Changes in above- versus belowground biomass distribution in permafrost regions in response to climate warming.

Permafrost regions contain approximately half of the carbon stored in land ecosystems and have warmed at least twice as much as any other biome. This warming has influenced vegetation activity, leading to changes in plant composition, physiology, and biomass storage in aboveground and belowground components, ultimately impacting ecosystem carbon balance. Yet, little is known about the causes and magnitude of long-term changes in the above- to belowground biomass ratio of plants (η). Here, we analyzed η values using 3,013 plots and 26,337 species-specific measurements across eight sites on the Tibetan Plateau from 1995 to 2021. Our analysis revealed distinct temporal trends in η for three vegetation types: a 17% increase in alpine wetlands, and a decrease of 26% and 48% in alpine meadows and alpine steppes, respectively. These trends were primarily driven by temperature-induced growth preferences rather than shifts in plant species composition. Our findings indicate that in wetter ecosystems, climate warming promotes aboveground plant growth, while in drier ecosystems, such as alpine meadows and alpine steppes, plants allocate more biomass belowground. Furthermore, we observed a threefold strengthening of the warming effect on η over the past 27 y. Soil moisture was found to modulate the sensitivity of η to soil temperature in alpine meadows and alpine steppes, but not in alpine wetlands. Our results contribute to a better understanding of the processes driving the response of biomass distribution to climate warming, which is crucial for predicting the future carbon trajectory of permafrost ecosystems and climate feedback.

The Ca2+-dependent phosphatase calcineurin dephosphorylates TBK1 to suppress antiviral innate immunity.

Tumor necrosis factor receptor-associated factor family member-associated NF-κB activator-binding kinase 1 (TBK1) plays a key role in the induction of the type 1 interferon (IFN-I) response, which is an important component of innate antiviral defense. Viruses target calcium (Ca2+) signaling networks, which participate in the regulation of the viral life cycle, as well as mediate the host antiviral response. Although many studies have focused on the role of Ca2+ signaling in the regulation of IFN-I, the relationship between Ca2+ and TBK1 in different infection models requires further elucidation. Here, we examined the effects of the Newcastle disease virus (NDV)-induced increase in intracellular Ca2+ levels on the suppression of host antiviral responses. We demonstrated that intracellular Ca2+ increased significantly during NDV infection, leading to impaired IFN-I production and antiviral immunity through the activation of calcineurin (CaN). Depletion of Ca²+ was found to lead to a significant increase in virus-induced IFN-I production resulting in the inhibition of viral replication. Mechanistically, the accumulation of Ca2+ in response to viral infection increases the phosphatase activity of CaN, which in turn dephosphorylates and inactivates TBK1 in a Ca2+-dependent manner. Furthermore, the inhibition of CaN on viral replication was counteracted in TBK1 knockout cells. Together, our data demonstrate that NDV hijacks Ca2+ signaling networks to negatively regulate innate immunity via the CaN-TBK1 signaling axis. Thus, our findings not only identify the mechanism by which viruses exploit Ca2+ signaling to evade the host antiviral response but also, more importantly, highlight the potential role of Ca2+ homeostasis in the viral innate immune response.IMPORTANCEViral infections disrupt intracellular Ca2+ homeostasis, which affects the regulation of various host processes to create conditions that are conducive for their own proliferation, including the host immune response. The mechanism by which viruses trigger TBK1 activation and IFN-I induction through viral pathogen-associated molecular patterns has been well defined. However, the effects of virus-mediated Ca2+ imbalance on the IFN-I pathway requires further elucidation, especially with respect to TBK1 activation. Herein, we report that NDV infection causes an increase in intracellular free Ca2+ that leads to activation of the serine/threonine phosphatase CaN, which subsequently dephosphorylates TBK1 and negatively regulates IFN-I production. Furthermore, depletion of Ca2+ or inhibition of CaN activity exerts antiviral effects by promoting the production of IFN-I and inhibiting viral replication. Thus, our results reveal the potential role of Ca2+ in the innate immune response to viruses and provide a theoretical reference for the treatment of viral infectious diseases.

Family Cohesion Moderates the Relation between Parent-Child Neural Connectivity Pattern Similarity and Youth's Emotional Adjustment.

Despite a recent surge in research examining parent-child neural similarity using fMRI, there remains a need for further investigation into how such similarity may play a role in children's emotional adjustment. Moreover, no prior studies explored the potential contextual factors that may moderate the link between parent-child neural similarity and children's developmental outcomes. In this study, 32 parent-youth dyads (parents: M age = 43.53 years, 72% female; children: M age = 11.69 years, 41% female) watched an emotion-evoking animated film while being scanned using fMRI. We first quantified how similarly emotion network interacts with other brain regions in responding to the emotion-evoking film between parents and their children. We then examined how such parent-child neural similarity is associated with children's emotional adjustment, with attention to the moderating role of family cohesion. Results revealed that higher parent-child similarity in functional connectivity pattern during movie viewing was associated with better emotional adjustment, including less negative affect, lower anxiety, and greater ego resilience in youth. Moreover, such associations were significant only among families with higher cohesion, but not among families with lower cohesion. The findings advance our understanding of the neural mechanisms underlying how children thrive by being in sync and attuned with their parents, and provide novel empirical evidence that the effects of parent-child concordance at the neural level on children's development are contextually dependent.SIGNIFICANCE STATEMENT What neural processes underlie the attunement between children and their parents that helps children thrive? Using a naturalistic movie-watching fMRI paradigm, we find that greater parent-child similarity in how emotion network interacts with other brain regions during movie viewing is associated with youth's better emotional adjustment including less negative affect, lower anxiety, and greater ego resilience. Interestingly, these associations are only significant among families with higher cohesion, but not among those with lower cohesion. Our findings provide novel evidence that parent-child shared neural processes to emotional situations can confer benefits to children, and underscore the importance of considering specific family contexts in which parent-child neural similarity may be beneficial or detrimental to children's development, highlighting a crucial direction for future research.

Neural Reward Anticipation Moderates Longitudinal Relation between Parents' Familism Values and Latinx American Youth's School Disengagement.

Parents' familism values predict a variety of Latinx American youth's academic adjustment. However, it is unclear how cultural values such as familism interact with youth's brain development, which is sensitive to sociocultural input, to shape their academic adjustment. Using a sample of 1916 Latinx American youth (mean age = 9.90 years, SD = .63 years; 50% girls) and their primary caregivers (mean age = 38.43 years, SD = 6.81 years; 90% mothers) from the Adolescent Brain Cognitive Development Study, this study examined the longitudinal relation between parents' familism values and youth's school disengagement, as well as the moderating role of youth's neural sensitivity to personal reward. Parents' familism values predicted youth's decreased school disengagement 1 year later, adjusting for their baseline school disengagement and demographic covariates. Notably, this association was more salient among youth who showed lower (vs. higher) neural activation in the ventral striatum and the lateral OFC during the anticipation of a personal reward. These findings underscore the protective role of familism for Latinx American youth, highlighting the necessity of developing culturally informed interventions that take into consideration a youth's brain development.

Risk factors for prostate cancer: An umbrella review of prospective observational studies and mendelian randomization analyses.

BACKGROUND: The incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses. METHODS AND FINDINGS: We searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices. CONCLUSIONS: In this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.

Identification of novel protein biomarkers from the blood and urine for the early diagnosis of bladder cancer via proximity extension analysis.

BACKGROUND: Bladder cancer (BC) is a very common urinary tract malignancy that has a high incidence and lethality. In this study, we identified BC biomarkers and described a new noninvasive detection method using serum and urine samples for the early detection of BC. METHODS: Serum and urine samples were retrospectively collected from patients with BC (n = 99) and healthy controls (HC) (n = 50), and the expression levels of 92 inflammation-related proteins were examined via the proximity extension analysis (PEA) technique. Differential protein expression was then evaluated by univariate analysis (p < 0.05). The expression of the selected potential marker was further verified in BC and adjacent tissues by immunohistochemistry (IHC) and single-cell sequencing. A model was constructed to differentiate BC from HC by LASSO regression and compared to the detection capability of FISH. RESULTS: The univariate analysis revealed significant differences in the expression levels of 40 proteins in the serum (p < 0.05) and 17 proteins in the urine (p < 0.05) between BC patients and HC. Six proteins (AREG, RET, WFDC2, FGFBP1, ESM-1, and PVRL4) were selected as potential BC biomarkers, and their expression was evaluated at the protein and transcriptome levels by IHC and single-cell sequencing, respectively. A diagnostic model (a signature) consisting of 14 protein markers (11 in serum and three in urine) was also established using LASSO regression to distinguish between BC patients and HC (area under the curve = 0.91, PPV = 0.91, sensitivity = 0.87, and specificity = 0.82). Our model showed better diagnostic efficacy than FISH, especially for early-stage, small, and low-grade BC. CONCLUSION: Using the PEA method, we identified a panel of potential protein markers in the serum and urine of BC patients. These proteins are associated with the development of BC. A total of 14 of these proteins can be used to detect early-stage, small, low-grade BC. Thus, these markers are promising for clinical translation to improve the prognosis of BC patients.

Longitudinal study of peer victimization, social support, and mental health during early adolescence.

BACKGROUND: Peer victimization predicts the development of mental health symptoms in the transition to adolescence, but it is unclear whether and how parents and school environments can buffer this link. METHODS: We analyzed two-year longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study, involving a diverse sample of 11 844 children across the United States (average at baseline = 9.91 years; standard deviation = 0.63; range = 8.92-11.08; complete case sample = 8385). Longitudinal associations between peer victimization and two-year changes in mental health symptoms of major depression disorder (MDD), separation anxiety (SA), prodromal psychosis (PP), and attention-deficit/hyperactivity disorder (ADHD) were examined including a wide range of covariates. Mixed linear models were used to test for the moderating effects of parental warmth and prosocial school environment. RESULTS: 20% of children experienced peer victimization. Higher exposure to peer victimization was associated with increases in MDD, SA, and ADHD symptoms. Parental warmth was associated with decreases in MDD symptoms but did not robustly buffer the link between peer victimization and mental health symptoms. Prosocial school environment predicted decreases in PP symptoms and buffered the link between peer victimization and MDD symptoms but amplified the link between peer victimization and SA and ADHD symptoms. CONCLUSIONS: Peer victimization is associated with increases in mental health symptoms during the transition to adolescence. Parental warmth and prosocial school environments might not be enough to counter the negative consequences of peer victimization on all mental health outcomes.

Promoting Nitrite-to-Ammonia Electroreduction over Amorphous CoS2 Nanorods.

Electrocatalytic nitrite reduction to ammonia (NO2RR) emerges as a promising route to simultaneously attain harmful NO2- removal and green NH3 synthesis. In this study, amorphous CoS2 nanorods (a-CoS2) are first demonstrated as an effective NO2RR catalyst, which exhibits the maximum FENH3 of 88.7% and NH3 yield rate of 438.1 µmol h-1 cm-2 at -0.6 V vs RHE. Detailed experimental and computational investigations reveal that the high NO2RR performance of a-CoS2 originates from the amorphization-induced S vacancies to facilitate NO2- activation and hydrogenation, boost the electron transport kinetics, and inhibit the competitive hydrogen evolution.

Aconitum coreanum and processed products on its base prevent stroke via the PI3K/Akt and KEAP1/NRF2 in the in vivo study.

Aconitum coreanum (A. coreanum), a traditional Chinese medicine, has been proved to treat ischemic stroke (IS). However, the mechanisms of A. coreanum's anti-stroke is currently unknown. This study aimed to uncover the effect and mechanisms of A. coreanum. And study raw Aconitum coreanum (RA) and steamed Aconitum coreanum (SA) and Aconitum coreanum processed with ginger and Alumen (GA) on the mechanism of the pharmacological action of treating IS. Determining whether the efficacy is affected after processing. The right unilateral ligation of the carotid artery of gerbils was used to mimic IS. The neurological function score, infarct volume, oxidative stress level and inflammatory factor expression were measured in gerbils after IS. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins. Metabolomic analyzes IS-related metabolic pathways in urinary metabolites. RA, SA and GA significantly improved the infarct volume and behavioral score of IS gerbils, increased the expression of brain tissue superoxide dismutase (SOD), glutathione (GSH), nitric oxide (NO) and decreased the content of malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α). Western blot and immunofluorescence analysis results showed that RA, SA and GA significantly increased the expression of P-Akt, PI3K, HO-1 and KEAP1. Metabolomic studies identified 112 differential metabolites, including L-Proline, Riboflavin, Leukotriene D4, and 7-Methylxanthine, as potential biomarkers of stroke, involving 14 metabolic pathways including riboflavin metabolism, pyrimidine metabolism, and purine metabolism. Our findings indicated that A. coreanum protected against cerebral ischemia injury probably via the PI3K/Akt and KEAP1/NRF2 pathway. A. coreanum before and after processing both had a protective effect against IS brain injury in gerbils. The A. coreanum efficacy was not reduced after processing. Even compared to RA, SA had better efficacy.

Nomogram for predicting venous thromboembolism after spinal surgery.

PURPOSE: This study aimed to establish a nomogram to predict the risk of venous thromboembolism (VTE), identifying potential risk factors, and providing theoretical basis for prevention of VTE after spinal surgery. METHODS: A retrospective analysis was conducted on 2754 patients who underwent spinal surgery. The general characteristics of the training group were initially screened using univariate logistic analysis, and the LASSO method was used for optimal prediction. Subsequently, multivariate logistic regression analysis was performed to identify independent risk factors for postoperative VTE in the training group, and a nomogram for predict risk of VTE was established. The discrimination, calibration, and clinical usefulness of the nomogram were separately evaluated using the C-index, receiver operating characteristic curve, calibration plot and clinical decision curve, and was validated using data from the validation group finally. RESULTS: Multivariate logistic regression analysis identified 10 independent risk factors for VTE after spinal surgery. A nomogram was established based on these independent risk factors. The C-index for the training and validation groups indicating high accuracy and stability of the model. The area under the receiver operating characteristic curve indicating excellent discrimination ability; the calibration curves showed outstanding calibration for both the training and validation groups. Decision curve analysis showed the clinical net benefit of using the nomogram could be maximized in the probability threshold range of 0.01-1. CONCLUSION: Patients undergoing spinal surgery with elevated D-dimer levels, prolonger surgical, and cervical surgery have higher risk of VTE. The nomogram can provide a theoretical basis for clinicians to prevent VTE.

Heart Rate Variability in Patients with Spontaneous Intracerebral Hemorrhage and its Relationship with Clinical Outcomes.

BACKGROUND: Although abnormal heart rate variability (HRV) is frequently observed in patients with spontaneous intracerebral hemorrhage (ICH), its time course and presentation of different indices remain unclear, and few studies have focused on its association with clinical outcomes. METHODS: We prospectively recruited consecutive patients with spontaneous ICH between June 2014 and June 2021. HRV was evaluated twice during hospitalization (within 7 days and 10-14 days after stroke). Time and frequency domain indices were calculated. A modified Rankin Scale score ≥ 3 at 3 months was defined as a poor outcome. RESULTS: Finally, 122 patients with ICH and 122 age- and sex-matched volunteers were included. Compared with controls, time domain and absolute frequency domain HRV parameters (total power, low frequency [LF], and high frequency [HF]) in the ICH group were significantly decreased within 7 days and 10-14 days. For relative values, normalized LF (LF%) and LF/HF were significantly higher, whereas normalized HF (HF%) was significantly lower, in the patient group than in the control group. Furthermore, LF% and HF% measured at 10-14 days were independently associated with 3-month outcomes. CONCLUSIONS: HRV values were impaired significantly within 14 days after ICH. Furthermore, HRV indices measured 10-14 days after ICH were independently associated with 3-month outcomes.

Family obligation in Chinese adolescents: Consequences and parental antecedents.

Adolescents' family obligation is a cultural strength that shows enduring prevalence in China. Given that the meaning of family obligation has undergone rapid changes in recent decades, it is crucial to examine the role of family obligation in adolescent adjustment in contemporary China. More importantly, although past research has investigated the consequences of family obligation on adolescents' adjustment, little is known about the antecedents of Chinese adolescents' family obligation. Using a two-wave longitudinal sample of 450 Chinese adolescents (mean age = 13.78 years, SD = .71 years; 49% female) and their parents, the current research explored two questions. First, this study examined the role of family obligation in adolescents' academic achievement, externalizing problems, and internalizing problems over early adolescence. Second, this study explored the role of parents in predicting Chinese adolescents' family obligation, specifically whether parental expectations or parental acceptance was predictive of adolescents' family obligation over time. Third, this study investigated whether family obligation is an underlying mechanism between parenting and Chinese adolescents' adjustment. Results showed that Chinese adolescents' family obligation was longitudinally associated with increased academic achievement and reduced externalizing problems. Moreover, perceived parental acceptance, but not parental expectations, was longitudinally associated with Chinese adolescents' greater family obligation. Notably, family obligation mediated the longitudinal effect of parental acceptance on Chinese adolescents' externalizing problems. By studying both the consequences and antecedents of Chinese adolescents' family obligation, this study helps provide a comprehensive understanding of this cultural strength.

Parental warmth buffers the negative impact of weaker fronto-striatal connectivity on early adolescents' academic achievement.

In past decades, the positive role of self-control in students' academic success has attracted plenty of scholarly attention. However, fewer studies have examined the link between adolescents' neural development of the inhibitory control system and their academic achievement, especially using a longitudinal approach. Moreover, less is known about the role of parents in this link. Using large-scale longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study (N = 9574; mean age = 9.94 years at baseline, SD = .63; 50% girls), the current study took an integrative biopsychosocial approach to explore the longitudinal link between early adolescents' fronto-striatal connectivity and their academic achievement, with attention to the moderating role of parental warmth. Results showed that weaker intrinsic connectivity between the frontoparietal network and the striatum was associated with early adolescents' worse academic achievement over 2 years during early adolescence. Notably, parental warmth moderated the association between fronto-striatal connectivity and academic achievement, such that weaker fronto-striatal connectivity was only predictive of worse academic achievement among early adolescents who experienced low levels of parental warmth. Taken together, the findings demonstrate weaker fronto-striatal connectivity as a risk factor for early adolescents' academic development and highlight parental warmth as a protective factor for academic development among those with weaker connectivity within the inhibitory control system.

Chinese Mothers' Reactions to Adolescents' Positive Emotions: Relations to Adolescents' Emotional Adjustment and Mothers' Socialization Goals.

When adolescents have positive emotions, parents' reactions that enhance or dampen the intensity or duration of adolescents' emotions have been documented to play a critical role in adolescents' emotional adjustment in Western societies. These parental reactions are theorized to be culturally embedded parenting practices in the emotion socialization process. However, research is limited in examining the implications of parents' enhancing and dampening reactions for adolescents' emotional adjustment in non-Western societies. Moreover, it remains to be explored how these parental reactions might be guided by parents' culturally shaped socialization goals for adolescents, and further influence adolescents' adjustment. To address these key issues, a two-wave longitudinal study spanning approximately 1.5 years was conducted among adolescents in China (N = 233; Mage = 12.19 years, SD = 0.60; 48% girls). Based on adolescents' reports, it was found that Chinese mothers' enhancing reactions to adolescents' positive emotions, which were related to their greater endorsement of self-development socialization goals (i.e., wanting adolescents to develop confidence, autonomy, and uniqueness), predicted adolescents' increased emotional well-being (i.e., self-esteem, vitality, and experience of positive emotions) and decreased emotional ill-being (i.e., depression, anxiety and experience of negative emotions) over time. Contrastingly, mothers' dampening reactions to adolescents' positive emotions, which were related to their less endorsement of self-development and greater endorsement of filial piety socialization goals (i.e., wanting adolescents to respect and obey parents), predicted adolescents' decreased emotional well-being over time. The findings broaden the cultural understanding of parents' emotion-related socialization practices, and provide insights into practical endeavors at optimizing parents' reactions to adolescents' positive emotions in culturally sensitive ways and ultimately promoting adolescents' mental health.

Gut Prevotellaceae-GABAergic septohippocampal pathway mediates spatial memory impairment in high-fat diet-fed ovariectomized mice.

Clarifying the risk factors and mechanisms that contribute to the onset of cognitive impairment following estrogen depletion is essential for improving the quality of life of older females. In the current study, using behavioral tests, 16S rDNA sequencing, in vivo and in vitro electrophysiology, optogenetics and chemogenetics, we found that high-fat diet (HFD)-accelerated impairment of hippocampus-dependent memory, gut microbiota, and hippocampal theta rhythmogenesis in ovariectomized (OVX) mice and fecal microbiota transplantation rescued these phenomena. The identification of fasting-activated medial septal neurons showed that PV+ GABAergic neurons in the medial septal area (MSA) respond to gut sensory signals. Optogenetic activation of septohippocampal PV+ GABAergic fibers (but not cholinergic fibers) significantly rescued hippocampal theta rhythmogenesis and spatial memory in HFD-fed OVX mice. Resistant starch supplementation (RSHFD) rectified the gut Prevotellaceae and considerably alleviated reduced septal gut-responsive neurons, decreased hippocampal theta rhythm, and impaired hippocampus-dependent memory in HFD-fed OVX mice. Furthermore, chemogenetic inhibition of septal PV+ GABAergic neurons reversed the neuroprotective effects of resistant starch supplementation. These findings highlight the notable gut-sensory nature of medial septal PV+ GABAergic neurons. A HFD accelerates estrogen deficiency-induced cognitive impairment by disrupting the gut Prevotellaceae-septo-hippocampal pathway. This study contributes to a better understanding of the precise gut-brain control of cognition and cognitive impairment in postmenopausal females.

Epidemiological and genetic evidence for the relationship between ABO blood group and human cancer.

To comprehensively evaluate the etiological role of ABO blood group in human cancer, we conducted a large-scale meta-analysis of 127 publications totaling 20 million participants including 231 737 patients of 20 cancers, supplemented by genetic evidence. Effects of A, AB and B groups on cancer risk were investigated by respectively comparing with O group and their combined counterparts, and subgroup analysis by ethnicity was conducted for O-referent models. For cancer categories, A group increased risk of cancers of oral cavity and nasopharynx, digestive and female genital organs, while both AB and B groups showed associations with cancers of digestive and female genital organs. For individual cancers, A group significantly increased the risk of nine cancers including oral cavity (OR = 1.17, P = .013), stomach (OR = 1.19, P = 3.90 × 10-15 ), pancreas (OR = 1.33, P = 9.89 × 10-33 ), colorectum (OR = 1.09, P = .001), liver (OR = 1.23, P = .011), ovary (OR = 1.13, P = .001), cervix (OR = 1.17, P = .025), bladder (OR = 1.12, P = .025) and breast (OR = 1.06, P = .043). AB group showed associations with only three cancers: stomach (OR = 1.10, P = .007), pancreas (OR = 1.21, P = .001) and ovary (OR = 1.28, P = .006). B group, except for shared associations with A group on pancreas (OR = 1.20, P = 2.27 × 10-5 ) and cervix cancers (OR = 1.13, P = .011), had two distinct associations with esophagus (OR = 1.17, P = .002) and nonmelanoma skin cancers (OR = 0.96, P = .017). Ethnicity-specific analyses revealed the notable effects of non-O groups on pancreatic cancer both in Caucasians and Asians. In genetic analysis, four SNPs were associated with the risk of pancreatic cancer, with rs505922 corresponding to O group showing the strongest protective effect (P = 1.16 × 10-23 ). Our study provided comprehensive evidence of ABO blood group associated with cancers and highlighted its carcinogenic role.

Highly Accurate and Robust Absolute Quantification of Target Proteins in Formalin-Fixed Paraffin-Embedded (FFPE) Tissues by LC-MS.

Accurate, absolute liquid chromatography-mass spectrometry (LC-MS)-based quantification of target proteins in formalin-fixed paraffin-embedded (FFPE) tissues would greatly expand sample availability for pharmaceutical/clinical investigations but remains challenging owing to the following issues: (i) efficient/quantitative recovery of target signature peptides from FFPE tissues is essential but an optimal procedure for targeted, absolute quantification is lacking; (ii) most FFPE samples are long-term-stored; severe immunohistochemistry (IHC) signal losses of target proteins during storage were widely reported, while the effect of storage on LC-MS-based methods was unknown; and (iii) the proper strategy to prepare calibration/quality-control samples to ensure accurate targeted protein analysis in FFPE tissues remained elusive. Using targeted quantification of monoclonal antibody (mAb), antigen, and 40 tissue markers in FFPE tissues as a model system, we extensively investigate those issues and develope an LC-MS-based strategy enabling accurate and precise targeted protein quantification in FFPE samples. First, we demonstrated a surfactant cocktail-based procedure (f-SEPOD), providing high/reproducible recovery of target signature peptides from FFPE tissues. Second, a heat-accelerated degradation study within a roughly estimated 5 year storage period recapitulated the loss of protein IHC signals while LC-MS signals of all targets remained constant. This indicates that the storage of FFPE tissues mainly causes decreased immunoreactivity but unlikely chemical degradation of proteins, which strongly suggests that the storage of FFPE tissues does not cause significant quantitative bias for LC-MS-based methods. Third, while a conventional spike-and-extract approach for calibration caused substantial negative biases, a novel approach, using FFPE-treated calibration standards, enabled accurate and precise quantification. With the pipeline, we conducted the first-ever pharmacokinetics measurement of mAb and its target in FFPE tissues, where time courses by FFPE vs fresh tissues showed excellent correlation.

Identification of genetic and immune signatures for the recurrence of HER2-positive breast cancer after trastuzumab-based treatment.

PURPOSE: To determine the genetic and immune features associated with the recurrence of human epidermal growth factor receptor2-positive (HER2 +) breast cancer (BC) after trastuzumab-based treatment. METHODS: A retrospective cohort study of 48 patients who received trastuzumab-based treatment was divided into recurrent and non-recurrent groups according to clinical follow-up. Baseline samples from all 48 patients were analyzed for genetic variation, HLA allele type, gene expression, and immune features, which were linked to HER2 + BC recurrence. Statistics included logistic regression models, Kaplan-Meier plots, and Univariate Cox proportional hazards models. RESULTS: Compared with the non-recurrent group, the extracellular matrix-related pathway and 3 Hallmark gene sets were enriched in the recurrent group. The infiltration levels of immature B cells and activated B cells were significantly increased in the non-recurrent group, which correlated remarkably with improved overall survival (OS) in two other published gene expression datasets, including TCGA and METABRIC. In the TCGA cohort (n = 275), activated B cells (HR 0.23, 95%CI 0.13-0.43, p < 0.0001), and immature B cells (HR 0.26, 95%CI 0.12-0.59, p < 0.0001). In the METABRIC cohort (n = 236), activated B cells (HR 0.60, 95%CI 0.43-0.83, p = 0.002), and immature B cells (HR 0.65, 95%CI 0.47-0.91, p = 0.011). Cox regression suggested that immature B cells and activated B cells were protective factors for outcome OS. CONCLUSIONS: Aberrant activation of multiple pathways and low baseline tumor-infiltrating B cells are related to HER2 + BC trastuzumab-based recurrence, which primarily affects the antitumor activity of trastuzumab.

Biosynthesis of kratom opioids.

Mitragynine, an analgesic alkaloid from the plant Mitragyna speciosa (kratom), offers a safer alternative to clinical opioids such as morphine, owing to its more favorable side effect profile. Although kratom has been traditionally used for stimulation and pain management in Southeast Asia, the mitragynine biosynthesis pathway has remained elusive. We embarked on a search for mitragynine biosynthetic genes from the transcriptomes of kratom and other members of the Rubiaceae family. We studied their functions in vitro and in vivo. Our investigations led to the identification of several reductases and an enol methyltransferase that forms a new clade within the SABATH methyltransferase family. Furthermore, we discovered a methyltransferase from Hamelia patens (firebush), which catalyzes the final step. With the tryptamine 4-hydroxylase from the psychedelic mushroom Psilocybe cubensis, we accomplished the four-step biosynthesis for mitragynine and its stereoisomer, speciogynine in both yeast and Escherichia coli when supplied with tryptamine and secologanin. Although we have yet to pinpoint the authentic hydroxylase and methyltransferase in kratom, our discovery completes the mitragynine biosynthesis. Through these breakthroughs, we achieved the microbial biosynthesis of kratom opioids for the first time. The remarkable enzyme promiscuity suggests the possibility of generating derivatives and analogs of kratom opioids in heterologous systems.

The overlooked functions of trichomes: Water absorption and metal detoxication.

Trichomes are epidermal outgrowths on plant shoots. Their roles in protecting plants against herbivores and in the biosynthesis of specialized metabolites have long been recognized. Recently, studies are increasingly showing that trichomes also play important roles in water absorption and metal detoxication, with these roles having important implications for ecology, the environment, and agriculture. However, these two functions of trichomes have been largely overlooked and much remains unknown. In this review, we show that the trichomes of 37 plant species belonging to 14 plant families are involved in water absorption, while the trichomes of 33 species from 13 families are capable of sequestering metals within their trichomes. The ability of trichomes to absorb water results from their decreased hydrophobicity compared to the remainder of the leaf surface as well as the presence of special structures for collecting and absorbing water. In contrast, the metal detoxication function of trichomes results not only from the good connection of their basal cells to the underlying vascular tissues, but also from the presence of metal-chelating ligands and transporters within the trichomes themselves. Knowledge gaps and critical future research questions regarding these two trichome functions are highlighted. This review improves our understanding on trichomes.