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Extreme urban heat poses significant challenges to the resilience and livability of cities. Urban squares are important open public spaces in cities, serving as main locations for residents' leisure and recreational activities and reflect the identity and cultural background of the cities. Improvement in thermal comfort in urban squares can improve the quality of the urban environment and help mitigate the urban heat island effect. This study developed 18 layout and landscape combination scenarios based on statistical analysis of data from 100 urban squares in regions with hot summers and cold winters. Further, the effectiveness of the proposed design solutions in improving the thermal environment was comprehensively analyzed. The results show that: 1) The block array layout with vegetation, water bodies, and permeable tiles is the most effective scenario, with a PET of 31.84 °C, approaching a comfortable level of heat stress; 2) Among the three layouts, the block array layout optimizes thermal comfort better than the main view entrance layout and main view center layout, and reduces physiological equivalent temperature by 10.51–10.77 °C compared with that of the other two layouts; 3) Scenarios incorporating water bodies provide better optimization effects than those with only trees, even when the total area covered by greenery remains unchanged; and 4) Permeable paving materials with high albedo more effectively improve the thermal comfort. Our results highlight a great potential of comprehensively using multiple landscape strategies to improve outdoor thermal comfort, and provides design basis for enhancing thermal comfort in similar sized urban squares in hot summer and cold winter areas.

Aims: Vascular calcification is strongly linked to the development of major adverse cardiovascular events, but effective treatments are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an emerging category of oral hypoglycemic drugs that have displayed marked effects on metabolic and cardiovascular diseases, including recently reported vascular medial calcification. However, the roles and underlying mechanisms of SGLT2 inhibitors in vascular calcification have not been fully elucidated. Thus, we aimed to further determine whether SGLT2 inhibitors protect against vascular calcification and to investigate the mechanisms involved. Methods and results: A computed tomography angiography investigation of coronary arteries from 1554 patients with type 2 diabetes revealed that SGLT2 inhibitor use was correlated with a lower Agatston calcification score. In the vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease-induced medial calcification and Western diet-induced atherosclerotic intimal calcification models, dapagliflozin (DAPA) substantially alleviated vascular calcification in the aorta. Furthermore, we showed that DAPA reduced vascular calcification via Runx2-dependent osteogenic transdifferentiation in vascular smooth muscle cells (VSMCs). Transcriptome profiling revealed that thioredoxin domain containing 5 (TXNDC5) was involved in the attenuation of vascular calcification by DAPA. Rescue experiments showed that DAPA-induced TXNDC5 downregulation in VSMCs blocked the protective effect on vascular calcification. Furthermore, TXNDC5 downregulation disrupted protein folding-dependent Runx2 stability and promoted subsequent proteasomal degradation. Moreover, DAPA downregulated TXNDC5 expression via amelioration of oxidative stress and ATF6-dependent endoplasmic reticulum stress. Consistently, the class effects of SGLT2 inhibitors on vascular calcification were validated with empagliflozin in intimal and medial calcification models. Conclusions: SGLT2 inhibitors ameliorate vascular calcification through blocking endoplasmic reticulum stress-dependent TXNDC5 upregulation and promoting subsequent Runx2 proteasomal degradation, suggesting that SGLT2 inhibitors are potentially beneficial for vascular calcification treatment and prevention.

Introduction and Objectives: Type 2 Diabetes Mellitus (T2DM), a prevalent metabolic disorder, often coexists with a range of complications, with retinopathy being particularly common. Recent studies have shed light on a potential connection between diabetic retinopathy (DR) and hepatic fibrosis, indicating a possible shared pathophysiological foundation in T2DM. This study investigates the correlation between retinopathy and hepatic fibrosis among individuals with T2DM, as well as evaluates the diagnostic value of DR for significant hepatic fibrosis. Materials and Methods: Our cross-sectional analysis incorporated 5413 participants from the National Health and Nutrition Examination Survey (NHANES) 2005-2008. The Fibrosis-4 score (FIB-4) classified hepatic fibrosis into different grades (F0-F4), with significant hepatic fibrosis marked as F2 or higher. Retinopathy severity was determined using retinal imaging and categorized into four levels. The analysis of variance or Chi-square tests facilitated group comparisons. Additionally, the receiver operating characteristic (ROC) analysis appraised the predictive accuracy of retinopathy for significant hepatic fibrosis in the T2DM population. Results: Among 5413 participants, the mean age was 59.56 ± 12.41, with 50.2% male. And 20.6% were diagnosed with T2DM. Hepatic fibrosis grading was positively associated with retinopathy severity (OR [odds ratio]: 1.521, 95%CI [confidence interval]: 1.152-2.008, P = 0.003) across the entire population. The association was amplified in the T2DM population according to Pearson's analysis results. The ROC curve demonstrated retinopathy's diagnostic capacity for significant hepatic fibrosis in the T2DM population (AUC [area under curve] = 0.72, 95%CI: 0.651-0.793, P < 0.001). Conclusions: Retinopathy could serve as an independent predictor of significant hepatic fibrosis in T2DM population. Ophthalmologists are advised to closely monitor T2DM patients with retinopathy.

Objectives: To enhance the ability of predicting self-harm behaviors through multidimensional data and machine learning methods, and provide a foundation for future comprehensive interventions. Methods: One hundred and twelve young adults aged 18-22 years with self-harm behaviors participated in this study as an experimental group, 98 in the control group. Eighty-three social-demographic and genetic features were collected and analyzed by an extreme gradient boosting (XGBoost) approach. Results: We found significant differences in social-demographic and genetic features between the self-harm and control groups (p

Unmanned aerial vehicles (UAVs) have been generally applied in the field of communication due to their small size, flexible mobility, and convenient deployment. As a mobile base station, the UAV node can quickly establish a line-of-sight link with the ground node, thereby improving communication performance. In this paper, we study a multi-UAV assisted data collecting system. Specifically, in the case of limited system energy consumption, UAV flight energy consumption and ground node data transmission energy consumption are considered as an general limitation, and considering the channel interference between nodes, a multi-UAV assisted data collection model is studied. An non-convex problem that maximizes the minimum amount of data collected from ground nodes is further formulated. Since the original optimization problem is non-convex that difficult to solve directly, the problem is first decomposed into four sub-problems, and then the solution of each sub-problem is obtained by using successive convex approximation and block coordinate descent method. Finally, based on the solution of the four subproblems, an iterative algorithm for joint optimization of data transmission planning, transmission power, UAV trajectory and mission time is proposed. Simulation experiments show that the proposed algorithm can obtain more transmission data than the baseline algorithms.

Propylene glycol (PG) and vegetable glycerin (VG) are the most common solvents used in electronic cigarette liquids. No long-term inhalation toxicity assessments have been performed combining conventional and multi-omics approaches on the potential respiratory effects of the solvents in vivo. In this study, the systemic toxicity of aerosol generated from a ceramic heating coil-based e-cigarette was evaluated. First, the aerosol properties were characterized, including carbonyl emissions, the particle size distribution, and aerosol temperatures. To determine toxicological effects, rats were exposed, through their nose only, to filtered air or a propylene glycol (PG)/ glycerin (VG) (50:50, %W/W) aerosol mixture at the target concentration of 3 mg/L for six hours daily over a continuous 28-day period. Compared with the air group, female rats in the PG/VG group exhibited significantly lower body weights during both the exposure period and recovery period, and this was linked to a reduced food intake. Male rats in the PG/VG group also experienced a significant decline in body weight during the exposure period. Importantly, rats exposed to the PG/VG aerosol showed only minimal biological effects compared to those with only air exposure, with no signs of toxicity. Moreover, the transcriptomic, proteomic, and metabolomic analyses of the rat lung tissues following aerosol exposure revealed a series of candidate pathways linking aerosol inhalation to altered lung functions, especially the inflammatory response and disease. Dysregulated pathways of arachidonic acids, the neuroactive ligand-receptor interaction, and the hematopoietic cell lineage were revealed through integrated multi-omics analysis. Therefore, our integrated multi-omics approach offers novel systemic insights and early evidence of environmental-related health hazards associated with an e-cigarette aerosol using two carrier solvents in a rat model.

Yak milk is a characteristic animal product of yaks in the Qinghai-Tibet Plateau. Although yak milk production is low, it is richer in nutrients such as protein, fat, and lactose, a more comprehensive range of bioactive components, and unique microbial resources than Holstein cow milk. The plateau environment makes yak milk resistant to hypoxia, anti-fatigue, antioxidant, antibacterial, and relieves chronic diseases. In this paper, based on the systematic analysis of yak milk research results in the past 20 years using CiteSpace 6.1.R2, we reviewed yak lactation performance and nutritional efficacy of yak milk. This paper summarizes the improvement of traditional yak dairy processing technology, and also focuses on the microbial diversity of yak milk sources and their beneficial effects. The purpose of this review is to provide scientific support for the development of a quality yak milk industry on the Tibetan plateau.

Increased numbers and functional overactivity of osteoclasts are the pathological basis for bone loss diseases such as osteoporosis, which are characterized by cortical bone thinning, decreased trabecular bone quantity, and reduced bone mineral density. Effective inhibition of osteoclast formation and bone resorption are important means of treating such skeletal diseases. Anemoside B4 (AB4), the main active component of Pulsatilla chinensis, possesses a wide range of anti-inflammatory and immunoregulatory effects. However, its effect and mechanism in osteoclast differentiation remain unclear. In this study, we found through tartrate-resistant acidic phosphatase (TRAcP) staining and immunofluorescence staining that AB4 inhibited the differentiation, fusion, and bone-resorption functions of osteoclasts induced by receptor activator of nuclear factor κB ligand (RANKL) in vitro. Additionally, real time PCR (RT-qPCR) and western blot analysis showed AB4 downregulated the expression of osteoclast marker genes, including Nfatc1, Fos, and Ctsk, while upregulating Nrf2 expression. AB4 (5 mg/kg) alleviated bone loss in ovariectomized mice by inhibiting osteoclast formation. Furthermore, the knockout of Nrf2 weakened the inhibitory effects of AB4 on osteoclast formation and related gene expression. In summary, the results suggest AB4 can inhibit osteoclast differentiation and function by activating Nrf2 and indicate AB4 may be a candidate drug for osteoporosis.

Background: P2Y receptors are a family of G protein-coupled receptor genes that have an important function in cancer development and metastasis. However, systematic studies have not been conducted on human tumors. This study attempted to explore the role of P2Y family genes (P2Ys) in pan-cancer. Methods: Gene expression and clinical data were downloaded from The Cancer Genome Alas dataset. Gene differential expression, mutation, prognosis, tumor microenvironment (TME) (containing immune cells infiltration, Estimate/immune/stromal scores, immune checkpoints, immune and molecular subtypes, DNA repair genes and methyltransferase), clinical correlation, protein-protein interaction network and functional enrichment analysis were performed. In addition, experiments such as western blots were performed for validation. Results: Eight P2Ys were differentially expressed in most tumor and normal tissues, and their abnormal expression in a variety of cancers could significantly reduce the survival rate of patients. Expression levels of P2Ys, especially P2Y6, P2Y12, P2Y13, P2Y14, were correlated significantly with immune cells, immune checkpoint genes, immune and molecular subtypes and Estimate/immune/stromal scores in a variety of cancers such as uveal melanoma, liver hepatocellular carcinoma, stomach adenocarcinoma, colorectal cancer (CRC), prostate adenocarcinoma, breast invasive carcinoma and uterine corpus endometrial carcinoma (all p

Background: KMT2D mutation (KMT2DMT) was found to play an important role in cancer immunity and response to immune checkpoint inhibitors (ICIs). The present study aims to investigate the association between KMT2D exon 39 mutation (K-ex39MT) and molecular and clinical characteristics in colorectal adenocarcinoma (CRAD). Methods: We performed profiling of KMT2DMT and K-ex39MT via Kaplan–Meier analysis, cBioportal, Immune-related functional analysis and correlation analysis with TCGA and MSK cohorts to explore their effects on the prognosis, immune landscape, molecular characteristics and drug sensitivity in CRAD. Panel gene sequencing of 30 in-house CRAD tissues and multiple immunofluorescences (mIF) were also used. Results: In multi-cancer, patients with KMT2DMT have a worse overall survival (OS), and CRAD with K-ex39MT exhibited a greater degree of immune cellular infiltration. For CRAD, compared with KMT2D exon39 wild type (K-ex39WT), K-ex39MT patients had higher tumor mutational burden (TMB) and lower copy number alteration (CNA), and were accompanied by more immune cell infiltration including activated T cells, NK cells, Treg cells and exhausted T cells and enrichment of immune-related genes and pathways. In drug sensitivity prediction, K-ex39MT patients have a lower CTX-S score and IC50 of 5-Fluorouracil and irinotecan, and higher Tumor Immune Dysfunction and Rejection (TIDE) dysfunction score. Conclusions: CRAD patients with K-ex39MT have more abundant immune cell infiltration and enrichment of immune-related pathways and signatures. And they may be more sensitive to some chemotherapies but less to cetuximab.

Apolipoprotein E (ApoE) is a multifunctional protein involved in lipid transport and lipoprotein metabolism, mediating lipid distribution/redistribution in tissues and cells. It can also regulate inflammation and immune function, maintain cytoskeleton stability, and improve neural tissue Function. Due to genetic polymorphisms of ApoE (ε2, ε3, and ε4), its three common structural isoforms (ApoE2, ApoE3, ApoE4) are also associated with the risk of many diseases, especially degenerative diseases, such as vascular degenerative diseases including atherosclerosis (AS), coronary heart disease (CHD), and neurodegenerative disease like Alzheimer's disease (AD). The frequency of the ε4 allele and APOE variants were significantly higher than that of the ε2 and ε3 alleles in the patients with CHD or AD. In recent years, ApoE has frequently appeared in tumor research and become a tumor biomarker gradually. It has been found that ApoE is highly expressed in most solid tumor tissues, such as glioblastoma, gastric cancer, pancreatic ductal cell carcinoma, etc. Studies illustrated that ApoE could regulate the polarization changes of macrophages, participate in the construction of tumor immune microenvironment, regulate tumor inflammation and immune response and play a role in tumor progression, invasion, and metastasis. Of course, many functions of ApoE and its relationship with diseases are still under research. By reviewing the structure and function of ApoE from degeneration diseases to tumor neoplasms, we hope to better understand such a biomarker and further explore the value of ApoE in later studies.

Background & Aims: Non-invasive stratification of the liver decompensation risk remains unmet in people with compensated cirrhosis. This study aimed to develop a non-invasive tool (NIT) to predict hepatic decompensation. Methods: This retrospective study recruited 689 people with compensated cirrhosis (median age, 54 years; 441 men) from 5 centres from January 2016 to June 2020. Baseline abdominal computed tomography (CT), clinical features, and liver stiffness were collected, and then the first decompensation was registered during the follow-up. The spleen-based model was designed for predicting decompensation based on a deep learning segmentation network to generate the spleen volume and least absolute shrinkage and selection operator (LASSO)-Cox. The spleen-based model was trained on the training cohort of 282 individuals (Institutions I–III) and was validated in 2 external validation cohorts (97 and 310 individuals from Institutions IV and V, respectively) and compared with the conventional serum-based models and the Baveno VII criteria. Results: The decompensation rate at 3 years was 23%, with a 37.6-month median (IQR 21.1–52.1 months) follow-up. The proposed model showed good performance in predicting decompensation (C-index ≥0.84) and outperformed the serum-based models (C-index comparison test p

As a novel lactate-derived post-translational modification (PTM), lysine lactylation (Kla) is involved in diverse biological processes, and participates in human tumorigenesis. Identification of Kla substrates with their exact sites is crucial for revealing the molecular mechanisms of lactylation. In contrast with labor-intensive and time-consuming experimental approaches, computational prediction of Kla could provide convenience and increased speed, but is still lacking. In this work, although current identified Kla sites are limited, we constructed the first Kla benchmark dataset and developed a few-shot learning-based architecture approach to leverage the power of small datasets and reduce the impact of imbalance and overfitting. A maximum 11.7% (0.745 versus 0.667) increase of area under the curve (AUC) value was achieved in contrast to conventional machine learning methods. We conducted a comprehensive survey of the performance by combining 8 sequence-based features and 3 structure-based features and tailored a multi-feature hybrid system for synergistic combination. This system achieved >16.2% improvement of the AUC value (0.889 versus 0.765) compared with single feature-based models for the prediction of Kla sites in silico. Taken few-shot learning and hybrid system together, we present our newly designed predictor named FSL-Kla, which is not only a cutting-edge tool for Kla site profile but also could generate candidates for further experimental approaches. The webserver of FSL-Kla is freely accessible for academic research at http://kla.zbiolab.cn/.

Background: Gastroesophageal varices is a serious complication of compensated advanced chronic liver disease (cACLD). Primary prophylaxis to reduce the risk of variceal hemorrhage is recommended if high-risk varices (HRV) are detected. We performed this study to compare the accuracy, patients’ satisfaction and safety of detection of HRV by detachable string magnetically controlled capsule endoscopy (DS-MCCE) with esophagogastroduodenoscopy (EGD) as the reference. Methods: We prospectively recruited participants with cACLD from 12 university hospitals (11 in China and one in the United Kingdom) between November 2018 and December 2019 (ClinicalTrials.gov, NCT03749954). All participants underwent DS-MCCE, followed by EGD within a week in a blinded fashion. Following endoscopy, and on the same day, participants were asked to fill in a satisfaction questionnaire regarding their experience. Findings: A total of 105 eligible participants were enrolled. With EGD as the reference standard, the concordance index, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of DS-MCCE in diagnosis of HRV were 0•90 (95% confidence interval [CI]: 0•83–0•95), 92% (95% CI: 78–98%), 88% (95% CI: 78–95%), 80% (95% CI: 70–92%), 95% (95% CI: 90–100%), 7•91 (95% CI: 4•10–15•30), and 0•09 (95% CI: 0•03–0•30), respectively. The kappa score of 0•78 (95% CI: 0•65–0•90) suggested substantial agreement between DS-MCCE and EGD. Moreover, in participants undergoing EGD without sedation, the satisfaction of DS-MCCE was significantly better than that of EGD (p < 0•0001, d = 1•15 [95%CI: 0•88–1•42]). All participants confirmed the excretion of the capsule, and no adverse events occurred. Interpretation: DS-MCCE is an accurate alternative to EGD for detecting HRV in cACLD, which is safe and associated with better satisfaction. Funding: A full list of funding can be found in the Funding Support section.

Summary: Rationally designing drugs that last longer in the face of biological evolution is a critical objective of drug discovery. However, this goal is thwarted by the diversity and stochasticity of evolutionary trajectories that drive uncertainty in the clinic. Although biophysical models can qualitatively predict whether a mutation causes resistance, they cannot quantitatively predict the relative abundance of resistance mutations in patient populations. We present stochastic, first-principle models that are parameterized on a large in vitro dataset and that accurately predict the epidemiological abundance of resistance mutations across multiple leukemia clinical trials. The ability to forecast resistance variants requires an understanding of their underlying mutation biases. Beyond leukemia, a meta-analysis across prostate cancer, breast cancer, and gastrointestinal stromal tumors suggests that resistance evolution in the adjuvant setting is influenced by mutational bias. Our analysis establishes a principle for rational drug design: when evolution favors the most probable mutant, so should drug design. : Drug resistance is often addressed through next-generation drug design, but evolutionary diversity complicates these efforts. Here, Leighow et al. demonstrate that multi-scale models can quantitatively predict mutant frequency. We find that when heterogeneity is limited, analysis requires an understanding of substitution likelihood. We show that these models can inform evolutionarily optimized drug design. Keywords: drug resistance, predictive evolution, stochastic dynamics

Clinically significant portal hypertension (CSPH) is associated with an incremental risk of esophageal varices and overt clinical decompensations. However, hepatic venous pressure gradient (HVPG) measurement, the gold standard for defining CSPH (HVPG≥10 mm Hg) is invasive and therefore not suitable for routine clinical practice. This study aims to develop and validate a radiomics-based model as a noninvasive method for accurate detection of CSPH in cirrhosis.The prospective multicenter diagnostic trial (CHESS1701, ClinicalTrials.gov identifier: NCT03138915) involved 385 patients with cirrhosis from five liver centers in China between August 2016 and September 2017. Patients who had both HVPG measurement and contrast-enhanced CT within 14 days prior to the catheterization were collected. The noninvasive radiomics model, termed rHVPG for CSPH was developed based on CT images in a training cohort consisted of 222 consecutive patients and the diagnostic performance was prospectively assessed in 163 consecutive patients in four external validation cohorts.rHVPG showed a good performance in detection of CSPH with a C-index of 0·849 (95%CI: 0·786–0·911). Application of rHVPG in four external prospective validation cohorts still gave excellent performance with the C-index of 0·889 (95%CI: 0·752–1·000, 0·800 (95%CI: 0·614–0·986), 0·917 (95%CI: 0·772–1·000), and 0·827 (95%CI: 0·618–1·000), respectively. Intraclass correlation coefficients for inter- and intra-observer agreement were 0·92–0·99 and 0·97–0·99, respectively.A radiomics signature was developed and prospectively validated as an accurate method for noninvasive detection of CSPH in cirrhosis. The tool of rHVPG assessment can facilitate the identification of CSPH rapidly when invasive transjugular procedure is not available. Keywords: Portal hypertension, Liver cirrhosis, Hepatic venous pressure gradient, Radiomics, Noninvasive

Purpose: The BTF3 is involved in oncogenesis, while the biological roles in HSCC remain unclear. The aim of this study was to explore the impact of BTF3 knockdown on biological phenotypes of human HSCC in vivo and in vitro. Methods: The expression of BTF3 was assessed in HSCC and normal tissues. In vitro experiments were performed to explore impact of BTF3 knockdown on biological phenotypes of human HSCC cell line, including proliferation, cell cycle, and apoptosis. Moreover, nude mice were used to evaluate growth of xenograft tumors. Finally, gene chip was used to explore the potential signaling pathways of BTF3, with confirmation of potential BTF3-related genes. Results: Our results showed elevated expression of BTF3 was observed in HSCC tumors compared to paired adjacent normal tissues in 68 patients, and positively associated with lymph node metastasis and survival of this HSCC patient cohort. In addition, in vitro experiments showed that BTF3 knockdown significantly impaired regulation of proliferation, cell cycle, and apoptosis, potentially via ATM signaling pathway. Finally, in vivo experiments demonstrated that BTF3 functioned as an oncogene by promoting the development and progression of HSCC tumors, indicating its oncogenic role in HSCC. Conclusions: This study for the first time demonstrated that expression of BTF3 is upregulated in HSCC tumors and this upregulation is positively correlated with lymph node metastasis of this malignancy. The oncogenic role of BTF3 is further validated for tumor promotion and progression of HSCC in vivo, indicating that BTF3 is a potential therapeutic target and prognostic biomarker for HSCC.

Trimetazidine (TMZ) has been shown to optimize myocardial energy metabolism and is a common anti-ischemic agent. Our trial (ChiCTR-TRC-13003298) aimed to explore whether TMZ has any preventive effect on high-altitude fatigue (HAF), cardiac function and cardiorespiratory fitness upon acute high-altitude exposure and how it works on HAF. Thirty-nine healthy young subjects were enrolled in a randomized double-blinded placebo-controlled trial and were randomized to take oral TMZ (n = 20) or placebo (n = 19), 20 mg tid, 14 days prior to departure until the end of study. The 2018 Lake Louise Score questionnaire, echocardiography, assessments of physical working capacity, circulating markers of myocardial energy metabolism and fatigue were performed both before departure and arrival at highland. At follow-up, TMZ significantly reduced the incidence of HAF (p = 0.038), reversed cardiorespiratory fitness impairment, decreased left ventricular end-systolic volume (LVESV, p = 0.032) and enhanced left ventricular ejection fraction (LVEF, p = 0.015) at highland. Relative to the placebo group, the TMZ group had significantly lower LDH (p = 0.025) and lactate levels before (p

Summary: In addition to oncogene inhibition, targeting tumor suppressor deficiency could provide potential venues for precision cancer medicine. However, the full spectrum of drug vulnerability conferred by tumor suppressor loss remains unclear. We systematically analyzed how loss of 59 common tumor suppressors each affected cellular sensitivity to 26 different types of anticancer therapeutics. The experiments were performed in a one-gene, one-drug manner, and through such a large gene-drug iteration study, we were able to generate a drug sensitivity map that describes numerous examples of drug resistance or hypersensitivity conferred by tumor suppressor loss. We further delineated the mechanisms of several gene-drug interactions, showing that loss of tumor suppressors could modify drug sensitivity at various steps of drug action. This systematic drug sensitivity map highlights potential drug vulnerabilities associated with tumor suppressor loss, which may help expand precision cancer medicine on the basis of tumor suppressor status. : Ding et al. describe how deficiencies of tumor suppressors affect cellular sensitivities to 26 types of anticancer drugs. The study reveals tumor suppressor-drug interactions potentially useful for cancer therapy. Keywords: tumor suppressor, drug sensitivity, SETD2, CREBBP, BAP1

PTPN12 is an important tumor suppressor that plays critical roles in various physiological processes. However, the molecular basis underlying the substrate specificity of PTPN12 remains uncertain. Here, enzymological and crystallographic studies have enabled us to identify two distinct structural features that are crucial determinants of PTPN12 substrate specificity: the pY+1 site binding pocket and specific basic charged residues along its surface loops. Key structurally plastic regions and specific residues in PTPN12 enabled recognition of different HER2 phosphorylation sites and regulated specific PTPN12 functions. In addition, the structure of PTPN12 revealed a CDK2 phosphorylation site in a specific PTPN12 loop. Taken together, our results not only provide the working mechanisms of PTPN12 for desphosphorylation of its substrates but will also help in designing specific inhibitors of PTPN12.

Topological charge susceptibility χt for pure gauge SU(3) theory at finite temperature is studied using anisotropic lattices. The over-improved stout-link smoothing method is utilized to calculate the topological charge. Near the phase transition point we find a rapid declining behavior for χt with values decreasing from (188(1) MeV)4 to (67(3) MeV)4 as the temperature increased from zero temperature to 1.9Tc which demonstrates the existence of topological excitations far above Tc. The 4th order cumulant c4 of topological charge, as well as the ratio c4/χt is also investigated. Results of c4 show step-like behavior near Tc while the ratio at high temperature agrees with the value as predicted by the diluted instanton gas model.