The output of cataract surgery performed by trained non-ophthalmologist physicians in rural areas: study of cataract outcomes and up-take of services report 7.

BACKGROUND: Cataract is the leading cause of blindness worldwide and surgery can restore vision in most patients. Some patients have little access to surgical services due to lack of cataract surgeons and the unaffordable costs. In 2005 we built a service model that trained rural non-ophthalmologist physicians to perform cataract surgeries in rural China. This study evaluates the long-term impacts of this model. METHODS: We conducted a retrospective cohort study to analyze patients' hand-written medical records and electronic outpatient record between January 2005 and December 2019 at two rural health clinics in Southern China. RESULTS: In total, 34,601 patients (49,942 eyes) underwent cataract surgery by non-ophthalmologist physicians from 2005 to 2019.Visual acuity was clearly documented in 38,251 eyes. Before surgery, the unaided distance visual acuity (UDVA) of 60.7% (23,205/38,251) eyes was less than 0.05 decimal. On the first day after surgery, the percentage of UDVA < 0.05 eyes was reduced to 6.0%, and 96.7% (36,980/38,251) of the eyes achieved a better UDVA compared to pre-operation. Surgical-related complications occurred in 218 eyes. The most common complication was posterior capsule rupture (114, 0.23%). 44.3% (15,341/34,601) of the patients chose to have a second eye cataract surgery (SECS) in the same clinic. At one of the outpatient clinics, 21,595 patients received basic eye care apart from cataract surgery between 2018 and 2020. CONCLUSIONS: Non-ophthalmologist physicians trained for cataract surgeries in rural clinics can improve cataract related visual acuity and basic eye care to the local population.

Chidamide represses MYC expression and might improve survival for patients with double expressor lymphoma.

Double expressor lymphoma (DEL), characterized by high expressions of both MYC and BCL-2, displays poor prognosis after current therapies. The HDAC inhibitor chidamide has been approved for treatment of T cell lymphoma, but its efficacy on B cell lymphoma is unclear. Here, by combining inhibition screening and transcriptomic analyses, we found that the sensitivity of B lymphoma cells to chidamide was positively correlated with the expression levels of MYC. Chidamide treatment reduced MYC protein levels and repressed MYC pathway in B lymphoma cells with high MYC expressions. Ectopic expression of MYC in chidamide-insensitive B lymphoma cells increased their response to chidamide. Thus, we proposed that adding chidamide into R-CHOP (CR-CHOP) might be effective for DEL, and retrospectively analyzed 185 DEL patients treated in West China Hospital. 80% of patients showed response to CR-CHOP treatment. In the median follow-up of 42 months, CR-CHOP significantly improve the survival for DEL patients with R-IPI ≤2. Totally 35 patients underwent autologous stem cell transplantation (ASCT) in remission and demonstrated a trend for better survival. Combining CR-CHOP with ASCT resulted in the most superior PFS and OS above all. For response patients, CR-CHOP reduced relapse with better PFS than R-CHOP-like regimens with or without ASCT. Taken together, our data indicated that chidamide repressed the MYC pathway in B lymphoma and is potentially efficacious to treat DEL.

Glycolysis in the tumor microenvironment: a driver of cancer progression and a promising therapeutic target.

Even with sufficient oxygen, tumor cells use glycolysis to obtain the energy and macromolecules they require to multiply, once thought to be a characteristic of tumor cells known as the "Warburg effect". In fact, throughout the process of carcinogenesis, immune cells and stromal cells, two major cellular constituents of the tumor microenvironment (TME), also undergo thorough metabolic reprogramming, which is typified by increased glycolysis. In this review, we provide a full-scale review of the glycolytic remodeling of several types of TME cells and show how these TME cells behave in the acidic milieu created by glucose shortage and lactate accumulation as a result of increased tumor glycolysis. Notably, we provide an overview of putative targets and inhibitors of glycolysis along with the viability of using glycolysis inhibitors in combination with immunotherapy and chemotherapy. Understanding the glycolytic situations in diverse cells within the tumor immunological milieu will aid in the creation of subsequent treatment plans.

Characteristics and seasonal variations of cirrus clouds from ground-based lidar and satellite observations over Shouxian Area, China.

This study investigates the macroscopic and optical properties of cirrus clouds in the 32N region from July 2016 to May 2017, leveraging data from ground-based lidar observations and CALIOP to overcome the inconsistencies in detected cirrus cloud samples. Through extensive data analysis, statistical characteristics of cirrus clouds were discerned, revealing lidar ratio values of 28.5 ± 10.8 from ground-based lidar and 27.4 ± 11.2 from CALIOP. Validation with a decade of CALIOP data (2008-2018) confirmed these findings, presenting a consistent lidar ratio of 27.4 ± 12.0. A significant outcome of the analysis was the identification of a positive correlation between the lidar ratio and cloud centroid temperature, indicating a gradual decrease in the lidar ratio as temperatures dropped. The study established a fundamental consistency in their macroscopic properties, including cloud base height, cloud top height, cloud thickness, cloud centroid height, and cloud centroid temperature. The results for ground-based lidar (CALIOP) are: 10.0 ± 2.1 km (10.0 ± 2.2 km), 11.8 ± 2.1 km (11.5 ± 2.3 km), 1.87 ± 0.83 km (1.52 ± 0.71 km), and 10.5 ± 2.2 km, -46.9 ± 9.7°C (-47.1 ± 10.0°C).These properties exhibited seasonal variations, with cirrus clouds reaching higher altitudes in summer and lower in winter, influenced by the height of the tropopause. The optical properties of cirrus clouds were also analyzed, showing an annual average optical depth of 0.31 ± 0.35 for ground-based lidar and 0.32 ± 0.44 for CALIOP. The study highlighted the distribution of subvisible, thin, and thick cirrus clouds, with a notable prevalence of subvisible clouds during summer, suggesting their frequent formation above 14 km. Furthermore, the study observed linear growth in geometric thickness and optical depth up to 2.5 km from CALIOP and 2.9 km from ground-based lidar. Maximum optical depth was observed at cloud centroid temperatures of -35°C for CALIOP and -40°C for ground-based lidar, with optical depth decreasing as temperatures fell. This suggests that fully glaciated cirrus clouds exhibit the highest optical depth at warmer temperatures, within the complete glaciation temperature range of -35°C to -40°C.

Atomic Level-Macroscopic Structure-Activity of Inhomogeneous Localized Aggregates Enabled Ultra-Low Temperature Hybrid Aqueous Batteries.

The utilization of hybrid aqueous electrolytes has significantly broadened the electrochemical and temperature ranges of aqueous batteries, such as aqueous zinc and lithium-ion batteries, but the design principles for extreme operating conditions remain poorly understood. Here, we systematically unveil the ternary interaction involving salt-water-organic co-solvents and its intricate impacts on both the atomic-level and macroscopic structural features of the hybrid electrolytes. This highlights a distinct category of micelle-like structure electrolytes featuring organic-enriched phases and nanosized aqueous electrolyte aggregates, enabled by appropriate low donor number co-solvents and amphiphilic anions. Remarkably, the electrolyte enables exceptional high solubility, accommodating up to 29.8 m zinc triflate within aqueous micelles. This configuration maintains an intra-micellar salt-in-water setup, allowing for a broad electrochemical window (up to 3.86 V), low viscosity, and state-of-the-art ultralow-temperature zinc ion conductivity (1.58 mS cm-1 at -80°C). Building upon the unique nature of the inhomogeneous localized aggregates, this micelle-like electrolyte facilitates dendrite-free Zn plating/stripping, even at -80°C. The assembled Zn||PANI battery showcases an impressive capacity of 71.8 mAh g-1 and an extended lifespan of over 3000 cycles at -80°C. This study opens up a promising approach in electrolyte design that transcends conventional local atomic solvation structures, broadening the water-in-salt electrolyte concept.

PTBP1 mediates Sertoli cell actin cytoskeleton organization by regulating alternative splicing of actin regulators.

Spermatogenesis is a biological process within the testis that produces haploid spermatozoa for the continuity of species. Sertoli cells are somatic cells in the seminiferous epithelium that orchestrate spermatogenesis. Cyclic reorganization of Sertoli cell actin cytoskeleton is vital for spermatogenesis, but the underlying mechanism remains largely unclear. Here, we report that RNA-binding protein PTBP1 controls Sertoli cell actin cytoskeleton reorganization by programming alternative splicing of actin cytoskeleton regulators. This splicing control enables ectoplasmic specializations, the actin-based adhesion junctions, to maintain the blood-testis barrier and support spermatid transport and transformation. Particularly, we show that PTBP1 promotes actin bundle formation by repressing the inclusion of exon 14 of Tnik, a kinase present at the ectoplasmic specialization. Our results thus reveal a novel mechanism wherein Sertoli cell actin cytoskeleton dynamics is controlled post-transcriptionally by utilizing functionally distinct isoforms of actin regulatory proteins, and PTBP1 is a critical regulatory factor in generating such isoforms.

Impact of Nonnative Interactions on the Binding Kinetics of Intrinsically Disordered p53 with MDM2: Insights from All-Atom Simulation and Markov State Model Analysis.

Intrinsically disordered proteins (IDPs) lack a well-defined tertiary structure but are essential players in various biological processes. Their ability to undergo a disorder-to-order transition upon binding to their partners, known as the folding-upon-binding process, is crucial for their function. One classical example is the intrinsically disordered transactivation domain (TAD) of the tumor suppressor protein p53, which quickly forms a structured α-helix after binding to its partner MDM2, with clinical significance for cancer treatment. However, the contribution of nonnative interactions between the IDP and its partner to the rapid binding kinetics, as well as their interplay with native interactions, is not well understood at the atomic level. Here, we used molecular dynamics simulation and Markov state model (MSM) analysis to study the folding-upon-binding mechanism between p53-TAD and MDM2. Our results suggest that the system progresses from the nascent encounter complex to the well-structured encounter complex and finally reaches the native complex, following an induced-fit mechanism. We found that nonnative hydrophobic and hydrogen bond interactions, combined with native interactions, effectively stabilize the nascent and well-structured encounter complexes. Among the nonnative interactions, Leu25p53-Leu54MDM2 and Leu25p53-Phe55MDM2 are particularly noteworthy, as their interaction strength is close to the optimum. Evidently, strengthening or weakening these interactions could both adversely affect the binding kinetics. Overall, our findings suggest that nonnative interactions are evolutionarily optimized to accelerate the binding kinetics of IDPs in conjunction with native interactions.

TRPV4 affects visual signals in photoreceptors and rod bipolar cells.

Introduction: Mechanical sensitive channels expressed in mammalian retinas are effectors of elevated pressure stresses, but it is unclear how their activation affects visual function in pressure-related retinal disorders. Methods: This study investigated the role of the transient potential channel vanilloid TRPV4 in photoreceptors and rod bipolar cells (RBCs) with immunohistochemistry, confocal microscopy, electroretinography (ERG), and patch-clamp techniques. Results: TRPV4 immunoreactivity (IR) was found in the outer segments of photoreceptors, dendrites and somas of PKCα-positive RBCs and other BCs, plexiform layers, and retinal ganglion cells (RGCs) in wild-type mice. TRPV4-IR was largely diminished in the retinas of homozygous TRPV4 transgenic mice. Genetically suppressing TRPV4 expression moderately but significantly enhanced the amplitude of ERG a- and b-waves evoked by scotopic and mesopic lights (0.55 to 200 Rh*rod-1 s-1) and photopic lights (105-106 Rh*rod-1 s-1) compared to wild-type mice in fully dark-adapted conditions. The implicit time evoked by dim lights (0.55 to 200 Rh*rod-1 s-1) was significantly decreased for b-waves and elongated for a-waves in the transgenic mice. ERG b-wave evoked by dim lights is primarily mediated by RBCs, and under voltage-clamp conditions, the latency of the light-evoked cation current in RBCs of the transgenic mice was significantly shorter compared to wild-type mice. About 10% of the transgenic mice had one eye undeveloped, and the percentage was significantly higher than in wild-type mice. Conclusions: The data indicates that TRPV4 involves ocular development and is expressed and active in outer retinal neurons, and interventions of TRPV4 can variably affect visual signals in rods, cones, RBCs, and cone ON BCs.

Effect of Luhong formula on the cardiac rehabilitation of patients with chronic heart failure.

BACKGROUND: Current treatments for chronic heart failure (CHF) are therapeutically ineffective. The optimization of treatments for this disease needs to be explored and analyzed. AIM: To analyze the effect of using Luhong Formula in the cardiac rehabilitation of patients with CHF and its influence on cardiopulmonary function (CPF) and prognosis. METHODS: In total, 160 patients with CHF admitted between June 2022 and June 2023 were selected, including 75 receiving perindopril (control group) and 85 receiving Luhong Formula (research group). We conducted comparative analyses on the curative effects of traditional Chinese medicine (TCM) syndromes and cardiac function, CPF [oxygen consumption at the anaerobic threshold (VO2 AT) and at peak exercise (peak VO2)], echocardiographic indexes [left atrial volume index (LAVI), left ventricular muscle mass index (LVMI), left ventricular ejection fraction (LVEF)], and prognosis [major adverse cardiovascular events (MACEs) at 6 months follow-up]. RESULTS: The research group showed markedly higher curative effects of TCM syndromes and cardiac function than the control group. In addition, post-treatment VO2 AT, peak VO2, LVMI and LVEF in the research group were significantly higher, whereas LAVI was significantly lower, than those of the control group. Furthermore, fewer patients in the research group developed MACEs at the 6-month follow-up. CONCLUSION: Luhong Formula is more therapeutically effective than perindopril for the cardiac rehabilitation of patients with CHF, specifically in enhancing CPF and prognosis.

Engineering Oxygen Vacancies in In2O3 with Enhanced Polysulfides Immobilization and Selective Catalytic Capability.

Lithium-sulfur (Li-S) battery is identified as an ideal candidate for next-generation energy storage systems in consideration of its high theoretical energy density and abundant sulfur resources. However, the shuttling behavior of soluble polysulfides (LiPSs) and their sluggish reaction kinetics severely limit the practical application of the current Li-S battery. In this work, a series of In2O3 nanocubes with different oxygen vacancy concentrations are designed and prepared via a facile self-template method. The introduced oxygen vacancy on In2O3 can effectively rearrange the charge distribution and enhance sulfiphilic property. Moreover, the In2O3 with high oxygen vacancy concentration (H-In2O3) can slightly slow down the solid-liquid conversion process and significantly accelerate the liquid-solid conversion process, thus reducing the accumulation of LiPSs in electrolyte and inhibiting the shuttle effect. Contributed by the unique selective catalytic capability, the prepared H-In2O3 exhibits excellent electrochemical performance when used as sulfur host. For instance, a high reversible capacity of 609 mAh g-1 is obtained with only 0.044% capacity decay per cycle over 1000 cycles at 1.0 C. This work presents a typical example for designing advanced sulfur hosts, which is crucial for the commercialization of Li-S battery.

The Variety of Mechanosensitive Ion Channels in Retinal Neurons.

Alterations in intraocular and external pressure critically involve the pathogenesis of glaucoma, traumatic retinal injury (TRI), and other retinal disorders, and retinal neurons have been reported to express multiple mechanical-sensitive channels (MSCs) in recent decades. However, the role of MSCs in visual functions and pressure-related retinal conditions has been unclear. This review will focus on the variety and functional significance of the MSCs permeable to K+, Na+, and Ca2+, primarily including the big potassium channel (BK); the two-pore domain potassium channels TRAAK and TREK; Piezo; the epithelial sodium channel (ENaC); and the transient receptor potential channels vanilloid TRPV1, TRPV2, and TRPV4 in retinal photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells. Most MSCs do not directly mediate visual signals in vertebrate retinas. On the other hand, some studies have shown that MSCs can open in physiological conditions and regulate the activities of retinal neurons. While these data reasonably predict the crossing of visual and mechanical signals, how retinal light pathways deal with endogenous and exogenous mechanical stimulation is uncertain.

Noninvasive imaging-guided ultrasonic neurostimulation with arbitrary 2D patterns and its application for high-quality vision restoration.

Retinal degeneration, a leading cause of irreversible low vision and blindness globally, can be partially addressed by retina prostheses which stimulate remaining neurons in the retina. However, existing electrode-based treatments are invasive, posing substantial risks to patients and healthcare providers. Here, we introduce a completely noninvasive ultrasonic retina prosthesis, featuring a customized ultrasound two-dimensional array which allows for simultaneous imaging and stimulation. With synchronous three-dimensional imaging guidance and auto-alignment technology, ultrasonic retina prosthesis can generate programmed ultrasound waves to dynamically and precisely form arbitrary wave patterns on the retina. Neuron responses in the brain's visual center mirrored these patterns, evidencing successful artificial vision creation, which was further corroborated in behavior experiments. Quantitative analysis of the spatial-temporal resolution and field of view demonstrated advanced performance of ultrasonic retina prosthesis and elucidated the biophysical mechanism of retinal stimulation. As a noninvasive blindness prosthesis, ultrasonic retina prosthesis could lead to a more effective, widely acceptable treatment for blind patients. Its real-time imaging-guided stimulation strategy with a single ultrasound array, could also benefit ultrasound neurostimulation in other diseases.

Comparison of allo-SCT, auto-SCT and chemotherapy for the treatment of patients with low- or intermediate-risk acute myeloid leukemia: a network meta-analysis.

BACKGROUND: The therapeutic status of allogeneic stem cell transplantation (allo-SCT) as a post-remission treatment for patients with high-risk acute myeloid leukemia (AML) was well-accepted. However, the optimal treatment for patients with low/favorable- or intermediate-risk AML who achieve complete remission has remained controversial. Therefore, we conducted a network meta-analysis to discuss this disputed problem. METHODS: We compared the effects of treatment strategies including allo-SCT, autologous stem cell transplantation (auto-SCT) and consolidation chemotherapy (CT) for patients with low/favorable- or intermediate-risk AML. The pooled HRs and 95% CIs for overall survival and disease-free survival were estimated with Stata12 and R software. Thirty clinical studies with 6682 patients were included in the meta-analysis. RESULTS: The results indicated that the treatment outcome of allo-SCT was the best, followed by auto-SCT, and CT was likely the worst in the total AML patients. In patients with low/favorable-risk AML, the treatment outcome of auto-SCT was likely ranked first, followed by allo-SCT, and CT was the worst. In patients with intermediate-risk AML, the treatment outcome of haploidentical stem cell transplantation (haplo-SCT) was the best, followed by allo-SCT (excluding haplo-SCT), and auto-SCT and CT were the worst. However, the median age of the haplo-SCT group was much younger than that of the control group, which may be one of the reasons for the better prognosis of the haplo-SCT group. CONCLUSIONS: Patients with low/favorable- and intermediate-risk (non-high-risk) AML should prioritize allo-SCT if they are eligible for transplantation, and auto-SCT is optional. However, in the subgroup analysis, auto-SCT was the optimal treatment choice for patients with low/favorable-risk AML, and allo-SCT was the priority selection for patients with intermediate-risk AML, especially young patients. These findings could provide references for clinical practice.

Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles.

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S-BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid-catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3-benzylideneindoline-2-thione derivatives have been established. The first hetero-(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3-catalyzed [2π+2σ] reaction with 1,1,2-trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E-1,1,2-trisubstituted alkenes. Additionally, the hetero-(4+3) cycloaddition may involve a concerted nucleophilic ring-opening mechanism.

Effect of Ethanol Extract of Tea on the Microstructural Features and Retrogradation Characteristics of Glutinous Rice Starch.

The glutinous rice starch (GRS) regeneration process could lead to decreased product quality and shorter shelf life. The purpose of this study was to analyze the effect of an ethanol extract of tea (EET) on the regeneration properties of GRS. The microstructure of starch was determined via scanning electron microscopy (SEM), Fourier-transform infrared (FT-IR) spectroscopy was used to determine the microstructure of starch-polyphenol molecular groups, an X-ray diffraction (XRD) instrument was used to determine the starch crystal structure, a differential scanning calorimeter (DSC) was used to determine the thermodynamic properties of starch, and the inhibitory effect of EET on GRS regeneration was comprehensively evaluated. The effect of EET on the in vitro digestion properties of GRS was also determined. The results showed that the addition of EET in GRS resulted in an increase in solubility and swelling power and a decrease in crystallinity and ΔHr. Compared to the control group, when retrograded for 10 days, the ΔHr of GRS with 1%, 2.5%, 5%, and 10% addition of EET decreased by 34.61%, 44.53%, 52.93%, and 66.79%, respectively. Furthermore, the addition of EET resulted in a decrease in the content of RDS and an increase in the content of SDS and RS in GRS. It was shown that the addition of EET could significantly inhibit the retrogradation of GRS, improve the processability, and prolong the shelf life of GRS products.

Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

Dihydroartemisinin induces ferroptosis of hepatocellular carcinoma via inhibiting ATF4-xCT pathway.

Management of hepatocellular carcinoma (HCC) remains challenging due to population growth, frequent recurrence and drug resistance. Targeting of genes involved with the ferroptosis is a promising alternative treatment strategy for HCC. The present study aimed to investigate the effect of dihydroartemisinin (DHA) against HCC and explore the underlying mechanisms. The effects of DHA on induction of ferroptosis were investigated with the measurement of malondialdehyde concentrations, oxidised C11 BODIPY 581/591 staining, as well as subcutaneous xenograft experiments. Activated transcription factor 4 (ATF4) and solute carrier family 7 member 11 (SLC7A11 or xCT) were overexpressed with lentiviruses to verify the target of DHA. Here, we confirmed the anticancer effect of DHA in inducing ferroptosis is related to ATF4. High expression of ATF4 is related to worse clinicopathological prognosis of HCC. Mechanistically, DHA inhibited the expression of ATF4, thereby promoting lipid peroxidation and ferroptosis of HCC cells. Overexpression of ATF4 rescued DHA-induced ferroptosis. Moreover, ATF4 could directly bound to the SLC7A11 promoter and increase its transcription. In addition, DHA enhances the chemosensitivity of sorafenib on HCC in vivo and in vitro. These findings confirm that DHA induces ferroptosis of HCC via inhibiting ATF4-xCT pathway, thereby providing new drug options for the treatment of HCC.

TRIM47-CDO1 axis dictates hepatocellular carcinoma progression by modulating ferroptotic cell death through the ubiquitin‒proteasome system.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer, characterized by high morbidity and mortality rates, as well as unfavorable treatment outcomes. Tripartite motif-containing protein 47 (TRIM47) has been implicated in various diseases including tumor progression with the activity of E3 ubiquitin ligase. However, the precise regulatory mechanisms underlying the involvement of TRIM47 in HCC remain largely unexplored. Here, we provide evidence that TRIM47 exhibits heightened expression in tumor tissues, and its expression is in intimate association with clinical staging and patient prognosis. TRIM47 promotes HCC proliferation, migration, and invasion as an oncogene by in vitro gain- and loss-of-function experiments. TRIM47 knockdown results in HCC ferroptosis induction, primarily through CDO1 involvement to regulate GSH synthesis. Subsequent experiments confirm the interaction between TRIM47 and CDO1 dependent on B30.2 domain, wherein TRIM47 facilitates K48-linked ubiquitination, leading to a decrease in CDO1 protein abundance in HCC. Furthermore, CDO1 is able to counteract the promotional effect of TRIM47 on HCC biological functions. Overall, our research provides novel insight into the mechanism of TRIM47 in CDO1-mediated ferroptosis in HCC cells, highlighting its value as a potential target candidate for HCC therapeutic approaches.

Multi-omics analysis identifies sex-specific hepatic protein-metabolite networks in yellow catfish (Pelteobagrus fulvidraco) exposed to chronic hypoxia.

Hypoxia disrupts the endocrine system of teleosts. The liver plays important roles in the endocrine system, energy storage, and metabolic processes. The aim of this study was to investigate the sex-specific hepatic response of yellow catfish under chronic hypoxia at the multi-omics level. Common hepatic responses in both sexes included the HIF-1 signaling pathway, glycolysis/gluconeogenesis, and steroid biosynthesis. Hypoxia dysregulated primary bile acid biosynthesis, lipid metabolism, and vitellogenin levels in female fish. Endoplasmic reticulum function in females also tended to be disrupted by hypoxia, as evidenced by significantly enriched pathways, including ribosome, protein processing in the endoplasmic reticulum, and RNA degradation. Other pathways, including the TCA cycle, oxidative phosphorylation, and Parkinson's and Huntington's disease, were highly enriched by hypoxia in male fish, suggesting that mitochondrial function was dysregulated. In both sexes of yellow catfish, the cell cycle was arrested and apoptosis was inhibited under chronic hypoxia. Multi-omics suggested that SLC2A5, CD209, LGMN, and NEDD8 served as sex-specific markers in these fish under chronic hypoxia. Our results provide insights into hepatic adaptation to chronic hypoxia and facilitate our understanding of sex-specific responses in fish.

Prognostic value of tumor deposits and positive lymph node ratio in stage III colorectal cancer: a retrospective cohort study.

BACKGROUND: In colorectal cancer (CRC), tumor deposits (TD) have been used to guide the N staging only in node-negative patients. It remains unknown about the prognostic value of TD in combination with positive lymph node ratio (LNR) in stage III CRC. PATIENTS AND METHODS: The authors analyzed data from 31 139 eligible patients diagnosed with stage III CRC, including 30 230 from the Surveillance, Epidemiology, and End Results (SEER) database as a training set and 909 from two Chinese hospitals as a validation set. The associations of TD and LNR with cancer-specific survival (CSS) and overall survival (OS) were evaluated using the Kaplan-Meier method and Cox regression models. RESULTS: Both TD-positive and high LNR (value ≥0.4) were associated with worse CSS in the training [multivariable hazard ratio (HR), 1.50; 95% CI: 1.43-1.58 and HR, 1.74; 95% CI: 1.62-1.86, respectively] and validation sets (HR, 1.90; 95% CI: 1.41-2.54 and HR, 2.01; 95% CI: 1.29-3.15, respectively). Compared to patients with TD-negative and low LNR (value<0.4), those with TD-positive and high LNR had a 4.09-fold risk of CRC-specific death in the training set (HR, 4.09; 95% CI: 3.54-4.72) and 4.60-fold risk in the validation set (HR, 4.60; 95% CI: 2.88-7.35). Patients with TD-positive/H-LNR CRC on the right side had the worst prognosis ( P <0.001). The combined variable of TD and LNR contributed the most to CSS prediction in the training (24.26%) and validation (32.31%) sets. A nomogram including TD and LNR showed satisfactory discriminative ability, and calibration curves indicated favorable consistency in both the training and validation sets. CONCLUSIONS: TD and LNR represent independent prognostic predictors for stage III CRC. A combination of TD and LNR could be used to identify those at high-risk of CRC deaths.