhanced IgG1 antibody responses against life-threatening organisms.

Evolutionary pressures sculpt population genetics, whereas immune adaptation fortifies humans against life-threatening organisms. How the evolution of selective genetic variation in adaptive immune receptors orchestrates the adaptation of human populations to contextual perturbations remains elusive. Here, we show that the G396R coding variant within the human immunoglobulin G1 (IgG1) heavy chain presents a concentrated prevalence in Southeast Asian populations. We uncovered a 190-kb genomic linkage disequilibrium block peaked in close proximity to this variant, suggestive of potential Darwinian selection. This variant confers heightened immune resilience against various pathogens and viper toxins in mice. Mechanistic studies involving severe acute respiratory syndrome coronavirus 2 infection and vaccinated individuals reveal that this variant enhances pathogen-specific IgG1+ memory B cell activation and antibody production. This G396R variant may have arisen on a Neanderthal haplotype background. These findings underscore the importance of an IGHG1 variant in reinforcing IgG1 antibody responses against life-threatening organisms, unraveling the intricate interplay between human evolution and immune adaptation.

METTL16 Promotes Stability of SYNPO2L mRNA and leading to Cancer Cell Lung Metastasis by Secretion of COL10A1 and attract the Cancer-Associated Fibroblasts.

The occurrence of metastasis is a major factor contributing to poor prognosis in colorectal cancer. Different stages of the disease play a crucial role in distant metastasis. Furthermore, m6A has been demonstrated to play a significant role in regulating tumor metastasis. Therefore, we conducted an analysis of transcriptome data from high-stage and low-stage colorectal cancer patients in The Cancer Genome Atlas (TCGA) to identify genes associated with m6A-related regulation. We identified SYNPO2L as a core gene regulated by m6A, and it is correlated with adverse prognosis and metastasis in patients. Additionally, we demonstrated that the m6A writer gene Mettl16 can regulate the stability of SYNPO2L through interaction with YTHDC1. Subsequently, using Weighted Gene Co-expression Network Analysis (WGCNA), we discovered that SYNPO2L can regulate COL10A1, mediating the actions of Cancer-Associated Fibroblasts. SYNPO2L promotes the secretion of COL10A1 and the infiltration of tumor-associated fibroblasts, thereby facilitating Epithelial-Mesenchymal Transition (EMT) in tumor cells and making them more prone to distant metastasis.

Prognosis in HR-positive metastatic breast cancer with HER2-low versus HER2-zero treated with CDK4/6 inhibitor and endocrine therapy: a meta-analysis.

Background: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is currently the standard first-line treatment for patients with metastatic hormone receptor positive (HR+), and HER2-negative (HER2-) breast cancer. However, the impact of HER2 status on the prognosis of patients receiving CDK4/6i and ET remains unclear. The meta-analysis was conducted to evaluate different outcomes between HER2-low and HER2-zero patients in advanced HR+ breast cancer receiving CDK4/6i and ET. Methods: A systematic search was performed in PubMed and EMBASE databases for relevant published literature. Objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were pooled by fixed or random effects models. Results: Overall, 12 studies with 3567 patients were eligible for analysis. The pooled analysis suggested that no significant differences were observed in terms of ORR and OS between HER2-low and HER2-zero patients who underwent CDK4/6i and ET. Similarly, no significant difference in PFS was found between HER2-low and HER2-zero patients who underwent post-line CDK4/6i and ET or first-line Palbociclib and ET. However, in patients who received mixed-line (not a single treatment line) or first-line CDK4/6i and ET, the PFS was significantly shorter in the HER2-low subgroup than in the HER2-zero subgroup (mixed-line: HR = 1.36; 95% CI = 1.11-1.65; P = 0.002; first-line: HR = 1.14; 95% CI = 1.01-1.28; P = 0.04). A similar phenomenon was observed in patients who received mixed-line or post-line Palbociclib and ET (mixed-line: HR = 1.60; 95% CI = 1.09-2.34; P = 0.02; post-line: HR = 1.43; 95% CI = 1.03-2.00; P = 0.03). Conclusion: These results indicated that HER2-low status did not have a significant association with ORR and OS, but it may have a worse impact on PFS in patients who received mixed-line or first-line CDK4/6i and ET, as well as mixed-line or post-line palbociclib plus ET.

Healthy first-degree relatives from multiplex families versus simplex families have a higher subclinical intestinal inflammation, a distinct fecal microbial signature, and harbor a higher risk of developing Crohn's disease.

BACKGROUND & AIMS: Unaffected first-degree relatives (FDRs) from families with two or more affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex versus simplex families and to investigate the risk of future CD onset accounting for potential confounders. METHODS: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy FDRs of patients with CD. Genome-wide CD-polygenic risk scores (CD-PRS), urinary fractional excretion of lactulose-to-mannitol ratio (LMR), fecal calprotectin (FCP), and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between CD multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future CD onset. RESULTS: There were 4051 participants from simplex families and 334 from CD multiplex families. CD multiplex status was significantly associated with higher baseline FCP (p=0.026) but not with baseline CD-PRS or LMR. Three bacterial genera were found to be differentially abundant between both groups. CD multiplex status at recruitment was independently associated with an increased risk of developing CD (adjusted hazard ratio 3.65, 95% confidence interval 2.18 - 6.11, p < 0.001). CONCLUSION: Within FDRs of patients with CD, participants from multiplex families had a 3-fold increased risk of CD onset, a higher FCP, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in FDRs from multiplex families.

Predicting Peptide Ionization Efficiencies for Electrospray Ionization Mass Spectrometry Using Machine Learning.

Mass spectrometry (MS) is inherently an information-rich technique. In this era of big data, label-free MS quantification for nontargeted studies has gained increasing popularity, especially for complex systems. One of the cornerstones of successful label-free quantification is the predictive modeling of ionization efficiency (IE) based on solutes' physicochemical properties. While many have studied IE modeling for small molecules, there are limited reports on peptide IEs. In this study, we leverage the stoichiometric relationship in trypsin digests of well-characterized monoclonal antibodies (mAbs) to compile a data set of relative ionization efficiencies (RIEs) for 241 peptides. From each peptide's sequence, we computed a set of physiochemical descriptors, which were then used to train machine learning regression models to predict RIEs. Peptides shorter than 20 amino acids had RIEs that were highly correlated to their molecular weight. A random forest (RF) model was able to best predict the RIEs of a test data set with a mean relative error of 23.9%. For larger peptides, a multilayer perceptron (MLP) model improved RIE prediction compared to current best practices, reducing mean relative error from 60.5% to 32.0%. Finally, we also show the application of the RF model in label-free relative protein quantification and improving the quantification of peptide post-translational modifications (PTMs). This approach to predicting peptide IEs from their sequences enables the development of accurate label-free quantification workflows for peptide and protein analysis.

Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study.

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.