Miracle-dz/UniFAR-FTUs huggingface dataset:
Unveiling the domain-specific and RAS isoform-specific details of BRAF kinase regulation

BRAF is a key member in the MAPK signaling pathway essential for cell growth, proliferation, and differentiation. Mutant BRAF is often the underlying cause of various types of cancer and mutant RAS, the upstream regulator of BRAF, is a driver of up to one-third of all cancers. BRAF interacts with RAS and undergoes a conformational change from an inactive, autoinhibited monomer to an active dimer, which propagates downstream signaling. Because of BRAF’s complex regulation mechanism, the exact order and magnitude of its activation steps have yet to be confirmed experimentally. By studying the inter- and intramolecular interactions of BRAF, we unveil the domain-specific and isoform-specific details of BRAF regulation through pulldown assays, open surface plasmon resonance (OpenSPR), and hydrogen-deuterium exchange mass spectrometry (HDX-MS). We demonstrate that the BRAF specific region (BSR) and cysteine rich domain (CRD) play a crucial role in regulating the activation of BRAF in a RAS isoform-specific manner. Moreover, we quantified the binding affinities between BRAF N-terminal and kinase domains (KD) to reveal their individual roles in autoinhibition. Our findings also indicate that oncogenic BRAF-KDD594G mutant has a lower affinity for the N-terminal domains, implicating that pathogenic BRAF acts through decreased propensity for autoinhibition. Collectively, our study provides valuable insight into the activation mechanism of BRAF kinase to guide the development of new therapeutic strategies for cancer treatment.
Surveillance Outcome and Genetic Findings in Individuals at High Risk of Pancreatic Cancer

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate. PDAC surveillance is recommended in high-risk individuals (HRIs) with strong PDAC family history or a pathogenic germline variant (PGV) in a PDAC susceptibility gene. We aimed to explore a potential correlation between genetic status, extent of family history, pancreatic findings, and surveillance implications in heterogeneous PDAC HRIs. METHODS: A total of 239 HRIs from 202 families were tested genetically and underwent prospective pancreatic surveillance for 6 years. RESULTS: The cohort was divided into 3 groups: familial pancreatic cancer (FPC; 70 individuals, 54 families), familial non-FPC (81 individuals, 73 families), and hereditary pancreatic cancer (PC) (88 individuals, 75 families). PGVs were detected in 37.6% of all families, including 11.1% of FPC families and 9.6% of familial non-FPC families. The hereditary PC group had earlier onset of PDAC compared with the other 2 groups. BRCA2 PGV carriers showed earlier onset of PDAC and pancreatic cysts. Of the 239 HRIs, PDAC was detected in 11 individuals (4.6%), with 73% diagnosed at an early stage; 4 (1.67%) had pancreatic neuroendocrine tumor; 6 (2.5%) had main-duct intraductal papillary neoplasm (IPMN); and 41 (17.15%) had side-branch IPMN. Seventeen individuals were referred to surgery, and 12 were alive at the end of the study. DISCUSSION: The percentage of PDAC was similar in the 3 groups studied. The hereditary PC group, and particularly BRCA2 PGV carriers, had an earlier age of PDAC onset. PGVs were detected in a significant percentage of HRIs with PC. Surveillance seems effective for detection of early-stage PDAC and precursor lesions.
Integrating network pharmacology and transcriptomic omics reveals that akebia saponin D attenuates neutrophil extracellular traps‐induced neuroinflammation via NTSR1/PKAc/PAD4 pathway after intracerebral hemorrhage

Neutrophils and their production of neutrophil extracellular traps (NETs) significantly contribute to neuroinflammation and brain damage after intracerebral hemorrhage (ICH). Although Akebia saponin D (ASD) demonstrates strong anti‐inflammatory activities and blood–brain barrier permeability, its role in regulating NETs formation and neuroinflammation following ICH is uncharted. Our research focused on unraveling the influence of ASD on neuroinflammation mediated by NETs and the mechanisms involved. We found that increased levels of peripheral blood neutrophils post‐ICH are correlated with worse prognostic outcomes. Through network pharmacology, we identified ASD as a promising therapeutic target for ICH. ASD administration significantly improved neurobehavioral performance and decreased NETs production in neutrophils. Furthermore, ASD was shown to upregulate the membrane protein NTSR1 and activate the cAMP signaling pathway, confirmed through transcriptome sequencing, western blot, and immunofluorescence. Interestingly, the NTSR1 inhibitor SR48692 significantly nullified ASD's anti‐NETs effects and dampened cAMP pathway activation. Mechanistically, suppression of PKAc via H89 negated ASD's anti‐NETs effects but did not affect NTSR1. Our study suggests that ASD may reduce NETs formation and neuroinflammation, potentially involving the NTSR1/PKAc/PAD4 pathway post‐ICH, underlining the potential of ASD in mitigating neuroinflammation through its anti‐NETs properties.
Impact of gender and age at onset on Sjögren's syndrome presentation and outcome: state of the art.

Sjögren's syndrome (SS) is a complex and heterogeneous disease that typically affects middle-aged women. However, while it is rare, the disease may occur in male patients and in females during their childhood/adolescence or in the elderly. Contrasting data have been reported on these three subgroups clinical features and long-term outcomes. Notably, recent studies have pinpointed the severity of the disease in male patients and in both the early and the late-onset subgroups.The aim of this review is, therefore, to summarise the available evidence from the recent literature on these phenotypes. The focus will be on the clinical and laboratory features, and on the lymphoma risk observed in the three subgroups distinct phenotypes: of male patients as well as young-onset SS and elderly-onset SS. Ultimately, an accurate phenotypic stratification may represent the first step towards individualised medical approaches.
Improved outcomes of localized diffuse large B‐cell lymphoma at the Waldeyer ring in comparison to the sinonasal area in the rituximab era

Abstract Background Diffuse large B‐cell lymphoma (DLBCL) of the head‐and‐neck area primarily involves the Waldeyer ring (WR) and sinonasal area (SN). However, the differential clinical outcomes between patients with WR‐DLBCL and those with SN‐DLBCL in the rituximab era remain unclear. Methods To avoid confounding factors contributed by advanced DLBCL with WR and SN involvement, we assessed the clinical outcomes of patients with stage I/II WR‐DLBCL and SN‐DLBCL and compared them with those having corresponding stages of DLBCL in the lymph nodes but without other extranodal involvement (LN‐DLBCL) in the same period. We compared the patients' clinical characteristics, treatment modalities, event‐free survival (EFS), and overall survival (OS) among the three subgroups. Results We analyzed 67, 15, and 106 patients with WR‐DLBCL, SN‐DLBCL, and LN‐DLBCL, respectively, between January 2000 and December 2019. All patients received front‐line rituximab‐based regimens, and > 80% received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone‐based regimens. More patients with SN‐DLBCL had revised International Prognostic Index (R‐IPI) score 3 (27%) when compared with those with WR‐DLBCL (7%) and those with LN‐DLBCL (10%, p = 0.181). Patients with WR‐DLBCL, LN‐DLBCL, and SN‐DLBCL had 5‐year EFS and OS rates of 80.7%, 59.5%, and 41.9% (p = 0.021) and 83.7%, 70.8%, and 55.8% (p = 0.032), respectively. Compared to patients with LN‐DLBCL, those with WR‐DLBCL also had a significantly favorable 5‐year EFS rate (p = 0.021) and 5‐year OS rate (p = 0.023). Three of the 15 patients with SN‐DLBCL experienced lymphoma recurrence in the brain after front‐line treatment. In multivariate analyses, R‐IPI scores of 1–2 and 3 served as significantly poor prognostic factors for patients with poor EFS and OS. Conclusions Compared to patients with LN‐DLBCL, patients with WR‐DLBCL receiving front‐line rituximab‐based treatments had favorable clinical outcomes; however, patients with SN‐DLBCL had worse clinical outcomes. Further studies on molecular prognostic factors and treatment strategies for SN‐DLBCL are warranted.
RESPONSE OF LATE SHOWN WHEAT (TRITICUM AESTIVUM) TO FYM, BIOFERTILIZERS AND INORGANIC N ALONE AND IN DIFFERENT COMBINATIONS

A field experiment was conducted on late sown wheat at C.S. Azad University of Agriculture and Technology, Kanpur (U.P.), India; during rabi season of 2008-09. The treatments consisted lone application of FYM 5 t/ha or biofertilizer (Azotobacter or Azospirilium) 5 kg/ha and their individual or combined integration with 40 kg N/ha against lone application of 40, 80 or 120 kg N/ha alongwith one control. The results revealed that integrated use of 40 kg N/ha + 5 t/ha FYM + 5 kg/ha biofertilizer (Azotobacter) produced highest grain yield of 36.29 q/ha and earned maximum net income of Rs. 24641/ha. It was followed by integration of 40 kg N/ha + 5 t/ha FYM + 5 kg/ha Azospirilium with 35.66 q/ha grain yield and Rs. 23864/ha net income and by lone application of 120 kg N/ha with 34.89 q/ha grain yield and Rs. 23173/ha net income. These 3 treatments remained significantly at per with each other. All fertility treatments produced significantly higher yield and earned more income than control treatment. It was also observed that integration of FYM or biofertilizer with 40 kg N/ha recorded yield and income at per with 80 kg N/ha. It is thus proved that application of inorganic N fertilizer may be reduced by 66.7% with integrated use of 40 kg N + 5 t FYM + 5 kg biofertilizer per hectare in late sown wheat crop.
Fruits and vegetable consumption, and its association with hypertension among women in Ghana: a cross-sectional study

Abstract Objective: This study aimed to examine the association between fruit and vegetable consumption (FVC) and the risk of hypertension among women in Ghana. Design: Data from the 2014 Ghana Demographic and Health Survey were used. Bivariate and multivariate logistic regression analyses were performed using Stata version 14. The study reports the adjusted OR (AOR) and CI. Setting: Ghana Participants: A total sample of 4168 women was used in the analysis. Results: Among women who met the WHO’s recommended intake of FVC, 13·1 % had hypertension. The intake of the recommended servings of fruit and vegetables was not significantly associated with hypertension. However, the likelihood of being hypertensive was significantly associated with increasing age (AOR = 6·1; 95 % CI = 4·29, 8·73), being married (AOR = 1·7; 95 % CI = 1·14, 2·57) or formerly married (AOR = 2·3; 95 % CI = 1·44, 3·70), and being overweight (AOR = 1·6; 95 % CI = 1·24, 2·07) or obese (AOR = 2·4; 95 % CI = 1·82, 3·20). Conclusion: The study concludes that there is no significant association between FVC and hypertension risk among women in Ghana. While this study did not find a significant association between FVC and hypertension risk among women in Ghana, it underscores the point that other multifaceted factors influence hypertension risk. As such, public health campaigns should emphasise a balanced and holistic approach to promoting cardiovascular health, including factors beyond FVC. The findings also highlight the need to target high-risk populations (i.e. older women, married and formerly married women, and overweight or obese women) with hypertension prevention education and related interventions.
Antipodoplanin antibody enhances the antitumor effects of CTLA‐4 blockade against malignant mesothelioma by natural killer cells

Abstract Combination immunotherapy with multiple immune checkpoint inhibitors (ICIs) has been approved for various types of malignancies, including malignant pleural mesothelioma (MPM). Podoplanin (PDPN), a transmembrane sialomucin‐like glycoprotein, has been investigated as a diagnostic marker and therapeutic target for MPM. We previously generated and developed a PDPN‐targeting Ab reagent with high Ab‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity (CDC). However, the effects of anti‐PDPN Abs on various tumor‐infiltrating immune cells and their synergistic effects with ICIs have remained unclear. In the present study, we established a novel rat–mouse chimeric anti‐mouse PDPN IgG2a mAb (PMab‐1‐mG2a) and its core‐fucose‐deficient Ab (PMab‐1‐mG2a‐f) to address these limitations. We identified the ADCC and CDC activity of PMab‐1‐mG2a‐f against the PDPN‐expressing mesothelioma cell line AB1‐HA. The antitumor effect of monotherapy with PMab‐1‐mG2a‐f was not sufficient to overcome tumor progression in AB1‐HA‐bearing immunocompetent mice. However, PMab‐1‐mG2a‐f enhanced the antitumor effects of CTLA‐4 blockade. Combination therapy with anti‐PDPN Ab and anti‐CTLA‐4 Ab increased tumor‐infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab‐1‐mG2a‐f and CTLA‐4 blockade in vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM.
Beverage industry TV advertising shifts after a stepwise mandatory food marketing restriction: achievements and challenges with regulating the food marketing environment

Abstract Objective: Sugar-sweetened beverages (SSB) are heavily advertised globally, and SSB consumption is linked to increased health risk. To reduce unhealthy food marketing, Chile implemented a regulation for products classified as high in energies, sugar, saturated fat or sodium, starting with a 2016 ban on child-targeted advertising of these products and adding a 06.00–22.00 daytime advertising ban in 2019. This study assesses changes in television advertising prevalence of ready-to-drink beverages, including and beyond SSB, to analyse how the beverage industry shifted its marketing strategies across Chile’s implementation phases. Design: Beverage advertisements were recorded during two randomly constructed weeks in April-May of 2016 (pre-implementation) through 2019 (daytime ban). Ad products were classified as ‘high-in’ or ‘non-high-in’ according to regulation nutrient thresholds. Ads were analysed for their programme placement and marketing content. Setting: Chile. Results: From pre-regulation to daytime ban, child-targeted, daytime and total ads decreased by 51·8 percentage points (p.p.), 51·5 p.p. and 61·8 p.p. for high-in products and increased by 62·9 p.p., 54·9 p.p. and 61·8 p.p. for non-high-in products (Ps < 0·001). Additionally, total ready-to-drink beverage ads increased by 5·4 p.p. and brand-only ads (no product shown) by 7 p.p. Conclusions: After the regulation implementation, ‘high-in’ ads fell significantly, but ‘non-high-in’ ads rose and continued using strategies targeting children and being aired during daytime. Given research showing that advertising one product can increase preferences for a different product from that same brand and product categories, broader food marketing regulation approaches may be needed to protect children from the harmful effects of food marketing.
Factors associated with thrombotic disease in dogs with renal proteinuria: A retrospective of 150 cases

Abstract Background Knowledge of additional risk factors for thrombotic disease (TD) among dogs with renal proteinuria is limited; these might differ for TD affecting the systemic arterial (AT), systemic venous (VT), and pulmonary circulation (PT). Hypothesis/Objectives To compare signalment and clinicopathological data between dogs with renal proteinuria with or without TD, and between dogs with AT, VT, and PT. Animals One hundred fifty client‐owned dogs with renal proteinuria, 50 of which had TD. Methods Retrospective case‐controlled study. A database search (2004‐2021) identified proteinuric dogs (UPC > 2) with and without TD. Clinicopathological data were obtained from the records. TD and non‐TD (NTD) groups were compared by binary logistic regression, and AT, VT, and PT groups by multinomial regression. Normal data presented as mean ± SD, non‐normal data presented as median [25th, 75th percentiles]. Results Cavalier King Charles Spaniels were overrepresented in the TD group (OR = 98.8, 95% CI 2.09‐4671, P = .02). Compared to NTD cases, TD cases had higher concentration of neutrophils (11.06 [8.92, 16.58] × 109/L vs 7.31 [5.63, 11.06] × 109/L, P = .02), and lower concentration of eosinophils (0 [0, 0.21] × 109/L vs 0.17 [0.04, 0.41] × 109/L, P = .002) in blood, and lower serum albumin (2.45 ± 0.73 g/dL vs 2.83 ± 0.73 g/dL, P = .04). AT cases had higher serum albumin concentrations than VT cases (2.73 ± 0.48 g/dL vs 2.17 ± 0.49 g/dL, P = .03) and were older than PT cases (10.6 ± 2.6 years vs 7.0 ± 4.3 years, P = .008). VT cases were older (9.1 ± 4.2 years vs 7.0 ± 4.3 years, P = .008) and had higher serum cholesterol concentration (398 [309‐692 mg/dL] vs 255 [155‐402 mg/dL], P = .03) than PT cases. Conclusions and Clinical Importance Differences between thrombus locations could reflect differences in pathogenesis.
Cordyceps cicadae polysaccharides attenuate diabetic nephropathy via the miR‐30a‐3p/TRIM16 axis

Abstract Objective The molecular mechanism of the protective effect of Cordyceps cicadae polysaccharides (CCPs) on renal tubulointerstitial fibrosis in diabetic nephropathy (DN) is still unclear. This study aims to further understand the molecular mechanisms behind the therapeutic benefits of CCP on diabetic nephropathy. Methods Mice were randomly assigned into six groups (n = 8). Cordyceps cicadae polysaccharide dissolved in 5% dimethyl sulfoxide was administered by gavage for 12 consecutive weeks. The CCP doses were divided into low, medium, and high, 75, 150, and 300 mg/kg/day, respectively. The efficacy of CCP was determined by assessing the renal function and histological alterations in diabetic db/db mice. The degree of glomerular mesangial dilatation and sclerosis was evaluated using semiquantitative markers. Cell viability, apoptosis, epithelial–mesenchymal transition (EMT), inflammation, oxidative stress, and mitochondrial reactive oxygen species (ROS) in high glucose (HG)‐cultured MPC5 podocytes were determined. The interaction of miR‐30a‐3p and tripartite motif‐containing protein 16 (TRIM16) was examined by luciferase reporter assay. Western blotting, reverse transcription‐polymerase chain reaction, and immunofluorescence were used to analyze gene and protein expressions. Results The in vivo findings illustrated that CCP may protect mice with type 2 diabetes from inflammation and oxidative damage (P < 0.05). Furthermore, CCP has a therapeutic value in protecting renal function and morphology in diabetic nephropathy by reversing podocyte EMT. The in vitro results indicated that CCP dose‐dependently inhibited HG‐induced apoptosis, EMT, inflammation, oxidative stress, and mitochondrial ROS levels in MPC5 podocytes (P < 0.05). Luciferase reporter assay confirmed the interaction between miR‐30a‐3p and TRIM16 in MPC5 podocytes cultured in high glucose (P < 0.05). Conclusion The protective effect of CCP on HG‐induced MPC5 can be achieved by miR‐30a‐3p/TRIM16 axis.
No Evidence that Selection on Synonymous Codon Usage Affects Patterns of Protein Evolution in Bacteria

Abstract Bias in synonymous codon usage has been reported across all kingdoms of life. Evidence suggests that codon usage bias is often driven by selective pressures, typically for translational efficiency. These selective pressures have been shown to depress the rate at which synonymous sites evolve. We hypothesize that selection on synonymous codon use could also slow the rate of protein evolution if a non-synonymous mutation changes the codon from being preferred to unpreferred. We test this hypothesis by looking at patterns of protein evolution using polymorphism and substitution data in two bacterial species, Escherichia coli and Streptococcus pneumoniae. We find no evidence that non-synonymous mutations that change a codon from being unpreferred to preferred are more common than the opposite. Overall, selection on codon bias seems to have little influence over non-synonymous polymorphism or substitution patterns.
Long-term outcomes and associated prognostic risk factors of childhood-onset lupus nephritis.

Background This study investigated the clinical characteristics and kidney outcomes of childhood-onset lupus nephritis (LN), and risk factors associated with prognosis. Methods We enrolled 216 patients with histologically diagnosed LN during childhood. The Korean Society of Pediatric Nephrology organized a retrospective cohort study of childhood-onset LN in 13 major pediatric nephrology centers in South Korea. Results The mean age at kidney biopsy was 13.2 ± 3.22 years. The main forms of presentation were nephrotic syndrome and/or hematuria in 152 patients (70.4%), and the most common histological finding was World Health Organization (WHO) class IV in 138 patients (63.9%), followed by WHO class III in 34 patients (15.7%). In the outcome analysis, the mean follow-up period of the patients was 7.8 ± 5.11 years. At last follow-up, 32 patients (14.8%) developed advanced chronic kidney disease (CKD). Male sex and failure to achieve remission at 12 months of treatment were significant risk factors for developing advanced CKD (hazard ratio of 2.57 and 2.29, respectively). Conclusion Our study demonstrated the clinical characteristics and long-term outcomes of patients with childhood-onset LN. Male sex and failure to achieve remission in the first year of treatment were predictive of advanced CKD. Therefore, prompt awareness and close monitoring of these high-risk patients are needed, which may further improve the prognosis of children with LN.
Association of Sleep Status With Cognitive Functions in Centenarians: Evidence From Hainan Centenarian Cohort

Abstract Objectives This study aimed to analyze the association between sleep quality, sleep duration, and cognitive functions among centenarians. Methods The baseline data of the China Hainan Centenarians Cohort Study served as the foundation for this study. Logistic regression was utilized to demonstrate the relationship between sleep status and cognitive impairment. Moreover, a canonical correlation analysis was performed to analyze the correlation between these variables. Results A total of 994 centenarians were included. After adjustment, poor sleep quality centenarians had an odds ratio of 1.77 (95% confidence interval [CI]: 1.00–3.09) for cognitive impairment when compared to centenarians with normal sleep quality. Centenarians who slept for more than 9 hr had a stronger association with severe cognitive impairment, indicated by an odds ratio of 1.41 (95% CI: 1.02–1.96), compared to those who slept for 7–9 hr. Additionally, the canonical correlation analysis results revealed that the linear combination of sleep quality V1, primarily determined by sleep latency, daytime dysfunction, and subjective sleep quality, was associated with cognitive function; the linear combination of cognitive function W1, mainly determined by orientation, attention and calculation, and memory. Discussion There exists a correlation between poor sleep quality and cognitive impairment in centenarians, as well as a correlation between sleep duration >9 hr at night and severe cognitive impairment. The primary cognitive domains associated with sleep quality are orientation, calculation, and memory. It is imperative to monitor and safeguard the cognitive functions linked to poor sleep quality in the older individuals, with attention to orientation, calculation, and memory.