Loss-tailoring single-mode high-power supersymmetric lasers.

Diode lasers with high beam quality and high power have many promising applications. However, high beam quality is always in conflict with high power. In this Letter, we theoretically and experimentally confirm the mode instability property of supersymmetric structures at higher operating currents. Meanwhile, we propose a loss-tailoring diode laser based on a supersymmetric structure, which enables the higher-order lateral modes to obtain higher losses, raises the excitation threshold of the higher-order lateral modes, and achieves a stable fundamental-lateral-mode output at higher current operation. The device obtained a quasi-single-lobe lateral far-field distribution with the full width at half maximum (FWHM) of 7.58° at 350 mA under room temperature, which is a 65% reduction compared to the traditional Fabry-Perot (FP) diode lasers. Moreover, the M2 of 2.181@350 mA has an improvement of about 37% over traditional FP and supersymmetric structure lasers.

Hypertensive Disorders of Pregnancy and Risk of Early Brain Abnormalities on MRI at Term among Infants Born at ≤32 Weeks' Gestational Age.

OBJECTIVE: To evaluate the proximal effects of hypertensive disorders of pregnancy (HDP) on a validated measure of brain abnormalities in infants born at ≤32 weeks' gestational age (GA) using magnetic resonance imaging (MRI) at term-equivalent age. STUDY DESIGN: In a multisite prospective cohort study, 395 infants born at ≤32 weeks' GA, underwent 3T MRI scan between 39 through 44 weeks' postmenstrual age. A single neuroradiologist, blinded to clinical history, evaluated the standardized Kidokoro global brain abnormality score as the primary outcome. We classified infants as HDP-exposed by maternal diagnosis of chronic hypertension, gestational hypertension, preeclampsia, or eclampsia. Linear regression analysis identified the independent effects of HDP on infant brain abnormalities, adjusting for histologic chorioamnionitis, maternal smoking, antenatal steroids, magnesium sulfate, and infant sex. Mediation analyses quantified the indirect effect of HDP mediated via impaired intrauterine growth and prematurity and remaining direct effects on brain abnormalities. RESULTS: 170/395 infants (43%) were HDP-exposed. Adjusted multivariable analyses revealed HDP-exposed infants had 27% (95% CI 5-53%) higher brain abnormality scores than those without HDP exposure (p=0.02), primarily driven by increased white matter injury/abnormality scores (p=0.01). Mediation analyses showed HDP-induced impaired intrauterine growth significantly (p=0.02) contributed to brain abnormality scores (22% of the total effect). CONCLUSIONS: Maternal hypertension independently increased the risk for early brain injury and/or maturational delays in infants born at ≤32 weeks' GA with an indirect effect of 22% resulting from impaired intrauterine growth. Enhanced prevention/treatment of maternal hypertension may mitigate the risk of infant brain abnormalities and potential neurodevelopmental impairments.

Polyfluoroalkyl Tag Decoration Enables Significantly Enhanced Tumor Penetration Ability of a PTK7 Targeting Aptamer.

Aptamers are widely used molecular recognition tools in targeted therapy, but their ability to effectively penetrate deep into solid tumors remains a significant challenge, leading to suboptimal treatment efficacy. Here, we developed a polyfluoroalkyl (PFA) decoration strategy to enhance aptamer recognition, cell internalization, and solid tumor penetration. Our results indicate that PFA with around 11 fluorine atoms significantly improves aptamer internalization both in vitro and in vivo settings. However, we also observed that the use of PFA tags containing 19 and 23 fluorine atoms on aptamers resulted in nonspecific cell anchoring in control cell lines, affecting the specificity of aptamers. Overall, we found that using a chemical modification strategy could enhance the deep tumor penetration ability of aptamers and validate their effectiveness in vivo. This approach has significant practical applications in targeted drug delivery for cancer treatment.

Safety of repeated low-level red-light therapy for children with myopia.

BACKGROUD: To investigate the safety of repetitive low-level red-light therapy (RLRLT) in children with myopia. METHODS: Children with myopia were assigned to the RLRL and control groups. Axial length (AL) and spherical equivalent refraction (SER) were followed up at 3-, 6-, and 12-month. To evaluate the safety of RLRLT, at 6 and 12 months in the RLRL group, multifocal electroretinography (mfERG) and contrast sensitivity were recorded. Furthermore, optical coherence tomography was used to measure the relative reflectance of the ellipsoid zone (rEZR), photoreceptor outer segment (rPOSR), and retinal pigment epithelium (rRPER). RESULTS: A total of 108 children completed the trial (55 in the RLRL group and 53 in the control group). After 3, 6, and 12 months, AL was shorter and SER less myopic in the RLRL group than in the control group. Regarding the safety of the RLRLT, the response density and amplitude of the P1 wave of the first ring of the mfERG increased significantly at 6 months (P = 0.001 and P = 0.017, respectively). At 6 and 12 months, contrast sensitivity at the high spatial frequency increased. Moreover, the rEZR increased significantly at 6 months (P = 0.029), the rPOSR increased significantly at 6 and 12 months (both P < 0.001), and the increase in rPOSR was greater with greater AL regression. CONCLUSIONS: Based on retinal function and structure follow-up, RLRLT was safe within 12 months. However, rEZR and rPOSR increased, the effects of this phenomenon requires further observation.

Genetic effects and causal association analyses of 14 common conditions/diseases in multimorbidity patterns.

BACKGROUND: Multimorbidity has become an important health challenge in the aging population. Accumulated evidence has shown that multimorbidity has complex association patterns, but the further mechanisms underlying the association patterns are largely unknown. METHODS: Summary statistics of 14 conditions/diseases were available from the genome-wide association study (GWAS). Linkage disequilibrium score regression analysis (LDSC) was applied to estimate the genetic correlations. Pleiotropic SNPs between two genetically correlated traits were detected using pleiotropic analysis under the composite null hypothesis (PLACO). PLACO-identified SNPs were mapped to genes by Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA), and gene set enrichment analysis and tissue differential expression were performed for the pleiotropic genes. Two-sample Mendelian randomization analyses assessed the bidirectional causality between conditions/diseases. RESULTS: LDSC analyses revealed the genetic correlations for 20 pairs based on different two-disease combinations of 14 conditions/diseases, and genetic correlations for 10 pairs were significant after Bonferroni adjustment (P<0.05/91 = 5.49E-04). Significant pleiotropic SNPs were detected for 11 pairs of correlated conditions/diseases. The corresponding pleiotropic genes were differentially expressed in the brain, nerves, heart, and blood vessels and enriched in gluconeogenesis and drug metabolism, biotransformation, and neurons. Comprehensive causal analyses showed strong causality between hypertension, stroke, and high cholesterol, which drive the development of multiple diseases. CONCLUSIONS: This study highlighted the complex mechanisms underlying the association patterns that include the shared genetic components and causal effects among the 14 conditions/diseases. These findings have important implications for guiding the early diagnosis, management, and treatment of comorbidities.

Effect of Steel Slag on Hydration Kinetics and Rheological Properties of Alkali-Activated Slag Materials: A Comparative Study with Fly Ash.

The effects of steel slag (SS) and fly ash (FA) on hydration heat, fluidity, setting time and rheological properties of alkali-activated slag (AAS) pastes with different silicate modulus (Ms) values were comparatively investigated. The results show that the incorporation of SS shortens the induction period, increases the cumulative hydration heat, improves the initial fluidity and decreases the setting time at low Ms, but the opposite trend is found at high Ms. FA significantly retards the reaction, reduces the hydration heat, increases the fluidity and prolongs the setting time. The addition of SS or FA reduces the yield stress and plastic viscosity of AAS paste. SS improves the rheological properties of AAS paste more significantly than that of FA at high Ms. The yield stress and plastic viscosity of AAS paste with SS or FA rise with the increasing Ms and decline with the increasing water/binder (w/b) ratio.

Mitochondrial quality control in human health and disease.

Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

The essential role of adenine nucleotide translocase 4 on male reproductive function in mice.

Adenine nucleotide translocator 4 (Ant4), an ATP/ADP transporter expressed in the early phases of spermatogenesis, plays a crucial role in male fertility. While Ant4 loss causes early arrest of meiosis and increased apoptosis of spermatogenic cells in male mice, its other potential functions in male fertility remain unexplored. Here, we utilized Ant4 knockout mice to delineate the effects of Ant4-deficiency on male reproduction. Our observations demonstrated that Ant4-deficiency led to infertility and impaired testicular development, which was further investigated by evaluating testicular oxidative stress, autophagy, and inflammation. Specifically, the loss of Ant4 led to an imbalance of oxidation and antioxidants. Significant ultrastructural alterations were identified in the testicular tissues of Ant4-deficient mice, including swelling of mitochondria, loss of cristae, and accumulation of autophagosomes. Our results also showed that autophagic flux and AKT-AMPK-mTOR signaling pathway were affected in Ant4-deficient mice. Moreover, Ant4 loss increased the expression of pro-inflammatory factors. Overall, our findings underscored the importance of Ant4 in regulating oxidative stress, autophagy, and inflammation in testicular tissues. Taken together, these insights provided a nuanced understanding of the significance of Ant4 in testicular development.

Leveraging DNA-encoded Cell-mimics for Environment-adaptive Transmembrane Channel Release-induced Cell Death.

The advancement of cell-mimic materials, which can forge sophisticated physicochemical dialogues with living cells, has unlocked a realm of intriguing prospects within the fields of synthetic biology and biomedical engineering. Inspired by the evolutionarily acquired ability of T lymphocytes to release perforin and generate transmembrane channels on targeted cells for killing, herein we present a pioneering DNA-encoded artificial T cell mimic model (ARTC) that accurately mimics T-cell-like behavior. ARTC responds to acidic conditions similar to those found in the tumor microenvironment and then selectively releases a G-rich DNA strand (LG4) embedded with C12 lipid and cholesterol molecules. Once released, LG4 effectively integrates into the membranes of neighboring live cells, behaving as an artificial transmembrane channel that selectively transports K+ ions and disrupts cellular homeostasis, ultimately inducing apoptosis. We hope that the emergence of ARTC will usher in new perspectives for revolutionizing future disease treatment and catalyzing the development of advanced biomedical technologies.

Ni-Catalyzed Csp2 and Csp3 Coupling for Divergent Bisboronic Ester Synthesis.

Bisboronic esters are critical compounds in various research fields, including drug discovery, chemical biology, and material sciences. Currently, the bisboronic esters with reactive functional groups are difficult to synthesize; this is partially due to the lack of a robust method to produce these products with diverse structures and various functional groups at specific locations. To overcome this issue, this study introduced a Ni-catalysis approach to produce bisboronic esters efficiently via cross-coupling and homocoupling using readily available halogenated boronic esters as the starting material under mild reaction conditions. This newly developed strategy enables Csp2-Csp2, Csp3-Csp3, and Csp2-Csp3 couplings, demonstrating a broad substrate scope and excellent compatibility with various functional groups.

Self-Stimulated Photodynamic Nanoreactor in Combination with CXCR4 Antagonists for Antileukemia Therapy.

The treatment of acute myeloid leukemia (AML) remains unsatisfactory, owing to the absence of efficacious therapy regimens over decades. However, advances in molecular biology, including inhibiting the CXCR4/CXCL12 biological axis, have introduced novel therapeutic options for AML. Additionally, self-stimulated phototherapy can solve the poor light penetration from external sources, and it will overcome the limitation that traditional phototherapy cannot be applied to the treatment of AML. Herein, we designed and manufactured a self-stimulated photodynamic nanoreactor to enhance antileukemia efficacy and suppress leukemia recurrence and metastasis in AML mouse models. To fulfill our design, we utilized the CXCR4/CXCL12 biological axis and biomimetic cell membranes in conjunction with self-stimulated phototherapy. This nanoreactor possesses the capability to migrate into the bone marrow cavity, inhibit AML cells from infiltrating into the visceral organ, significantly enhance the antileukemia effect, and prolong the survival time of leukemic mice. Therefore, this nanoreactor has significant potential for achieving high success rates and low recurrence rates in leukemia treatment.

Massively parallel screen uncovers many rare 3' UTR variants regulating mRNA abundance of cancer driver genes.

Understanding the function of rare non-coding variants represents a significant challenge. Using MapUTR, a screening method, we studied the function of rare 3' UTR variants affecting mRNA abundance post-transcriptionally. Among 17,301 rare gnomAD variants, an average of 24.5% were functional, with 70% in cancer-related genes, many in critical cancer pathways. This observation motivated an interrogation of 11,929 somatic mutations, uncovering 3928 (33%) functional mutations in 155 cancer driver genes. Functional MapUTR variants were enriched in microRNA- or protein-binding sites and may underlie outlier gene expression in tumors. Further, we introduce untranslated tumor mutational burden (uTMB), a metric reflecting the amount of somatic functional MapUTR variants of a tumor and show its potential in predicting patient survival. Through prime editing, we characterized three variants in cancer-relevant genes (MFN2, FOSL2, and IRAK1), demonstrating their cancer-driving potential. Our study elucidates the function of tens of thousands of non-coding variants, nominates non-coding cancer driver mutations, and demonstrates their potential contributions to cancer.

Mediating effect of the NLR on the relationship between HbA1c and left atrial stiffness in overweight patients with hypertension.

BACKGROUND: We aimed to investigate the association between hemoglobin A1c (HbA1c) and left atrial (LA) stiffness in patients with hypertension and to explore the mediating effect of the neutrophil/lymphocyte ratio (NLR) on this association. METHODS: Essential hypertensive patients (n=292) aged 18 to 83 years were enrolled and divided into two groups based on the LA stiffness index (LASI): Group I (LASI≤0.32, n=146) and Group II (LASI>0.32, n=146). The LASI was defined as the ratio of early diastolic transmitral flow velocity/lateral mitral annulus myocardial velocity (E/e') to LA reservoir strain. Multivariate linear regression analysis was performed to determine the independent predictors of the LASI. RESULTS: Age, BMI, SBP, HbA1c, CRP and the NLR were significantly greater in Group II than in Group I (P<0.05). Additionally, Group II had a greater LA volume index (LAVI), left ventricular mass index (LVMI), and E/e' and lower LA reservoir, conduit and booster pump strains than Group I (P<0.001). Univariate and multivariate linear regression models revealed that age, SBP, HbA1c, and the NLR were independently associated with the LASI. Further mediation analysis was performed to determine the mediating effect of the NLR on the association between HbA1c and the LASI and revealed that the NLR had a mediating role only in overweight hypertensive patients, and the proportion of the mediating effect was 21.9%. CONCLUSIONS: The NLR was independently correlated with the LASI and played a mediating role in the relationship between HbA1c and the LASI in overweight hypertensive patients.

Spatial-temporal patterns and influencing factors for hemorrhagic fever with renal syndrome: A 16-year national surveillance analysis in China.

Background: China is confronted with the significant menace posed by hemorrhagic fever with renal syndrome (HFRS). Nevertheless, the long-term spatial-temporal variations, regional prevalence patterns, and fundamental determinants' mechanisms for HFRS remain inadequately elucidated. Methods: Newly diagnosed cases of HFRS from January 2004 to December 2019 were acquired from the China Public Health Science Data repository. We used Age-period-cohort and Bayesian Spacetime Hierarchy models to identify high-risk populations and regions in mainland China. Additionally, the Geographical Detector model was employed to quantify the determinant powers of significant driver factors to the disease. Results: A total of 199,799 cases of HFRS were reported in mainland China during 2004-2019. The incidence of HFRS declined from 1.93 per 100,000 in 2004 to 0.69 per 100,000 in 2019. The incidence demonstrated an inverted U-shaped trend with advancing age, peaking in the 50-54 age group, with higher incidences observed among individuals aged 20-74 years. Hyperendemic areas were mainly concentrated in the northeastern regions of China, while some western provinces exhibited a potential upward trend. Geographical detector model identified that the spatial variations of HFRS were significantly associated with the relative humidity (Q = 0.36), forest cover (Q = 0.26), rainfall (Q = 0.18), temperature (Q = 0.16), and the surface water resources (Q = 0.14). Conclusions: This study offered comprehensive examinations of epidemic patterns, identified high-risk areas quantitatively, and analyzed factors influencing HFRS transmission in China. The findings may contribute to the necessary implementations for the effective prevention and control of HFRS.

Changes in the global epidemiological characteristics of cystic echinococcosis over the past 30 years and projections for the next decade: Findings from the Global Burden of Disease Study 2019.

Background: Despite ongoing changes in the global epidemiology of cystic echinococcosis (CE), there is a lack of research conducted to date. Methods: We extracted data on incidence and disability-adjusted life years for 204 countries and territories from 1990 to 2019 to evaluate the epidemiological characteristics and burden of CE through the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. We used locally weighted linear regression to analyse the primary driving factors of the prevalence of CE at the national and regional levels and utilised a Bayesian Age-Period-Cohort model to forecast the global incidence of CE in the next decade. Results: Globally, the incidence of CE remained constantly high from 1990 (2.65 per 100 000 population) to 2019 (2.60 per 100 000 population), resulting in an estimated 207 368 new cases in 2019. We observed substantial variations in the disease burden regarding its spatiotemporal distribution, population demographics, and Socio-Demographic Index levels. According to established models, factors such as health care capacity, livestock husbandry, agricultural activities, rural populations, and education levels are likely to play significant roles in determining the prevalence of CE across different countries. By 2030, the worldwide number of CE cases could reach as high as 235 628, representing an increase of 13.63% compared to 2019. Conclusions: Over the past three decades, the global burden of CE has persistently remained high, especially in Central Asia, as well as North Africa and the Middle East. Efforts should focus on more effective prevention and control measures in these key regions and should specifically target vulnerable populations to prevent the escalation of epidemics.

Glutamine prevents high-fat diet-induced hepatic lipid accumulation in mice by modulating lipolysis and oxidative stress.

Metabolic-associated fatty liver disease (MAFLD) is related to metabolic dysfunction and is characterized by excess fat storage in the liver. Several studies have indicated that glutamine could be closely associated with lipid metabolism disturbances because of its important role in intermediary metabolism. However, the effect of glutamine supplementation on MAFLD progression remains unclear. Here, we used a high-fat diet (HFD)-induced MAFLD C57BL/6 mouse model, and glutamine was supplied in the drinking water at different time points for MAFLD prevention and reversal studies. A MAFLD prevention study was performed by feeding mice an HFD concomitant with 4% glutamine treatment for 24 weeks, whereas the MAFLD reversal study was performed based on 4% glutamine treatment for 13 weeks after feeding mice an HFD for 10 weeks. In the prevention study, glutamine treatment ameliorated serum lipid storage, hepatic lipid injury, and oxidative stress in HFD-induced obese mice, although glutamine supplementation did not affect body weight, glucose homeostasis, energy expenditure, and mitochondrial function. In the MAFLD reversal study, there were no noticeable changes in the basic physiological phenotype and hepatic lipid metabolism. In summary, glutamine might prevent, but not reverse, HFD-induced MAFLD in mice, suggesting that a cautious attitude is required regarding its use for MAFLD treatment.

Multivalent Aptamer-Based Lysosome-Targeting Chimeras (LYTACs) Platform for Mono- or Dual-Targeted Proteins Degradation on Cell Surface.

Selective protein degradation platforms have opened novel avenues in therapeutic development and biological inquiry. Antibody-based lysosome-targeting chimeras (LYTACs) have emerged as a promising technology that extends the scope of targeted protein degradation to extracellular targets. Aptamers offer an advantageous alternative owing to their potential for modification and manipulation toward a multivalent state. In this study, a chemically engineered platform of multivalent aptamer-based LYTACs (AptLYTACs) is established for the targeted degradation of either single or dual protein targets. Leveraging the biotin-streptavidin system as a molecular scaffold, this investigation reveals that trivalently mono-targeted AptLYTACs demonstrate optimum efficiency in degrading membrane proteins. The development of this multivalent AptLYTACs platform provides a principle of concept for mono-/dual-targets degradation, expanding the possibilities of targeted protein degradation.

THE EFFECTS OF DRAINAGE TUBE ON PAIN AND FUNCTIONAL RECOVERY AFTER UNICOMPARTMENTAL KNEE ARTHROPLASTY.

Objective: The objective of this study was to evaluate the impact of drainage tube placement on postoperative pain, recovery, and opioid consumption within a 72-hour period following unicompartmental knee arthroplasty (UKA). Methods: Patients with medial knee osteoarthritis who underwent UKA from January 2019 to August 2020 were enrolled in the study and divided into two groups based on whether they received a drain postoperatively. Results: The drainage group had significantly lower VAS scores on day 1, day 2, and day 3, in addition to significantly smaller changes in the circumference of the knee joint within 3 days postoperatively (P <0.05). The ROM in the drainage group significantly increased at 3 days and 1 month post-surgery, with a statistically significant difference in morphine consumption between the two groups at 3 days (P<0.05). The incidence of postoperative nausea and vomiting (5 cases) and wound bleeding (1 case) was lower in the drainage group compared to the non-drainage group (P<0.05). Conclusions: The placement of a drainage tube in UKA may reduce the swelling of knee joint and pain, which not only reduces the use of Opioid but also facilitates early functional activities of the knee joint. Level of Evidence III; Retrospective Comparative Study.

Objetivo: O objetivo deste estudo foi avaliar o impacto da implantação do tubo de drenagem na dor pós-operatória, na recuperação e no consumo de opioides em um período de 72 horas após a artroplastia unicompartimental do joelho (UKA). Métodos: Pacientes com osteoartrite medial do joelho submetidos à UKA de janeiro de 2019 a agosto de 2020 foram incluídos no estudo e divididos em dois grupos com base no fato de terem ou não recebido um dreno no pós-operatório. Resultados: O grupo de drenagem apresentou escores EVA significativamente menores no dia 1, no dia 2 e no dia 3, além de alterações significativamente menores na circunferência da articulação do joelho em 3 dias de pós-operatório (P <0,05). A ADM no grupo de drenagem aumentou significativamente em 3 dias e 1 mês após a cirurgia, com uma diferença estatisticamente significativa no consumo de morfina entre os dois grupos em 3 dias (P<0,05). A incidência de náuseas e vômitos no pós-operatório(5 casos) e sangramento da ferida (1 caso) foi menor no grupo de drenagem em comparação com o grupo sem drenagem (P<0,05). Conclusão: A utilização de tubo de drenagem na UKA pode reduzir o edema articular do joelho e a dor, reduzindo o uso de opioides e facilitando as atividades funcionais iniciais da articulação do joelho. Nível de Evidência III; Estudo Comparativo Retrospectivo.

Stress systems exacerbate the inflammatory response after corneal abrasion in sleep-deprived mice via the IL-17 signaling pathway.

Sleep deprivation (SD) has a wide range of adverse health effects. However, the mechanisms by which SD influences corneal pathophysiology and its post-wound healing remain unclear. This study aimed to examine the basic physiological characteristics of the cornea in mice subjected to SD and determine the pathophysiological response to injury after corneal abrasion. Using a multi-platform water environment method as an SD model, we found that SD leads to disturbances of corneal proliferative, sensory, and immune homeostasis as well as excessive inflammatory response and delayed repair after corneal abrasion by inducing hyperactivation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Pathophysiological changes in the cornea mainly occurred through the activation of the IL-17 signaling pathway. Blocking both adrenergic and glucocorticoid synthesis and locally neutralizing IL-17A significantly improved corneal homeostasis and the excessive inflammatory response and delay in wound repair following corneal injury in SD-treated mice. These results indicate that optimal sleep quality is essential for the physiological homeostasis of the cornea and its well-established repair process after injury. Additionally, these observations provide potential therapeutic targets to ameliorate SD-induced delays in corneal wound repair by inhibiting or blocking the activation of the stress system and its associated IL-17 signaling pathway.