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Defect scattering is well known to suppress thermal transport. In this study, however, we perform both molecular dynamics and Boltzmann transport equation calculations, to demonstrate that introducing defect scattering in nanoscale heating zone could surprisingly enhance thermal conductance of the system by up to 75%. We further reveal that the heating zone without defects yields directional nonequilibrium with overpopulated oblique-propagating phonons which suppress thermal transport, while introducing defects redirect phonons randomly to restore directional equilibrium, thereby enhancing thermal conductance. We demonstrate that defect scattering can enable such thermal transport enhancement in a wide range of temperatures, materials, and sizes, and offer an unconventional strategy for enhancing thermal transport via the manipulation of phonon directional nonequilibrium. Defects in materials are well known to suppress thermal transport. Here, the authors demonstrate that introducing defects in nanoscale heating zone enhances thermal conductance by up to 75% through reducing directional phonon nonequilibrium.

High urate levels in circulation lead to the accumulation of urate crystals in joints and ultimately inflammation and gout. The reabsorption process of urate in the kidney by the urate transporter URAT1 plays a pivotal role in controlling serum urate levels. Pharmacological inhibition of URAT1 by uricosuric drugs is a valid strategy for gout management. Despite the clinical significance of URAT1, its structural mechanism and dynamics remain incompletely understood. Here, we report the structures of human URAT1 (hURAT1) in complex with substrate urate or inhibitors benzbromarone and verinurad at resolution ranges from 3.0 to 3.3 Å. We observe urate in the central substrate-binding site of hURAT1 in the outward-facing conformation and urate is wrapped in the center of hURAT1 by five phenylalanines and coordinated by two positively charged residues on each side. Uricosuric compounds benzbromarone and verinurad occupy the urate-binding site of hURAT1 in the inward-facing conformation. Structural comparison between different conformations of hURAT1 reveals the rocker-switch-like mechanism for urate transport. Benzbromarone and verinurad exert their inhibitory effect by blocking not only the binding of urate but also the structural isomerization of hURAT1. URAT1 reabsorbs urate in kidney and is a drug target for gout. Here, authors report the structures of human URAT1 in complex with substrate urate or inhibitors benzbromarone and verinurad to reveal the mechanism for urate transport and inhibition.

Glucose is a vital energy source essential for life and human health. Sodium-glucose cotransporter 2 (SGLT2) is a sodium-glucose symporter that utilizes the electrochemical gradient of sodium to reabsorb glucose from kidney filtrate back into circulation. SGLT2 plays a crucial role in maintaining blood glucose homeostasis and is an important drug target for type 2 diabetes. Despite its significance, the mechanisms by which SGLT2 recognizes and releases substrates during its transport cycle remain largely unknown. Here, we present structures of human SGLT2 in complex with a glucose analogue in the occluded conformation at 2.6 Å resolution, revealing a detailed hydrogen bonding network at the substrate binding site that governs substrate recognition. Additionally, structures of SGLT2 in both the substrate-bound inward-facing conformation and the substrate-free inward-facing conformations illustrate the structural changes that occur during substrate release into cytosol. Our structural analysis, combined with mutagenesis results, identifies specific polar interactions that are essential for maintaining the outer and inner gates in their closed conformations. SGLT2 reabsorbs glucose in the kidney by harnessing the electrochemical gradient of sodium ions. Here, the authors present structures of human SGLT2 at multiple states, revealing the molecular mechanism underlying substrate recognition and release.

Background The effect of dairy products intake on breast cancer (BC) is highly controversial. This study aims to investigate the relationship between dairy intake and BC incidence. Methods A search was carried out in PubMed, EBSCO, Web of Science, and Cochrane Library databases before January 2021. The primary objective was the risk of BC and intake of dairy products were exposure variables. Results The meta-analysis comprised 36 articles with 1,019,232 participants. Total dairy products have a protective effect on female population (hazard ratio (HR) =0.95, 95% confidence interval (CI) =0.91–0.99, p  = 0.019), especially for estrogen receptor-positive (ER+) (HR = 0.79, p  = 0.002) and progesterone receptor-positive (PR+) BC (HR = 0.75, p  = 0.027). For ER+/PR+ BC, there is a trend of protection, but it has not reached statistical significance (HR = 0.92, p  = 0.075). Fermented dairy products can reduce BC risk in postmenopausal population (HR = 0.96, 95%CI = 0.93–0.99, p  = 0.021), but have no protective effect on premenopausal population (HR = 0.98, 95%CI = 0.94–1.03, p  = 0.52). Non-fermented dairy products have no significant effect on BC occurrence ( p  > 0.05). High-fat dairy products are harmful to women, without statistical difference (HR = 1.06, 95%CI = 1.00–1.13, p  = 0.066). On the contrary, low-fat dairy products can protect the premenopausal population (HR = 0.94, 95%CI = 0.89–1.00, p  = 0.048). Conclusion The intake of dairy products can overall reduce BC risk in the female population, but different dairy products have varying effects on different BC subtypes and menopausal status.

TRPC3/6/7 channels are cation channels that are directly activated by the second messenger diacylglycerol (DAG). These channels play crucial physiological roles and are implicated in various disease conditions; however, the binding mechanism of DAG to these channels remains incompletely understood. In this study, we present the structures of human TRPC3 in complex with DAG or synthetic activators, 4n and GSK1702934A. The structural analysis reveals that DAG binds at the L2 site, located near the pore on the extracellular side of TRPC3. Functional assays confirmed that the L2 site serves as the activating site for DAG. Notably, both 4n and GSK1702934A competitively bind to the same site, facilitating channel activation. Moreover, based on the pharmacophore identified from the DAG-bound structure, we found that monoacylglycerols (MAGs) are endogenous activators of TRPC3/6/7 channels, providing new insights into their regulatory mechanisms. TRPC3/6/7 are DAG-activated cation channels. The authors report structures of human TRPC3 in complex with DAG or synthetic activators 4n and GSK1702934A. These results lead to the identification of monoacylglycerols as endogenous activators of TRPC3/6/7 channels.

Phonon modal nonequilibrium is believed to widely exist around nanoscale hotspots, which can significantly affect the performance of nano‐electronic and optoelectronic devices. However, such a phenomenon has not been explicitly observed in 3D device semiconductors at the nanoscale. Here, by employing a tip‐enhanced Raman thermal measurement approach, substantial phonon nonequilibrium in gallium nitride near sub‐10 nm laser‐excited hotspots is directly revealed for the first time. As further evidence, quantitative agreements between measurements and accurate first‐principles‐based phonon Boltzmann transport equation calculations are obtained. The large nonequilibrium is attributed to the strong Fröhlich coupling of electrons with longitudinal optical phonons and the large acoustic‐optical phonon frequency gap in gallium nitride, which is further demonstrated in other common III‐V semiconductors. This work establishes a viable approach for understanding nanoscale nonequilibrium phonon transport and can potentially benefit the future modulation of hot carrier dynamics. This study achieves direct characterization of intricate nanoscale phonon transport in semiconductors by developing refined a tip‐enhanced Raman thermal measurement technique. For the first time, substantial phonon nonequilibrium is directly observed near sub‐10nm laser‐excited hotspots in gallium nitride, as also evidenced by quantitative agreement with first‐principles‐based phonon Boltzmann transport equation calculations, which potentially benefit future modulation of energy carrier dynamics.

Long noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N 6 -methyladenosine (m 6 A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m 6 A-modified lncRNA in diffuse large B cell lymphoma (DLBCL) has remained poorly defined. In the present study, we showed that lncRNA TRERNA1 was associated with the poor prognosis of DLBCL patients. TRERNA1 with internal m 6 A modification was highly correlated with the demethylase ALKBH5 expression. We further demonstrated that TRERNA1 was a potential downstream target of ALKBH5-mediated m 6 A modification by m 6 A-RNA sequencing and m 6 A-RIP assays. Decreased m 6 A methylation of TRERNA1 regulated by ALKBH5 was shown to regulate cell proliferation in vitro and in vivo. The results of mechanism analyses revealed that TRERNA1 recruited EZH2 to epigenetically silence the expression of the cyclin-dependent kinases inhibitor p21 by H3K27me3 modification of its promoter region. In addition, ALKBH5 further inhibited p21 expression. Taken together, our results elucidate the functional roles and epigenetic alterations of TRERNA1 through m 6 A modification in DLBCL. TRERNA1, the expression of which is upregulated by ALKBH5, acts as a scaffold that decreases p21 expression. The results of the present study provide novel targets for the diagnosis and treatment of DLBCL.

Accurate clustering is a challenging task with unlabeled data. Ensemble clustering aims to combine sets of base clusterings to obtain a better and more stable clustering and has shown its ability to improve clustering accuracy. Dense representation ensemble clustering (DREC) and entropy-based locally weighted ensemble clustering (ELWEC) are two typical methods for ensemble clustering. However, DREC treats each microcluster equally and hence, ignores the differences between each microcluster, while ELWEC conducts clustering on clusters rather than microclusters and ignores the sample–cluster relationship. To address these issues, a divergence-based locally weighted ensemble clustering with dictionary learning (DLWECDL) is proposed in this paper. Specifically, the DLWECDL consists of four phases. First, the clusters from the base clustering are used to generate microclusters. Second, a Kullback–Leibler divergence-based ensemble-driven cluster index is used to measure the weight of each microcluster. With these weights, an ensemble clustering algorithm with dictionary learning and the L2,1-norm is employed in the third phase. Meanwhile, the objective function is resolved by optimizing four subproblems and a similarity matrix is learned. Finally, a normalized cut (Ncut) is used to partition the similarity matrix and the ensemble clustering results are obtained. In this study, the proposed DLWECDL was validated on 20 widely used datasets and compared to some other state-of-the-art ensemble clustering methods. The experimental results demonstrated that the proposed DLWECDL is a very promising method for ensemble clustering.

On the interface of the Cu-Al composite plate from horizontal continuous casting, the eutectic microstructure layer thickness accounts for more than 90% of the total interface thickness, and the deformation in rolling forming plays an important role in the quality of the composite plate. The eutectic microstructure material on the interface of the Cu-Al composite plate was prepared by changing the cooling rate of ingot solidification and the deformation in hot compression was investigated. The results show that when the deformation temperature is over 300°C, the softening effect of dynamic recrystallization of α-Al is greater than the hardening effect, and uniform plastic deformation of eutectic microstructure is caused. The constitutive equation of flow stress in the eutectic microstructure layer was established by Arrhenius hyperbolic-sine mathematics model, providing a reliable theoretical basis for the deformation of the Cu-Al composite plate.

Background The optimal duration and choice of anticoagulant for the treatment of Peripherally inserted central catheters (PICC)-related upper extremity deep vein thrombosis (UEDVT) in cancer patients are still undetermined. Objectives The aim of this study was to assess the efficacy and safety of rivaroxaban for the treatment of PICC-related UEDVT in cancer patients. Methods We conducted a retrospective cohort study including consecutive cancer patients for the management of acute symptomatic PICC-related UEDVT. The efficacy outcome of the study was the 180-day recurrence of any venous thromboembolism (VTE), while the safety outcome was the 180-day incidence of all bleeding events. The Kaplan‒Meier method was used to estimate the overall incidence. Hazard ratios (HRs) were obtained with a Cox proportional hazards model to estimate the risk of the outcome events. Results A total of 217 patients were included in the final analysis with a median age of 56 years old, 41.5% of whom had metastases. After the initial 3–5 days of nadroparin, patients received sequential anticoagulation, either with nadroparin (118 patients) or with rivaroxaban (99 patients). Four patients with recurrent VTE were observed (nadroparin, n  = 2; rivaroxaban, n  = 2). The 180-day cumulative VTE recurrence rates were 1.7% and 2.0% ( p  = 0.777) in patients receiving nadroparin and rivaroxaban, respectively. The overall bleeding rate at 180 days was 8.8%. Although no major bleeding events were observed, nineteen patients with clinically relevant nonmajor bleeding (CRNMB) were observed. The 180-day cumulative rate of CRNMB was 5.1% for nadroparin and 13.1% for rivaroxaban (HR = 3.303, 95% CI 1.149–9.497, p  = 0.027). Conclusion Our study supported the efficacy of rivaroxaban for treating PICC-related UEDVT in cancer patients. However, data on anticoagulation therapy for PICC-related UEDVT presented with a low risk of VTE recurrence and a relatively high risk of CRNMB bleeding events. Considering the risk–benefit ratio, further well-designed trials are required to optimize the drug selection and duration for the treatment of PICC-related UEDVT in cancer patients.