A novel homozygous LRRC6 mutation causes male infertility with asthenozoospermia and primary ciliary dyskinesia in humans.

BACKGROUND: Dysfunction of motile cilia, including respiratory cilia and sperm flagella, typically leads to primary ciliary dyskinesia and male infertility or low fertility in humans. Genetic defects of LRRC6 have been associated with primary ciliary dyskinesia and asthenozoospermia due to abnormal ultrastructure of ciliated axonemes. OBJECTIVES: To identify novel mutations of the LRRC6 gene related to multiple morphological abnormalities of the sperm flagella and male infertility and investigate the underlying molecular mechanisms involved. MATERIALS AND METHODS: The LRRC6 mutations were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning, and transmission electron microscopy were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Further tandem mass tagging proteomics analyses were performed to explore the effect of mutations and confirmed by immunostaining and western blotting. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic LRRC6 mutations. RESULTS: In this study, we identified a novel homozygous LRRC6 mutation in a consanguineous family, characterized by asthenozoospermia and primary ciliary dyskinesia. Further Semen parameter and morphology analysis demonstrate that the novel LRRC6 mutation leads to a significant reduction in sperm flagella length, a decrease in sperm progressive motility parameters, and abnormalities of sperm ultrastructure. Specifically, the absence of outer dynein arms and inner dynein arms, and incomplete mitochondrial sheath in the flagellar mid-piece were observed by transmission electron microscopy. In addition, tandem mass tagging proteomics analysis revealed that spermatozoa obtained from patients harboring the LRRC6 mutation exhibited a significant decrease in the expression levels of proteins related to the assembly and function of dynein axonemal arms. Functional analysis revealed that this novel LRRC6 mutation disrupted the function of the leucine-rich repeat containing 6 protein, which in turn affects the expression of the dynein arm proteins and leucine-rich repeat containing 6-interacting proteins CCDC40, SPAG1, and ZMYND10. Finally, we reported a successful pregnancy through assisted reproductive technology with intracytoplasmic sperm injection in the female partner of the proband. DISCUSSION AND CONCLUSION: This study highlights the identification of a novel homozygous LRRC6 mutation in a consanguineous family and its impact on sperm progressive motility, morphology, and sperm kinetics parameters, which could facilitate the genetic diagnosis of asthenozoospermia and offer valuable perspectives for future genetic counseling endeavors.

Esketamine Exposure Impairs Cardiac Development and Function in Zebrafish Larvae.

Esketamine is a widely used intravenous general anesthetic. However, its safety, particularly its effects on the heart, is not fully understood. In this study, we investigated the effects of esketamine exposure on zebrafish embryonic heart development. Zebrafish embryos were exposed to esketamine at concentrations of 1, 10, and 100 mg/L from 48 h post-fertilization (hpf) to 72 hpf. We found that after exposure, zebrafish embryos had an increased hatching rate, decreased heart rate, stroke volume, and cardiac output. When we exposed transgenic zebrafish of the Tg(cmlc2:EGFP) strain to esketamine, we observed ventricular dilation and thickening of atrial walls in developing embryos. Additionally, we further discovered the abnormal expression of genes associated with cardiac development, including nkx2.5, gata4, tbx5, and myh6, calcium signaling pathways, namely ryr2a, ryr2b, atp2a2a, atp2a2b, slc8a3, slc8a4a, and cacna1aa, as well as an increase in acetylcholine concentration. In conclusion, our findings suggest that esketamine may impair zebrafish larvae's cardiac development and function by affecting acetylcholine concentration, resulting in weakened cardiac neural regulation and subsequent effects on cardiac function. The insights garnered from this research advocate for a comprehensive safety assessment of esketamine in clinical applications.

Stressors and coping styles of nursing students in the middle period of clinical practicum: a qualitative study.

BACKGROUND: Nursing students encounter various stressors during their clinical practicum; however, the stressors are not the same during different periods. At present, studies on the stressors and coping styles of nursing students in the middle period of their clinical practicum are rare. AIMS: The current study aimed to explore the stressors and coping styles of nursing students in the middle period of their clinical practicum. METHODS: A qualitative study with a descriptive phenomenological method was conducted to collect data from 10 nursing students undergoing the middle period of their clinical practicum from December 2020 to February 2021. The data were collected by semistructured interviews using interview outlines prepared in advance. The data were analyzed by Colaizzi's analysis method. RESULTS: The stressors experienced by nursing students in the middle period of their clinical practicum mainly included personal reasons, teaching arrangements, interpersonal relationships, occupational particularity and career planning. Additionally, nursing students coped with the stressors that they face in the clinical practicum by eliminating stressors and regulating emotions. CONCLUSIONS: Nursing students experienced various stressors and used a variety of coping styles in the middle period of their clinical practicum, which was different from what occurred in the early and late periods. Targeted interventions should be formulated and implemented to relieve nursing students' stress and guide them to adopt effective coping styles.

Effect of intraocular pressure reduction on progressive high myopia (PHM study): study protocol of a randomised controlled trial.

BACKGROUND: In adult patients with high myopia (HM), progressive axial elongation poses a significant risk for the development of subsequent ocular complications that may lead to visual impairment. Effective strategies to reduce or prevent further axial elongation in highly myopic adult patients have not been available so far. Recent studies suggested that medically lowering intraocular pressure (IOP) may reduce axial elongation. OBJECTIVE: This clinical randomised controlled trial (RCT) aims to evaluate the efficacy of medical IOP reduction in adult patients with progressive HM (PHM). TRIAL DESIGN: Single-centre, open-label, prospective RCT. METHODS: This RCT will recruit 152 participants with PHM at the Zhongshan Ophthalmic Center (ZOC). Randomised in a ratio of 1:1, participants will receive IOP-lowering eyedrops (intervention group) or will be followed without treatment (control group) for 12 months. Follow-up visits will be conducted at 1, 6 and 12 months after baseline. Only one eye per eligible participant will be included for analysis. The primary outcome is the change in axial length (AL) within the study period of 12 months. Secondary outcomes include the incidence and progression of visual field (VF) defects, changes in optic disc morphology and incidence and progression of myopic maculopathy. Difference in AL changes between the two groups will be analysed using linear regression analysis. For the secondary outcomes, a multifactor Poisson regression within a generalised linear model will be used to estimate the relative risk of progression in VF defects and myopic maculopathy, and the rate of thinning in retinal nerve fibre layer and ganglion cell-inner plexiform will be assessed through Kaplan-Meier curves and log-rank tests. ETHICS AND DISSEMINATION: Full ethics approval for this trial has been obtained from the Ethics Committee of ZOC, Sun Yat-sen University, China (ID: 2023KYPJ110). Results of this trial will be disseminated through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT05850936.

Study on Structural Design and Motion Characteristics of Magnetic Helical Soft Microrobots with Drug-Carrying Function.

Magnetic soft microrobots have a wide range of applications in targeted drug therapy, cell manipulation, and other aspects. Currently, the research on magnetic soft microrobots is still in the exploratory stage, and most of the research focuses on a single helical structure, which has limited space to perform drug-carrying tasks efficiently and cannot satisfy specific medical goals in terms of propulsion speed. Therefore, balancing the motion speed and drug-carrying performance is a current challenge to overcome. In this paper, a magnetically controlled cone-helix soft microrobot structure with a drug-carrying function is proposed, its helical propulsion mechanism is deduced, a dynamical model is constructed, and the microrobot structure is prepared using femtosecond laser two-photon polymerization three-dimensional printing technology for magnetic drive control experiments. The results show that under the premise of ensuring sufficient drug-carrying space, the microrobot structure proposed in this paper can realize helical propulsion quickly and stably, and the speed of motion increases with increases in the frequency of the rotating magnetic field. The microrobot with a larger cavity diameter and a larger helical pitch exhibits faster rotary advancement speed, while the microrobot with a smaller helical height and a smaller helical cone angle outperforms other structures with the same feature sizes. The microrobot with a cone angle of 0.2 rad, a helical pitch of 100 µm, a helical height of 220 µm, and a cavity diameter of 80 µm achieves a maximum longitudinal motion speed of 390 µm/s.

Fear of disease progression and resilience parallelly mediated the effect of post-stroke fatigue on post-stroke depression: A cross-sectional study.

AIMS: To explore the effect of post-stroke fatigue (PSF) on post-stroke depression (PSD) and examine the mediating effects of fear of disease progression (FOP) and resilience between PSF and PSD. DESIGN: A cross-sectional study. METHODS: A total of 315 stroke patients participated in the questionnaire survey between November 2022 and June 2023. Data were collected using the General Information Questionnaire, Fatigue Severity Scale, Fear of Disease Progression Questionnaire-Short Form, Connor-Davidson Resilience Scale-10 Item and Hospital Anxiety and Depression Scale-Depression Subscale. Data were analysed by descriptive analysis, Mann-Whitney U-test, Kruskal-Wallis H-test, Pearson or Spearman correlation, hierarchical regression analysis and mediation analysis. RESULTS: PSF had a significant positive total effect on PSD (ß = .354, 95% CI: .251, .454). Additionally, FOP and resilience played a partial parallel-mediating role in the relationship between PSF and PSD (ß = .202, 95% CI: .140, .265), and the total indirect effect accounted for 57.06% of the total effect. CONCLUSIONS: FOP and resilience parallelly mediated the effect of PSF on PSD, which may provide a novel perspective for healthcare professionals in preventing PSD. Targeted interventions aiming at reducing PSF, lowering FOP levels and enhancing resilience may be possible ways to alleviate PSD. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: Interventions that tail to reducing PSF, lowering FOP levels and enhancing resilience may be considered as possible ways to alleviate PSD. IMPACT: This study enriched the literature by exploring the effect of PSF on PSD and further examining the mediating effects of FOP and resilience between PSF and PSD. Findings emphasized the important effects of PSF, FOP and resilience on PSD. REPORTING METHOD: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cross-sectional studies was used to guide reporting. PATIENT OR PUBLIC CONTRIBUTION: One tertiary hospital assisted participants recruitment.

Diagnostic accuracy of salivary active matrix metalloproteinase (aMMP)-8 point-of-care test for detecting periodontitis in adults: A systematic review and meta-analysis.

OBJECTIVE: To determine the accuracy of salivary active matrix metalloproteinase (aMMP)-8 point-of-care test (POCT) for detecting periodontitis in adults, through meta-analysis. MATERIALS AND METHODS: Diagnostic studies evaluating the accuracy of salivary/oral rinse aMMP-8 POCT for detecting periodontitis in adults, when compared with clinical examination, were considered eligible. A comprehensive search was performed up to 31 August 2023 through five databases. Quality Assessment of Diagnostic Accuracy Studies 2 was utilized to evaluate the methodological quality of the included articles. Meta-analysis was performed using Bayesian bivariate hierarchical model and subgroup analysis. RESULTS: From 368 screened studies, 6 studies (4 cross-sectional and 2 longitudinal studies) were included in the meta-analysis. Overall, the pooled sensitivity and specificity of salivary aMMP-8-POCT for detecting periodontitis were 0.63 (95% CI: 0.41-0.82) and 0.84 (95% CI: 0.65-0.95), respectively. Subgroup analyses revealed that the 95% CI for oral fluid types, predefined diagnostic thresholds and the POCT systems largely overlapped, indicating that the differences between them may not be significant. CONCLUSION: Salivary aMMP-8 POCT shows fair accuracy for detecting periodontitis. The diagnostic accuracy cannot be significantly influenced by the types of oral fluids, predefined diagnostic thresholds or the specific POCT systems used. More research is needed to confirm the clinical utility and implementation of aMMP-8 POCT in the diagnosis of periodontitis.

One-stone, two birds: One step regeneration of discarded copper foil in zinc battery for dendrite-free lithium deposition current collector.

The ever-growing requirement for electrochemical energy storage has exacerbated the production of spent batteries, and the recycling of valuable battery components has recently received a remarkable attention. Among all battery components, copper foil is widely utilized as a current collector for stable zinc platting and stripping in zinc metal batteries (ZMBs) due to the perfect lattice matching of between metal copper and zinc, which is accompanied by the formation of multiple copper-zinc alloy components during the cycling process. Herein, a novel "two birds with one-stone" strategy through a one simple heat treatment step to revive the discarded copper foil in zinc metal battery is reported to further obtain a lithiophilic current collector (CuxZny-Cu) with multiple copper-zinc alloy components on the surface of the discarded copper foil. Such revived CuxZny-Cu current collector greatly reduces the lithium nucleation overpotential and realizes uniform lithium deposition and further inhibits lithium dendrites growth. The formed multiple CuxZny alloy phases on the surface of discarded copper foil exhibit a low Li nucleation overpotential of only 15 mV at 0.5 mA cm-2 for the first cycle. Moreover, such a CuxZny-Cu current collector could achieve stable cycle for 220 cycles at 0.5 mA cm-2 and 110 cycles at 1 mA cm-2 with a Li plating capacity of 1 mAh cm-2. Theoretical calculations indicate that, compared with pure Cu foil, the formed multiple alloy components of CuZn5, CuZn8, Cu0.61Zn0.39 and CuZn have low adsorption energy of -2.17, -2.55, -2.16 and -2.35 eV with lithium atoms, respectively, which result in reduced lithium nucleation overpotential. The full cell composed of CuxZny alloy current collector with deposition of 5 mAh cm-2 metal Li anode coupled with LiFePO4 (LFP) cathode exhibits a reversible capacity of 125.6 mAh/g after 110 cycles at a current of 0.5 C with capacity retention of 85.1 %. This work proposed a promising strategy to regenerate the discarded copper foil in rechargeable batteries.

The effect of sleep problems on core self-evaluations in undergraduate nursing students and the role of emotion regulation and resilience: A cross-sectional study.

BACKGROUND: Nursing students are prone to sleep problems that affect their core self-evaluations. However, little attention has been paid to the specific roles of emotion regulation (including cognitive reappraisal and expressive suppression) and resilience in this process. OBJECTIVES: This study aimed to explore 1) the direct effect of sleep problems on core self-evaluations among nursing students; 2) the chain-mediating effect of cognitive reappraisal and resilience on the relationship between sleep problems and core self-evaluations; 3) the moderating effect of expressive suppression on the direct relationship between sleep problems and core self-evaluations; and 4) the moderating effect of expressive suppression on the indirect relationship between sleep problems affecting core self-evaluations through resilience. METHODS: A total of 345 nursing students completed a survey conducted between September and October 2022. Data was analyzed using descriptive analysis, Fisher exact test, Kruskal-Wallis H test, Spearman correlation analysis, and hierarchical regression analysis. Additionally, the SPSS PROCESS V4.0 plug-in was used to verify the moderated chain-mediating effect. RESULTS: Sleep problems directly affected core self-evaluations among nursing students. Cognitive reappraisal and resilience played a partial chain-mediating role in the relationship between sleep problems and core self-evaluations, with expressive suppression having a direct moderating effect. CONCLUSIONS: Opportunities exist for enhancing the core self-evaluations of nursing students by addressing their sleep problems, promoting cognitive reappraisal strategies, and increasing resilience. Additionally, encouraging expressive suppression can mitigate the negative impact of sleep problems on nursing students' core self-evaluations.

Four new isocoumarins from Cajanus cajan.

Four novel new isocoumarins, cajanolactone B, C, D1 and D2 (1-4), were isolated from ethanolic extracts of the leaves of Cajanus cajan. The structural elucidation has been completed mainly depending on extensive spectroscopic analysis including UV, IR, NMR (1D and 2D), HRESIMS and chiral analysis. Notably, all these new isocoumarins were found to exist in racemic forms, among which compounds 3 and 4 share the same planar structure. This finding suggests that at least the biosynthesis of isocoumarin in C. cajan is chiral tolerant. A plausible biogenetic pathway of compounds 1-4 is proposed.

Letrozole induced a polycystic ovary syndrome model in zebrafish by interfering with the hypothalamic-pituitary-gonadal axis.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease in women of childbearing age, with an incidence of 5-10%. This study compared the traits of zebrafish with three diagnostic criteria for human PCOS, and the diagnostic criteria for zebrafish PCOS were proposed: decreased fecundity, elevated testosterone (T) or 11-ketotestosterone (11-KT) levels and increased cortical-alveolar oocyte (CO) ratio, enhancing the zebrafish PCOS model's accuracy. According to the mammalian PCOS classification, the type of zebrafsh PCOS is divided into four phenotypes (A, B, C and D), but the four phenotypes of zebrafish PCOS are not fully covered in the existing studies (A and D). In this study, we successfully induced phenotype B zebrafish PCOS model using the aromatase inhibitor, letrozole (LET). That is, wild-type female zebrafish were exposed to 1000 µg/L LET for 30 days. Reproductive tests showed decreased fecundity in female zebrafish exposed to LET (Control: 132.63, 146.00, 173.00; LET: 29.20, 90.00, 82.71). Hormone analysis showed that female zebrafish exposed to LET had significantly lower 17ß-estradiol/testosterone (E2/T) ratios, indicating elevated T levels. Meanwhile, levels of 11-KT in the ovaries exposed to LET were significantly up-regulated (Control: 0.0076 pg/µg; LET: 0.0138 pg/µg). Pathological sections of the ovary showed fewer CO in the LET-exposed group (Control: 16.27%; LET: 8.38%). In summary, the zebrafish PCOS model summarized and studied in this study provide a reliable and economical tool for the screening of therapeutic drugs, as well as for the etiology research and treatment strategies of PCOS.

Deletion of ACTRT1 is associated with male infertility as sperm acrosomal ultrastructural defects and fertilization failure in human.

STUDY QUESTION: Could actin-related protein T1 (ACTRT1) deficiency be a potential pathogenic factor of human male infertility? SUMMARY ANSWER: A 110-kb microdeletion of the X chromosome, only including the ACTRT1 gene, was identified as responsible for infertility in two Chinese males with sperm showing acrosomal ultrastructural defects and fertilization failure. WHAT IS KNOWN ALREADY: The actin-related proteins (e.g. ACTRT1, ACTRT2, ACTL7A, and ACTL9) interact with each other to form a multimeric complex in the subacrosomal region of spermatids, which is crucial for the acrosome-nucleus junction. Actrt1-knockout (KO) mice are severely subfertile owing to malformed sperm heads with detached acrosomes and partial fertilization failure. There are currently no reports on the association between ACTRT1 deletion and male infertility in humans. STUDY DESIGN, SIZE, DURATION: We recruited a cohort of 120 infertile males with sperm head deformations at a large tertiary hospital from August 2019 to August 2023. Genomic DNA extracted from the affected individuals underwent whole exome sequencing (WES), and in silico analyses were performed to identify genetic variants. Morphological analysis, functional assays, and ART were performed in 2022 and 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: The ACTRT1 deficiency was identified by WES and confirmed by whole genome sequencing, PCR, and quantitative PCR. Genomic DNA of all family members was collected to define the hereditary mode. Papanicolaou staining and electronic microscopy were performed to reveal sperm morphological changes. Western blotting and immunostaining were performed to explore the pathological mechanism of ACTRT1 deficiency. ICSI combined with artificial oocyte activation (AOA) was applied for one proband. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a whole-gene deletion variant of ACTRT1 in two infertile males, which was inherited from their mothers, respectively. The probands exhibited sperm head deformations owing to acrosomal detachment, which is consistent with our previous observations on Actrt1-KO mice. Decreased expression and ectopic distribution of ACTL7A and phospholipase C zeta were observed in sperm samples from the probands. ICSI combined with AOA effectively solved the fertilization problem in Actrt1-KO mice and in one of the two probands. LIMITATIONS, REASONS FOR CAUTION: Additional cases are needed to further confirm the genetic contribution of ACTRT1 variants to male infertility. WIDER IMPLICATIONS OF THE FINDINGS: Our results reveal a gene-disease relation between the ACTRT1 deletion described here and human male infertility owing to acrosomal detachment and fertilization failure. This report also describes a good reproductive outcome of ART with ICSI-AOA for a proband. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023MSXM008 and 2023MSXM054). There are no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Backbone cyclization of Salmonella typhimurium diaminopropionate ammonia-lyase to enhance the activity and stability.

Diaminopropionate ammonia-lyase transforms D and L isomers of 2,3-diaminopropionate to pyruvate and ammonia. It catalyzes D- and l-serine less effectively. L-2,3-diaminopropionate is a precursor in the biosynthesis of oxalyl diaminopropionate as a neurotoxin in certain legume species. In this work, we cyclized the diaminopropionate ammonia-lyase from Salmonella typhimurium in vitro using the redox-responsive split intein, and identified that backbone cyclization afforded the enzyme with the improved activity, thermal stability and resistance to the exopeptidase proteolysis, different from effects of the incorporated sequence recognized by tobacco vein mottling virus protease at C-terminus. Using analyses of three fluorescent dyes including 8-anilino-1-naphthalenesulfonic acid, N-phenyl-1-naphthylamine, and thioflavin T, the same amounts of the cyclic protein displayed less fluorescence than those of the linear protein upon the heat treatment. The cyclic enzyme displayed the enhanced activity in Escherichia coli cells using the designed novel reporter. In this system, d-serine was added to the culture and transported into the cytoplasm. It was transformed by pre-overexpression of the diaminopropionate ammonia-lyase, and untransformed d-serine was oxidized by the coproduced human d-amino acid oxidase to generate hydrogen peroxide. This oxidant is monitored by the HyPer indicator. The current results presented that the cyclized enzyme could be applied as a better candidate to block the neurotoxin biosynthesis in certain plant species.

Three new anti-inflammatory stilbenoids and a diphenyl ether derivative from Cajanus cajan.

Three new stilbenoids, namely two rare plant-derived phenanthrenes denominated Cajananthrenes A and B (1, 2) and one bibenzyl named Cajanbenzyl (3), together with a diphenyl ether derivative designated Cajanether (4), as well as five other known compounds (5-9) were isolated from the ethanolic extract of the leaves of Cajanus cajan. Their structures were determined through extensive spectroscopic analysis including UV, IR, NMR (1D and 2D) and HRESIMS as well. A plausible biogenesis pathway was proposed for the biosynthesis of compounds 1-3. Compounds 1 and 2 displayed moderate anti-inflammatory activity as evident from the inhibitory effect on NO production in LPS-stimulated RAW 264.7 macrophages with IC50 values of 73.6 and 44.6 µM respectively.

Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males.

BACKGROUND: Multiple morphological abnormalities of sperm flagella is an idiopathic asthenoteratozoospermia characterized by absent, short, coiled, angulation, and irregular-caliber flagella. Genetic variants of DNAH1 gene have been identified as a causative factor of multiple morphological abnormalities of sperm flagella and intracytoplasmic sperm injection is an available strategy for infertile males with dynein axonemal heavy chain 1 defects to conceive. OBJECTIVES: To identify novel variants and candidate mutant hotspots of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans. MATERIALS AND METHODS: The DNAH1 variants were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning and transmission electron microscopy, and immunostaining were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic DNAH1 variants. RESULTS: We identified 18 different DNAH1 variants in 11 unrelated families, including nine missense variants (p.A2564T, p.T3657R, p.G1862R, p.L2296P, p.T4041I, p.L611P, p.A913D, p.R1932Q, p.R2356W) and nine loss-of-function variants (c.2301-1G>T, p.Q1518*, p.R1702*, p.D2845Mfs*2, p.P3909Rfs*33, p.Q4040Dfs*33, p.Q4058*, p.E4060Pfs*61, p.V4071Cfs*54). A total of 66.7% (12/18) of the identified variants were novel. Morphological analysis based on Papanicolaou staining and scanning electron microscopy demonstrated the typical multiple morphological abnormalities of sperm flagella characteristics of dynein axonemal heavy chain 1-deficient spermatozoa. Immunostaining further revealed the absence of inner dynein arms but not outer dynein arms, which induced a general ultrastructural disorganization, such as the loss of central pair and mis-localization of the microtubule doublets and outer dense fibers. To date, seven affected couples have accepted the intracytoplasmic sperm injection treatment, and three of them have given birth to five healthy babies. DISCUSSION AND CONCLUSION: These findings further expand the variant spectrum of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans, thus providing new information for the molecular diagnosis of asthenoteratozoospermia. The favorable fertility outcomes of intracytoplasmic sperm injection will facilitate the genetic counseling and clinical treatment of infertile males with multiple morphological abnormalities of sperm flagella in the future.

[68Ga]Ga­LNC1007 PET/CT in the evaluation of renal cell carcinoma: comparison with 2-[18F]FDG/[68Ga]Ga-PSMA PET/CT.

PURPOSE: To compare the potential efficiency of [68Ga]Ga-LNC1007 with 2-[18F]FDG/[68Ga]Ga-PSMA PET/CT for detecting renal cell carcinoma (RCC) and to explore parameters derived from [68Ga]Ga-LNC1007 PET/CT for discriminating pathological characteristics in RCC. METHODS: Twenty-five RCC patients confirmed by pathology were enrolled in this prospective study. The maximum standardized uptake value (SUVmax), mean SUV (SUVmean), gross tumor volume (GTV) and total lesion-tracer (TL-tracer) of lesions were calculated from the corresponding PET/CT images. Pathological characteristics included World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade and adverse pathological features (tumor necrosis or sarcomatoid or rhabdoid feature). RESULTS: [68Ga]Ga-LNC1007 PET/CT showed a higher detection rate for primary lesions than 2-[18F]FDG and [68Ga]Ga-PSMA (LNC1007 vs. FDG: 13/17 vs. 4/17, P = 0.005; LNC1007 vs. PSMA: 9/11 vs. 6/11, P = 0.361). [68Ga]Ga-LNC1007 PET/CT showed higher SUVmax (6.6 vs. 3.7, P = 0.005), SUVmean (4.1 vs. 2.3, P = 0.001) and TBR (2.6 vs. 1.7, P = 0.011) compared with 2-[18F]FDG PET/CT, and it also showed higher TBR (2.9 vs. 0.5, P = 0.003), TBR-delay (2.8 vs. 0.3, P = 0.003), GTV (84.1 vs. 42.9, P = 0.003) and TL-tracer (442.7 vs. 235.8, P = 0.008) compared with [68Ga]Ga-PSMA PET/CT. SUVmax and TBR derived from [68Ga]Ga-LNC1007 PET/CT could effectively differentiate WHO/ISUP grade (3-4 vs. 1-2) and adverse pathological features (positive vs. negative) (SUVmax: AUC 0.81, P = 0.04; AUC 0.80, P = 0.033; TBR: AUC 0.84, P = 0.026; AUC 0.85, P = 0.014). The SUVmax was positively correlated with the FAP expression, integrin αvß3 expression and the total expression of FAP and integrin αvß3 (r = 0.577, P = 0.006, r = 0.701, P < 0.001, and r = 0.702, P < 0.001, respectively). CONCLUSION: [68Ga]Ga-LNC1007 is a promising tracer for RCC imaging and can effectively identify aggressive pathological characteristics of RCC.

Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Thrombosis density ratio can predict the occurrence of pulmonary embolism and post-thrombotic syndrome in lower-extremity deep vein thrombosis patients.

OBJECTIVE: Deep vein thrombosis (DVT) formation of lower extremities can lead to serious complications including pulmonary embolism (PE) and chronic post-thrombotic syndrome (PTS). We aimed to explore the relationship between the ratio of thrombotic density and the occurrence of PE and PTS in patients with DVT of the lower extremities. METHODS: A retrospective analysis was conducted in patients who performed computed tomography venography, dividing into DVT with PE group (54 patients) and DVT-alone group (34 patients), The clinical data were recorded. Univariate and multivariate logistic regression analysis were used to analysis variables associated with PE. The ability of thrombosis density ratio and Wells score to diagnose PE was evaluated by using the receiver operating characteristic curve (ROC) area under the curve (AUC). According to the treatment and follow-up results, subgroup analysis was performed, and the Villata score was used to determine the presence or absence of PTS and its severity. RESULTS: Compare with the DVT-alone group, more patients had dyspnea and chest pain in the DVT with PE group. DVT with PE group had lower the percentage of neutrophils, white blood cell count and platelet count, while had higher blood cell count, D-dimer, wells score, thrombus and thrombus density ratio. Multivariate logistic analysis showed that percentage of neutrophils (OR(95% CIs)=1.15 (1.01,1.31), P = 0.040), platelets (OR(95% CIs)=0.96 (0.93,0.99), P = 0.011), and thrombus density ratio (OR(95% CIs)=5.99 (1.96,18.35), P = 0.002) are independent predictors of PE. The Wells score and thrombosis density ratio were consistent in the diagnostic efficacy of PE. In the subgroup analysis, there was a relevance between the ratio of thrombosis density and the Villalta score. CONCLUSION: Percentage of neutrophils, platelets, and thrombus density ratio are independent predictors of PE. The thrombosis density of DVT patients may be an index to predict the risk of PE and PTS in DVT patients.

Landscape changes and livelihood outcomes in rural tea farming communities: A case study in Fuding City, Fujian Province, Southeast China.

Landscape changes driven by cash crop plantations have been prevalent in tropical and subtropical regions worldwide in recent decades. Investigating the landscape changes and concluding livelihood outcomes are fundamental to figure out the solutions for rural sustainability. This paper examined the landscape changes which was caused by land use changes in tea plantations as well as investigated the resultant livelihood impacts, based on a case study in Fuding City, Southeast China. A questionnaire survey of 114 rural households in four sampled villages was conducted. Results demonstrated that expansion and intensification of tea plantations were two major proximate causes of landscape changes in recent decade. Our survey indicated that some existing intensively-managed tea plantations had derived from intensification and expansion of tea plantations, respectively. We identified four underlying driving forces of landscape changes, including economic benefit, governmental policies, wildlife destruction on grain crops, and rural return migration. Our study confirmed that landscape changes have significant positive effects on farmers' livelihoods, including increasing employment and incomes, raising living standards, enhancing livelihood assets and livelihood sustainability. Especially, the aged rural populations could have a relatively decent living standard. Meanwhile, the excessive expansion of tea plantations may impair livelihood resilience. Lastly, three policy suggestions based on different time scales have been put forward to promote rural households' livelihood sustainability and resilience.

Design scheme of a high dynamic semi-airborne transient electromagnetic receiving system based on a voltage-controlled amplifier.

The semi-airborne transient electromagnetic (SATEM) technique is established to examine subsurface targets. The SATEM approach is widely used in urban underground space exploration, hydrogeological search, and deep mineral exploration. However, the strength of SATEM signals declines exponentially with the depth of detection, and the SATEM system frequently operates in high electromagnetic noise environments, directly affecting the precision of deep information interpretation. This research presents a high dynamic semi-airborne transient electromagnetic (HDSATEM) receiving system to increase the late SATEM signal intensity. This system mainly comprises a voltage-controlled amplifier (VCA) and a function generator. In addition, the VCA is modulated using the gain voltage produced by the function generator. Consequently, a simulation model has been employed to analyze various functions to compare the dynamic ranges. The actual amplification performance and signal restoration capacity are confirmed using a laboratory test. A field experiment is also carried out to evaluate the actual detection performance of the proposed system compared to standard SATEM receiving and controlled source audio-frequency magneto-telluric systems. The findings indicate that the performance improvement of the HDSATEM receiving system is more than 50% in terms of depth detection compared to that of standard SATEM receiving systems.