Diverse functions of Tribbles homolog 3 in cancers and its potential as a therapeutic target.

Currently, cancer is the second leading cause of death worldwide, and potential targeted drugs and molecular pathways for cancer development and progression have been a hot research topic worldwide. In recent years, the importance of the kinase superfamily in diseases has been well demonstrated by studies on various molecular mechanisms of kinases and the successful application of their inhibitors in diseases. Pseudokinases are members of the kinase superfamily, which have been increasingly documented to play a crucial role in cancers year after year. As a member of pseudokinases, tribbles homolog 3 (TRIB3) also exerts diverse functions in different cancers through different interacting proteins and molecular pathways, especially in tumor immunity, stemness, drug resistance, metabolism, and autophagy. In addition, peptide drugs targeting TRIB3 have high specificity in preclinical studies, which shows great promise for TRIB3 application in diseases including cancers. In this review, we dissect diverse functions played by TRIB3 in different cancers, describing the underlying mechanisms in detail. Notably, inhibitors and agonists currently available for TRIB3 are discussed, indicating the potential for TRIB3 as a therapeutic target.

Adiposity indicators exhibit depot- and sex-specific associations with multimorbidity onset: A cohort study of the UK Biobank.

AIM: This study investigated the depot- and sex-specific associations of adiposity indicators with incident multimorbidity and comorbidity pairs. MATERIALS AND METHODS: We selected 382 678 adults without multimorbidity (≥2 chronic diseases) at baseline from the UK Biobank. General obesity, abdominal obesity and body fat percentage indices were measured. RESULTS: Cox proportional hazard regression analyses of general obesity indices revealed that for every one-unit increase in body mass index, the risk of incident multimorbidity increased by 5.2% (95% confidence interval 5.0%-5.4%). A dose-response relationship was observed between general obesity degrees and incident multimorbidity. The analysis of abdominal obesity indices showed that for every 0.1 increment in waist-to-height ratio and waist-to-hip ratio, the risk of incident multimorbidity increased by 42.0% (37.9%-46.2%) and 27.9% (25.7%-30.0%), respectively. Central obesity, as defined by waist circumference, contributed to a 23.2% increased risk of incident multimorbidity. Hip circumference and hip-to-height ratio had protective effects on multimorbidity onset. Consistent findings were observed for males and females. Body fat percentage elevated 3% (0.2%-5.9%) and 5.3% (1.1%-9.7%) risks of incident multimorbidity in all adults and females, respectively. Arm fat percentages elevated 5.3% (0.8%-9.9%) and 19.4% (11.0%-28.5%) risks of incident multimorbidity in all adults and males, respectively. The general obesity indices, waist circumference, waist-to-height ratio, waist-to-hip ratio and central obesity increased the onset of comorbidity pairs, whereas hip circumference and hip-to-height ratio decreased the onset of comorbidity pairs. These adiposity indicators mainly affect diabetes mellitus-related comorbidity onset in males and hypertensive-related comorbidity onset in females. CONCLUSIONS: Adiposity indicators are predictors of multimorbidity and comorbidity pairs and represent a promising approach for intervention.

Examining the Effects of PrEP Use on Sexual Behaviors and Sexually Transmitted Infections Among Chinese Men who have Sex with Men: A Cross-Sectional Study.

Men who have sex with men (MSM) is a high-risk population for HIV and sexually transmitted infections (STIs). Pre-exposure prophylaxis (PrEP) is effective in HIV prevention. This study aims to examine the differences in sexual behaviors, STI prevalence and HIV/STI testing across subgroups of MSM with various PrEP use. Data were collected via a cross-sectional survey in an MSM community in Xi'an, Shaanxi, from 2022.01 to 2022.09. Participants were categorized as 'PrEP-naïve and unwilling to use', 'PrEP-naïve but willing to use', and 'current or former PrEP users'. Shannon index was used to assess sexual act diversity and multivariate logistic regression analyzed factors associated with PrEP use. Of the 1,131 MSM participants, 23.52% were PrEP-naïve and unwilling, 64.98% were PrEP-naïve but willing, and 11.49% were current or former PrEP users. The PrEP-naïve but willing group had the highest recent STI testing rates at 73.06% and showed greater sexual act diversity (Shannon index 1.61). This group also had the highest syphilis rates (7.49% vs. 6.47% and2.54%, p < 0.01). Younger age (18-30: OR = 0.39 (0.18-0.85); 31-40: OR = 0.43 (0.20-0.96)) and lower education (high school/vocational: OR = 0.15 (0.04-0.58); associate degree: OR = 0.21 (0.06-0.71)) were factors that negatively influenced PrEP use. Current or former PrEP users had the highest oropharyngeal gonorrhea (14.39% vs. 9.68% and 5.80%, p < 0.01) and overall gonorrhea rates (20.86% vs. 17.17% and 8.37%, p < 0.001). 'PrEP-naïve but willing' participants consistently demonstrated high-risk sexual behavior, increased STI testing, and more diverse sexual acts, whereas PrEP users had the highest STI prevalence.

Notch signaling and targeted therapy in non-small cell lung cancer.

The Notch signaling pathway plays pivotal roles in cell proliferation, stemness and invasion of non-small cell lung cancer (NSCLC). The human Notch family consists of four receptors, namely Notch1, Notch2, Notch3, and Notch4. These receptors are transmembrane proteins that play crucial roles in various cellular processes. Notch1 mostly acts as a pro-carcinogenic factor in NSCLC but sometimes acts as a suppressor. Notch2 has been demonstrated to inhibit the growth and progression of NSCLC, whereas Notch3 facilitates these biological behaviors of NSCLC. The role of Notch4 in NSCLC has not been fully elucidated, but it is evident that Notch4 promotes tumor progression. At present, drugs targeting the Notch pathway are being explored for NSCLC therapy, a majority of which are already in the stage of preclinical research and clinical trials, with bright prospects in the clinical treatment of NSCLC.

Strain-mediated multistate skyrmion for neuron devices.

Magnetic skyrmions are potential candidates for neuromorphic computing because of their inherent topological stability, low drive current density and nanoscale size. However, an artificial neuron device based on current-driven skyrmion motion cannot satisfy the requirement of energy efficiency and integration density due to hundreds of millions of interconnected neurons and synapses present in the deep networks. Here, we present a compact and energy efficient skyrmion-based artificial neuron consisting of ferromagnetic/heavy metal/ferroelectric layers which uses strain-mediated voltage manipulation of skyrmion states to mimic the Integrate-and-Fire (IF) function of biological neurons. By implementation of a spiking neural network (SNN) based on the proposed skyrmionic neuronal devices, it can achieve a high accuracy of 95.08% on a modified National Institute of Standards and Technology (MNIST) handwritten digit dataset, as well as a low power consumption of ∼46.8 fJ per epoch per neuron. The present work suggests a novel way to realize energy-efficient and high-density neuromorphic computing.

ß-cell dedifferentiation in HOMA-ßlow and HOMA-ßhigh subjects.

CONTEXT: ß-cell dedifferentiation ratio is increased in type 2 diabetes; but its direct link to in vivo ß-cell function in human remains unclear. OBJECTIVE: The present study was designed to investigate whether ß-cell dedifferentiation in situ was closely associated with ß-cell function in vivo and to identify targets crucial for ß-cell dedifferentiation/function in human. METHODS: We acquired HOMA-ß values, calculated the number of hormone-negative endocrine cells and evaluated important markers and novel candidates for ß-cell dedifferentiation/function on paraneoplastic pancreatic tissues from 13 patients with benign pancreatic cystic neoplasm (PCN) or intrapancreatic accessory spleen. RESULTS: Both ß-cell dedifferentiation ratio and dedifferentiation marker (Aldh1a3) were inversely related with in vivo ß-cell function (HOMA-ß) and in situ ß-cell functional markers Glut2 and Ucn3 in human. Moreover, the islets from HOMA-ßlow subjects were manifested as 1) increased ß-cell dedifferentiation ratio, 2) enriched dedifferentiation maker Aldh1a3, and 3) lower expression of Glut2 and Ucn3, compared to those from HOMA-ßhigh subjects. We found that basic leucine zipper transcription factor 2 (Bach2) expression was significantly induced in islets from HOMA-ßlow patients and was positively correlated with the ratio of ß-cell dedifferentiation in human. CONCLUSIONS: Our findings emphasize the contribution of ß-cell dedifferentiation to ß-cell dysfunction in human. The Bach2 induction in ß-cells with higher frequency of dedifferentiation observed in HOMA-ßlow subjects reinforce its distinctive role as a pharmaceutical target of ß-cell dedifferentiation for the treatment of human diabetes.

Spatiotemporal role of SETD2-H3K36me3 in murine pancreatic organogenesis.

Pancreas development is tightly controlled by multilayer mechanisms. Despite years of effort, large gaps remain in understanding how histone modifications coordinate pancreas development. SETD2, a predominant histone methyltransferase of H3K36me3, plays a key role in embryonic stem cell differentiation, whose role in organogenesis remains elusive. Here, by combination of cleavage under targets and tagmentation (CUT&Tag), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and bulk RNA sequencing, we show a dramatic increase in the H3K36me3 level from the secondary transition phase and decipher the related transcriptional alteration. Using single-cell RNA sequencing, we define that pancreatic deletion of Setd2 results in abnormalities in both exocrine and endocrine lineages: hyperproliferative tip progenitor cells lead to abnormal differentiation; Ngn3+ endocrine progenitors decline due to the downregulation of Nkx2.2, leading to insufficient endocrine development. Thus, these data identify SETD2 as a crucial player in embryonic pancreas development, providing a clue to understanding the dysregulation of histone modifications in pancreatic disorders.

Association Between Geriatric Nutrition Risk Index and 90-Day Mortality in Older Adults with Chronic Obstructive Pulmonary Disease: a Retrospective Cohort Study.

Background: Malnutrition adversely affects prognosis in various medical conditions, but its implications in older adults with Chronic Obstructive Pulmonary Disease (COPD) in the ICU are underexplored. The geriatric nutritional risk index (GNRI) is a novel tool for assessing malnutrition risk. This study investigates the association between GNRI and 90-day mortality in this population. Methods: We selected older adults with COPD admitted to the ICU from Medical Information Mart for Intensive Care (MIMIC)-IV 2.2 database. A total of 666 patients were categorized into four groups based on their GNRI score: normal nutrition (>98), mild malnutrition (92-98), moderate malnutrition (82-91), and severe malnutrition (≤81) groups. We employed a restricted cubic spline (RCS) analysis to assess the presence of a curved relationship between them and to investigate any potential threshold saturation effect. Results: In multivariate Cox regression analyses, compared with individuals had normal nutrition (GNRI in Q4 >98), the adjusted HR values for GNRI in Q3 (92-98), Q2 (82-91), and Q1 (≤81) were 1.81 (95% CI: 1.27-2.58, p=0.001), 1.23 (95% CI: 0.84-1.79, p=0.296), 2.27 (95% CI: 1.57-3.29, p<0.001), respectively. The relationship between GNRI and 90-day mortality demonstrates an L-shaped curve (p=0.016), with an approximate inflection point at 101.5. Conclusion: These findings imply that GNRI is a useful prognostic tool in older adults with COPD in the ICU. An L-shaped relationship was observed between GNRI and 90-day mortality in these patients.

Chitosan toughened epoxy resin by chemical cross-linking: Enabling excellent mechanical properties and corrosion resistance.

There is a growing demand for the development of epoxy resin modified with biomaterials, aiming to achieve high toughness. Herein, chitosan crosslinked epoxy resin (CE) was synthesized by diisocyanate as a bridge. With 4,4'-diamino-diphenylmethane (DDM) as the curing agent, thanks to the unique cross-linking structure of the CE resin and the presence of carbamate groups, the cured CE/DDM exhibited superior properties compared to commercially available epoxy resin (E51). The tensile strength of the cured CE-3/DDM reached 90.17 MPa, the elongation at break was 11.2 %, and the critical stress intensity factor (KIC) measured 1.78 MPa m1/2. These values were 21.4 %, 151.6 %, and 81.6 % higher than those of the cured E51/DDM, respectively. It is worth noting that the addition of biomass material chitosan did not reduce the thermal stability of the resin. Additionally, the CE coatings on the metal substrate exhibited exceptional corrosion resistance, as evidenced by higher impedance values in electrochemical impedance spectroscopy (EIS) and polarization voltages in the Tafel curve compared to those of the E51 coating. This study opens up a novel approach to modifying epoxy resin with biomass materials with high toughness and corrosion resistance, without sacrificing other performance.

Fe oxides simultaneously improve stability of Cd and carbon in paddy soil：The underlying influence at aggregate level.

Iron (Fe) oxides have a strong adsorption affinity for Cd and organic carbon (SOC). However, under alternate wet-dry (IF) condition,the influences of Fe oxides on the speciation and disrtribution of Cd and SOC in soil aggregates are unkown. In the present study, soils untreated (S), removed (S-Fe) or added (S+Fe) Fe oxide soils were blended with cadmium chloride solution and cultivated for 56 days under different moisture management practices. Compared with the S-Fe soil, the IF treatment increased the contents of Fe oxide-bound SOC (Fe-OC) and Fe/Mn oxide-bound Cd (Fe/Mn-Cd) by 18.5-29.8-fold and 1.45-2.45-fold, repectively, in the S and S+Fe soils, corresponding to a 36 %-42 % increase in the recalcitrant C pool (RCP) and a 53 %-87 % decrease in the exchangeable Cd content. These results could be attributed to soil particle aggregation and Fe redistribution. Fe addition promoted the transfer of Cd/SOC accumulated in microaggregates to macroaggregates and increased the variable negative charge content in macroaggregates and the adsorption capacity of macroaggregates for Cd/SOC. More Cd/SOC accumulated in macroaggregates in Fe oxide-bound form, which reduced the risk of Cd migration and Cd availability and increased the physical protection of SOC. Therefore, Fe oxide has great potential to simultaneously reduce carbon emissions and cadmium toxicity in paddy soil.

Entangled Mesh Hydrogels with Macroporous Topologies via Cryogelation for Rapid Atmospheric Water Harvesting.

Sorption-based atmospheric water harvesting (SAWH) is a promising technology to alleviate freshwater scarcity. Recently, hygroscopic salt-hydrogel composites (HSHCs) have emerged as attractive candidates with their high water uptake, versatile designability, and scale-up fabrication. However, achieving high-performance SAWH applications for HSHCs has been challenging because of their sluggish kinetics, attributed to their limited mass transport properties. Herein, a universal network engineering of hydrogels using a cryogelation method is presented, significantly improving the SAWH kinetics of HSHCs. As a result of the entangled mesh confinements formed during cryogelation, a stable macroporous topology is attained and maintained within the obtained entangled-mesh hydrogels (EMHs), leading to significantly enhanced mass transport properties compared to conventional dense hydrogels (CDHs). With it, corresponding hygroscopic EMHs (HEMHs) simultaneously exhibit faster moisture sorption and solar-driven water desorption. Consequently, a rapid-cycling HEMHs-based harvester delivers a practical freshwater production of 2.85 Lwater kgsorbents -1 day-1 via continuous eight sorption/desorption cycles, outperforming other state-of-the-art hydrogel-based sorbents. Significantly, the generalizability of this strategy is validated by extending it to other hydrogels used in HSHCs. Overall, this work offers a new approach to efficiently address long-standing challenges of sluggish kinetics in current HSHCs, promoting them toward the next-generation SAWH applications.

Mutant kri1l causes abnormal retinal development via cell cycle arrest and apoptosis induction.

Damage to the ribosome or an imbalance in protein biosynthesis can lead to some human diseases, such as diabetic retinopathy (DR) and other eye diseases. Here, we reported that the kri1l gene was responsible for retinal development. The kri1l gene encodes an essential component of the rRNA small subunit processome. The retinal structure was disrupted in kri1l mutants, which resulted in small eyes. The boundaries of each layer of cells in the retina were blurred, and each layer of cells was narrowed and decreased. The photoreceptor cells and Müller glia cells almost disappeared in kri1l mutants. The lack of photoreceptor cells caused a fear of light response. The development of the retina started without abnormalities, and the abnormalities began two days after fertilization. In the kri1l mutant, retinal cell differentiation was defective, resulting in the disappearance of cone cells and Müller cells. The proliferation of retinal cells was increased, while apoptosis was also enhanced in kri1l mutants. γ-H2AX upregulation indicated the accumulation of DNA damage, which resulted in cell cycle arrest and apoptosis. The kri1l mutation reduced the expression of some opsin genes and key retinal genes, which are also essential for retinal development.

[Curative effect analysis of anterior cervical discectomy and fusion in patients with cervical spondylosis of vertebral artery type].

OBJECTIVE: To investigate the clinical effect of anterior cervical discectomy and fusion (ACDF) in the treatment of cervical spondylosis of vertebral artery type(CSA). METHODS: The clinical data of 42 patients with CSA from January 2020 to January 2022 were retrospectively analyzed. There were 25 males and 17 females, aged from 30 to 74 years old with an average of (53.9±11.0) years old. There were 18 cases with single-segment lesions, 17 cases with two-segment lesions, and 7 cases with three-segment lesions. The American Academy of Otolaryngology-Head and Neck Surgery's Hearing and Balance Committee score (CHE), the Neck Disability Index (NDI) and the cervical curvature Cobb angle were recorded before surgery and after surgery at 6 months. RESULTS: All 42 ACDF patients were followed up for 6 to 30 months with an average of (14.0±5.2) months. The operative time ranged from 95 to 220 min with an average of (160.38±36.77) min, the intraoperative blood loss ranged from 30 to 85 ml with an average of (53.60±18.98) ml. Tow patients had mild postoperative dysphagia, which improved with symptomatic treatment such as nebulized inhalation. CHE score decreased from (4.05±0.96) preoperatively to (2.40±0.70) at 6 months postoperatively (t=12.97, P<0.05). The number of improved vertigo at 6 months postoperatively was 38, with an improvement rate of 90.5%. NDI score was reduced from (34.43±8.04) preoperatively to (20.76±3.91) at 6 months postoperatively (t=11.83, P<0.05). The cervical curvature Cobb angle improved from (8.04±6.70)° preoperatively to (12.42±5.23)° at 6 months postoperatively (t=-15.96, P<0.05). CONCLUSION: The ACDF procedure has outstanding clinical efficacy in treating CSA. The operation can rapidly relieve patients' episodic vertigo symptoms by relieving bony compression and reconstructing cervical curvature. However, it is necessary to strictly grasp the indications for surgery and clarify the causes of vertigo in patients, and ACDF surgery is recommended for CSA patients for whom conservative treatment is ineffective.