Dams trigger exponential population declines of migratory fish.

The impact of dams on global migratory fish stocks is a major challenge and remains seriously underestimated. China has initiated a dozen fish rescue programs for the dams on the Yangtze River, focusing on five flagship species-Chinese sturgeon, Chinese paddlefish, Yangtze sturgeon, Chinese sucker, and Coreius guichenoti. Despite 40 years of effort, these five fishes are on the verge of extinction. Here, we propose an analytical tool that includes a framework of fish migration taxonomy and six life cycle models, the concepts of invalid stock and the dam impact coefficient, and a simplified population model. We then clarify the migration patterns and life cycles of these fishes and show that the Yangtze dams have severely disrupted the life cycle integrity of these species, causing seven types of invalid stocks and their exponential population declines. Last, we discuss six scientific misjudgments underpinning the fish rescue programs and recommend reforms to China's fish rescue strategy.

ANKZF1 knockdown inhibits glioblastoma progression by promoting intramitochondrial protein aggregation through mitoRQC.

Protein homeostasis is fundamental to the development of tumors. Ribosome-associated quality-control (RQC) is able to add alanine and threonine to the stagnant polypeptide chain C-terminal (CAT-tail) when protein translation is hindered, while Ankyrin repeat and zinc-finger domain-containing-protein 1 (ANKZF1) can counteract the formation of the CAT-tail, preventing the aggregation of polypeptide chains. In particular, ANKZF1 plays an important role in maintaining mitochondrial protein homeostasis by mitochondrial RQC (mitoRQC) after translation stagnation of precursor proteins targeting mitochondria. However, the role of ANKZF1 in glioblastoma is unclear. Therefore, the current study was aimed to investigate the effects of ANKZF1 in glioblastoma cells and a nude mouse glioblastoma xenograft model. Here, we reported that knockdown of ANKZF1 in glioblastoma cells resulted in the accumulation of CAT-tail in mitochondria, leading to the activated mitochondrial unfolded protein response (UPRmt) and inhibits glioblastoma malignant progression. Excessive CAT-tail sequestered mitochondrial chaperones HSP60, mtHSP70 and proteases LONP1 as well as mitochondrial respiratory chain subunits ND1, Cytb, mtCO2 and ATP6, leading to mitochondrial oxidative phosphorylation dysfunction, membrane potential impairment, and mitochondrial apoptotic pathway activation. Our study highlights ANKZF1 as a valuable target for glioblastoma intervention and provides an innovative insight for the treatment of glioblastoma through the regulating of mitochondrial protein homeostasis.

Investigating the Bidirectional Association of Rheumatoid Arthritis and Thyroid Function: A Methodologic Assessment of Mendelian Randomization.

OBJECTIVE: Rheumatoid arthritis (RA) and thyroid dysfunction are frequently observed in the same patient. However, whether they co-occur or exhibit a causal relationship remains uncertain. We aimed to systematically investigate the causal relationship between RA and thyroid function using a large sample and advanced methods. METHODS: Bidirectional two-sample Mendelian randomization (MR) analysis was performed based on RA and six thyroid function trait data sets from the European population. The robustness of the results was demonstrated using multiple MR methods and a series of sensitivity analyses. Multivariable MR using Bayesian model averaging (MR-BMA) was performed to adjust for possible competing risk factors. A sensitivity data set, which included data from patients with seropositive RA and controls, was used to repeat the analyses. Furthermore, enrichment analysis was employed to discover the underlying mechanism between RA and thyroid functions. RESULTS: A significantly positive causal effect was identified for RA on autoimmune thyroid disease (AITD) as well as for AITD on RA (P < 0.001). Further sensitivity analyses showed consistent causal estimates from a variety of MR methods. After removing the outliers, MR-BMA results showed that RA and AITD were independent risk factors in their bidirectional causality, even in the presence of other competing risk factors (adjusted P < 0.05). Enrichment analysis showed immune cell activation and immune response play crucial roles in them. CONCLUSION: Our results illustrate the significant bidirectional causal effect of RA and AITD, which holds even in multiple competing risk factors. Clinical screening for thyroid dysfunction in patients with RA deserves further attention, and vice versa.

Effect of ß-alanine on the athletic performance and blood amino acid metabolism of speed-racing Yili horses.

The objective of this study was to examine the effects of supplemental ß-alanine feeding on the athletic performance of Yili horses involved in speed racing, focusing on alterations in plasma free amino acid patterns pre and post exercise. Additionally, the research aimed to evaluate the effects of carnosine on the plasma acid-base buffering capacity and antioxidant levels in these horses. Twelve Yili horse stallions, averaging 3 years in age and 346.50 ± 21.39 kg in weight, were chosen and randomly divided into two groups: a control group and a test group, each comprising six horses. The control group received a supplementation of 300 mg/kg BW/day of α-alanine, while the test group received 300 mg/kg BW/day of ß-alanine. This supplementation regimen was maintained for a 30-day supplementation trial period, under identical feeding and management conditions. Throughout the trial, the horses participated in the 1,000 Speed Race, and three distinct blood samples were gathered for assessing plasma free amino acids, blood gases, biochemical parameters, and antioxidant parameters. The outcomes indicated a considerable enhancement in the 1,000 m exercise performance of the speed racing Yili horses in the test group compared to the control group, showcasing a noteworthy improvement of 12.01%, with the test group completing the race 13.29 s faster. Notably, the α-alanine content in the plasma of the control group Yili horses remained higher than that of the test group, demonstrating a consistent increasing trend. By contrast, the plasma ß-alanine content was notably higher in the test group than in the control group. Over the course of the supplementation period, plasma ß-alanine exhibited an escalating and then stabilizing trend in the test group, whereas in the control group, although ß-alanine content also increased, the trend was less pronounced. The plasma levels of histidine and carnosine showed minimal variance between the two groups. Overall, the test group of Yili horses exhibited slightly higher plasma levels of histidine and carnosine compared to the control group. The addition of ß-alanine to their diet for a duration of 30 days notably affected the plasma levels of amino acids both pre- and post-exercise in speed-racing Yili horses. Furthermore, ß-alanine demonstrated an inhibitory effect on the catabolism of these horses' bodies during high-intensity exercise. Ten marker amino acids, including valine, leucine, ß-alanine, isoleucine, carnosine, 3-methyl-histidine, lysine, ethanolamine, argnine, and taurine, displayed statistically significant changes. ß-alanine notably increased the blood glucose levels of Yili horses and played a role in expediting the restoration of blood gas levels post-exercise. Moreover, in the test group of Yili horses, the levels of superoxide dismutase, glutathione peroxidase, and total antioxidant capacity significantly increased both before and after the race, while the content of malondialdehyde, an oxidation product, exhibited an extremely significant decrease immediately after the race. These outcomes suggest that the addition of ß-alanine significantly augmented antioxidant levels during high-intensity exercise in Yili horses. Consequently, it reduced post-exercise injuries and accelerated the recovery process after exercise.

Cathepsin B as a key regulator of ferroptosis in microglia following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a subtype of stroke marked by elevated mortality and disability rates. Recently, mounting evidence suggests a significant role of ferroptosis in the pathogenesis of ICH. Through a combination of bioinformatics analysis and basic experiments, our goal is to identify the primary cell types and key molecules implicated in ferroptosis post-ICH. This aims to propel the advancement of ferroptosis research, offering potential therapeutic targets for ICH treatment. Our study reveals pronounced ferroptosis in microglia and identifies the target gene, cathepsin B (Ctsb), by analyzing differentially expressed genes following ICH. Ctsb, a cysteine protease primarily located in lysosomes, becomes a focal point in our investigation. Utilizing in vitro and in vivo models, we explore the correlation between Ctsb and ferroptosis in microglia post-ICH. Results demonstrate that ICH and hemin-induced ferroptosis in microglia coincide with elevated levels and activity of Ctsb protein. Effective alleviation of ferroptosis in microglia after ICH is achieved through the inhibition of Ctsb protease activity and protein levels using inhibitors and shRNA. Additionally, a notable increase in m6A methylation levels of Ctsb mRNA post-ICH is observed, suggesting a pivotal role of m6A methylation in regulating Ctsb translation. These research insights deepen our comprehension of the molecular pathways involved in ferroptosis after ICH, underscoring the potential of Ctsb as a promising target for mitigating brain damage resulting from ICH.

FGR-associated placental insufficiency and capillary angiogenesis involves disruptions in human placental miRNAs and mRNAs.

Fetal growth restriction (FGR) is one of the most common pregnancy complications culminating in adverse fetal outcome, including preterm birth, neonatal mortality and stillbirth. Compromised placental development and function, especially disruption in angiogenesis and inadequate nutrient supply are contributing factors. Fetal sex also influences placental function. Knowledge of gene expression changes and epigenetic factors contributing to placental dysfunction in FGR pregnancies will help identify biomarkers and help target interventions. This study tested the hypothesis that FGR pregnancies are associated with disruptions in miRNA - an epigenetic factor and mRNAs involving key mediators of angiogenesis and microvessel development. Changes in expression of key genes/proteins involved in placental dysfunction by RT-PCR and immunohistochemistry and miRNA changes by RNA sequencing were undertaken with term placenta from 12 control and 20 FGR pregnancies. Findings showed changes in expression of genes involved in steroidogenesis, steroid action, IGF family members, inflammatory cytokines and angiogenic factors in FGR pregnancies. In addition, upregulation of MIR451A and downregulation of MIR543 in placentas from FGR group with female newborns and upregulation of MIR520G in placentas from FGR group with male newborns were also noted. MIR451A and MIR543 have been implicated in angiogenesis. Consistent with gene changes, CD34, the microvessel angiogenesis marker, also showed reduced staining only in female FGR group. These findings provide evidence that epigentically regulated gene expression changes in angiogenesis and capillary development influence placental impairment in FGR pregnancies. Our preliminary observations also support for these changes to be driven in a sex-specific manner.

ERBB1 alleviates secondary brain injury induced by experimental intracerebral hemorrhage in rats by modulating neuronal death via PLC-γ/PKC pathway.

AIMS: Intracerebral hemorrhage (ICH) is a disease with high rates of disability and mortality. The role of epidermal growth factor receptor 1 (ERBB1) in ICH was elucidated in this study. METHODS: ICH model was constructed by injecting autologous arterial blood into the right basal ganglia. The protein level of ERBB1 was detected by western blot analysis. To up- and downregulation of ERBB1 in rats, intraventricular injection of a lentivirus overexpression vector of ERBB1 and AG1478 (a specific inhibitor of ERBB1) was used. The cell apoptosis, neuronal loss, and pro-inflammatory cytokines were assessed by TUNEL, Nissl staining, and ELISA. Meanwhile, behavioral cognitive impairment of ICH rats was evaluated after ERBB1-targeted interventions. RESULTS: ERBB1 increased significantly in brain tissue of ICH rats. Overexpression of ERBB1 remarkably reduced cell apoptosis and neuronal loss induced by ICH, as well as pro-inflammatory cytokines and oxidative stress. Meanwhile, the behavioral and cognitive impairment of ICH rats were alleviated after upregulation of ERBB1; however, the secondary brain injury (SBI) was aggravated by AG1478 treatment. Furthermore, the upregulation of PLC-γ and PKC in ICH rats was reversed by AG1478 treatment. CONCLUSIONS: ERBB1 can improve SBI and has a neuroprotective effect in experimental ICH rats via PLC-γ/PKC pathway.

Celastrol Ameliorates Neuronal Mitochondrial Dysfunction Induced by Intracerebral Hemorrhage via Targeting cAMP-Activated Exchange Protein-1.

Mitochondrial dysfunction contributes to the development of secondary brain injury (SBI) following intracerebral hemorrhage (ICH) and represents a promising therapeutic target. Celastrol, the primary active component of Tripterygium wilfordii, is a natural product that exhibits mitochondrial and neuronal protection in various cell types. This study aims to investigate the neuroprotective effects of celastrol against ICH-induced SBI and explore its underlying mechanisms. Celastrol improves neurobehavioral and cognitive abilities in mice with autologous blood-induced ICH, reduces neuronal death in vivo and in vitro, and promotes mitochondrial function recovery in neurons. Single-cell nuclear sequencing reveals that the cyclic adenosine monophosphate (cAMP)/cAMP-activated exchange protein-1 (EPAC-1) signaling pathways are impacted by celastrol. Celastrol binds to cNMP (a domain of EPAC-1) to inhibit its interaction with voltage-dependent anion-selective channel protein 1 (VDAC1) and blocks the opening of mitochondrial permeability transition pores. After neuron-specific knockout of EPAC1, the neuroprotective effects of celastrol are diminished. In summary, this study demonstrates that celastrol, through its interaction with EPAC-1, ameliorates mitochondrial dysfunction in neurons, thus potentially improving SBI induced by ICH. These findings suggest that targeting EPAC-1 with celastrol can be a promising therapeutic approach for treating ICH-induced SBI.

LPCAT3 exacerbates early brain injury and ferroptosis after subarachnoid hemorrhage in rats.

AIMS: Lysophosphatidylcholine acyltransferase 3 (LPCAT3) is known to play a pivotal role in lipid metabolism, but its role in the early brain injury (EBI) following subarachnoid hemorrhage (SAH) remains unclear. This study provides insights into LPCAT3 expression alterations and functional implications in EBI following SAH. METHODS: SAH models of adult male Sprague-Dawley (SD) rats were established by intravascular perforation. Lentivirus vectors were administered by intracerebroventricular injection (i.c.v.) to either induce LPCAT3 overexpression or knockdown 14 days before SAH induction. Western blot, immunofluorescence, Nissl staining, MDA detection, ROS detection, iron content detection, and short-term and long-term neurobehavioral tests were performed to investigate the effects of regulated-LPCAT3 after SAH. RESULTS: LPCAT3 levels were found to be significantly elevated in SAH. Suppression of LPCAT3 expression via shRNA improved oxidative stress, reduced brain edema, alleviated behavioral and cognitive deficits following SAH and decreased neuronal death, while upregulating LPCAT3 expression showed opposing effects. CONCLUSION: LPCAT3 is involved in SAH-induced EBI and associated with ferroptosis. Our findings provide a referential basis for potential therapeutic interventions aimed at alleviating EBI following SAH.

A 76-base pair duplication within the enhancer region of the HMX1 gene causes sheep microtia.

Sheep congenital microtia is characterized by underdeveloped ears and provides an ideal basis for studying human microtia. This study identified the causal mutation and regulatory mechanisms underlying this disorder. Whole-genome association analysis was conducted using 23 ear tissue samples from sheep with microtia and 28 samples from normal-eared sheep. A significant correlation was found between microtia and a 76-base pair duplication in the enhancer region of the HMX1 gene. Further analysis of offspring phenotypes confirmed an autosomal dominant inheritance pattern. Genotypic analysis showed that individuals that are homozygous for this duplication were earless, heterozygous individuals exhibited shortened ears, and wild-type individuals had normal ears. Moreover, luciferase assays confirmed that this duplication increased HMX1 gene expression, and duplication knock-in mice also exhibited shorter and narrower external ears compared to wild-type mice. Transcriptomic analysis further demonstrated that this duplication enhanced HMX1 gene expression in animal models. This study characterized the causal regulatory mutation underlying sheep microtia.

Association between Psoriasis and Renal Functions: An Integration Study of Observational Study and Mendelian Randomization.

Psoriasis is an autoimmune-mediated disease with several comorbidities in addition to typical skin lesions. Increasing evidence shows the relationships between psoriasis and renal functions, but the relationship and causality remain unclear. We aimed to investigate the associations and causality between psoriasis and four renal functions, including the estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), urine albumin to creatinine ratio (UACR), and chronic kidney disease (CKD). For the population-based study, we analyzed the National Health and Nutrition Examination Survey (NHANES) data from five cycles (2003-2006 and 2009-2014) on psoriasis and renal functions. Subgroup analyses were conducted among different categories of participants. Meanwhile, a bidirectional two-sample Mendelian randomization (TSMR) study in European populations was also performed using summary-level genetic datasets. Causal effects were derived by conducting an inverse-variance weighted (MR-IVW) method. A series of pleiotropy-robust MR methods was employed to validate the robustness. Multivariable MR (MVMR) was conducted to complement the result when five competing risk factors were considered. A total of 20,244 participants were enrolled in the cross-sectional study, where 2.6% of them had psoriasis. In the fully adjusted model, participants with psoriasis had significantly lower eGFR (p = 0.025) compared with the healthy group. Individuals who are nonoverweight are more likely to be affected by psoriasis, leading to an elevation of BUN (Pint = 0.018). In the same line, TSMR showed a negative association between psoriasis and eGFR (p = 0.016), and sensitive analysis also consolidated the finding. No causality was identified between psoriasis and other renal functions, as well as the inverse causality (p > 0.05). The MVMR method further provided quite consistent results when adjusting five confounders (p = 0.042). We detected a significant negative effect of psoriasis on eGFR, with marginal association between BUN, UACR, and CKD. The adverse of psoriasis on the renal should merit further attention in clinical cares.

[Analysis of a child with CLN1 neuronal ceroid lipofuscinosis in conjunct with Hereditary hyperferinemia cataract syndrome].

OBJECTIVE: To analyze the clinical data and genetic characteristics of a child with CLN1 neuronal ceroid lipofuscinosis in conjunct with Hereditary hyperferritinemia cataract syndrome (HHCS). METHODS: A child who was admitted to the PICU of the First Affiliated Hospital of Zhengzhou University in November 2020 was selected as the study subject. Clinical data of the child was collected. Genetic testing was carried out for the child, and the result was analyzed in the light of literature review to explore the clinical and genetic characteristics to facilitate early identification. RESULTS: The patient, a 3-year-old male, had mainly presented with visual impairment, progressive cognitive and motor regression, and epilepsy. Cranial magnetic resonance imaging revealed deepened sulci in bilateral cerebral hemispheres, and delayed myelination. The activity of palmitoyl protein thioesterase was low (8.4 nmol/g/min, reference range: 132.2 ~ 301.4 nmol/g/min), whilst serum ferritin was increased (2417.70 ng/mL, reference range: 30 ~ 400 ng/ml). Fundoscopy has revealed retinal pigment degeneration. Whole exome sequencing revealed that he has harbored c.280A>C and c.124-124+3delG compound heterozygous variants of the PPT1 gene, which were respectively inherited from his father and mother. Neither variant has been reported previously. The child has also harbored a heterozygous c.-160A>G variant of the FTL gene, which was inherited from his father. Based on the clinical phenotype and results of genetic testing, the child was diagnosed as CLN1 and HHCS. CONCLUSION: The compound heterozygous variants of the PPT1 gene probably underlay the disorders in this child. For children with CLN1 and rapidly progressing visual impairment, ophthalmological examination should be recommended, and detailed family history should be taken For those suspected for HHCS, genetic testing should be performed to confirm the diagnosis.

Environmental and economic assessments of industry-level medical waste disposal technologies - A case study of ten Chinese megacities.

Medical waste (MW) is exploding due to the COVID-19 pandemic, posing a significant environmental threat, and leading to the urgent requirement for affordable and environmentally friendly MW disposal technologies. Prior research on individual MW disposal plants is region-specific, applying these results to other regions may introduce bias. In this study, major MW disposal technologies in China, i.e., incineration technologies (pyrolysis incineration and rotary kiln incineration), and sterilization technologies (steam sterilization, microwave sterilization, and chemical disinfection) with residue landfill or incineration were analyzed from an industry-level perspective via life cycle assessment (LCA), life cycle costing (LCC) and net present value (NPV) methods. Life cycle inventories and economic cost data for 4-5 typical companies were selected from 128 distinct enterprises and academic sources for each technology. LCA results show that microwave sterilization with residue incineration has the lowest environmental impact, emitting only 480 kg CO2 eq. LCC and NPV analyses indicate that steam sterilization with landfilling is the most economical, yielding revenues of 1,210 CNY/t and breaking even in the first year. Conversely, pyrolysis and rotary kiln incineration break even between the 4th and 5th years. Greenhouse gas emissions from the MW disposal in ten cities with the largest MW production in 2020 increased by 7% over 2019 to 43,800 tons and other pollutants increased by 6% to 12%. Economically, Shanghai exhibits the highest cost-effectiveness, while Nanjing delivers the lowest. It can be observed that the adoption of optimal environmental technologies has resulted in a diminution of greenhouse gas emissions by 279,000 tons and energy conservation of 1.76 billion MJ.

Traditional uses, botany, phytochemistry, and pharmacology of Lonicerae japonicae flos and Lonicerae flos: A systematic comparative review.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicerae japonicae flos (LJF) and Lonicerae flos (LF) belong to different genera of Caprifoliaceae with analogous appearances and functions. Historically, they have been used as herbal medicines to treat various diseases with confirmed wind-heat evacuation, heat-clearing, and detoxification effects. However, the Chinese Pharmacopoeia (2005 Edition) lists LJF and LF under different categories. AIM OF THE STUDY: Few studies have systematically compared the similarities and dissimilarities of LJF and LF concerning their research achievements. This systematic review and comparison of the traditional use, identification, and phytochemical and pharmacological properties of LJF and LF provides valuable insights for their further application and clinical safety. MATERIALS AND METHODS: Related document information was collected from databases that included Web of Science, X-MOL, Science Direct, PubMed, and the China National Knowledge Infrastructure. RESULTS: The chemical constituents and pharmacological effects of LJF and LF were similar. A total of 337 and 242 chemical constituents were isolated and identified in LJF and LF, respectively. These included volatile oils, cyclic ether terpenes, flavonoids, phenolic acids, triterpenoids, and their saponins. Additionally, LJF plants contain more iridoids and flavonoids than LF plants. The latter have a variety of triterpenoid saponins and significantly higher chlorogenic acid content than LJF plants. Pharmacological studies have shown that LJF and LF have various anti-inflammatory, antiviral, antibacterial, anti-endotoxic, antioxidant, anti-tumor, anti-platelet, myocardial protective, and hepatoprotective effects. CONCLUSIONS: This review was undertaken to explore whether LJF and LF should be listed separately in the Chinese Pharmacopoeia in terms of their disease prevention and treatment strategies. Although LJF and LF showed promising effects, their action mechanisms remains unclear. Specifically, their impact on gut microbiota, gastrointestinal tract, and blood parameters requires further investigation. These studies will provide the foundation for scientific utilization and clinical/non-clinical applications of LJF and LF, and the maximum benefits from their mutual use.

Amygdalin and exercise training exert a synergistic effect in improving cardiac performance and ameliorating cardiac inflammation and fibrosis in a rat model of myocardial infarction.

This study investigated the effects of amygdalin (AMY, a cyanogenic glycoside widely distributed in the fruits and seeds of Rosaceae plants) on cardiac performance and ventricular remodeling in a rat model of myocardial infarction (MI). We also investigated whether the combination of AMY with exercise training (ExT) has a beneficial synergistic effect in treating MI rats. MI was induced by the ligation of the left anterior descending coronary artery in male SD rats. ExT or AMY treatment was started 1 week after MI and continued for 1 week (short-term) or 8 weeks (long-term). Cardiac function was evaluated by echocardiographic and hemodynamic parameters. Heart tissues were harvested and subjected to 2,3,5-triphenyl-tetrazolium chloride, Masson's trichrome, hematoxylin-eosin, and immunohistochemical staining. Gene expression was determined by quantitative polymerase chain reaction. Western blot gave a qualitative assessment of protein levels. AMY or ExT improved cardiac function and reduced infarct size in MI rats. AMY or ExT also suppressed myocardial fibrosis and attenuated inflammation in the infarct border zone of hearts from MI rats, as evidenced by inhibition of collagen deposition, inflammatory cell infiltration, and pro-inflammatory markers (interleukin 1ß, interleukin 6, tumor necrosis factor-α, and cyclooxygenase 2). Notably, the effects of AMY combined with ExT were superior to those of AMY alone or ExT alone. Mechanistically, these beneficial functions were correlated with the inhibition of MI-induced activation of the transforming growth factor-ß/Smad pathway. Collectively, AMY and ExT exert a synergistic effect on improving cardiac performance and ameliorating cardiac inflammation and fibrosis after MI, and the effects of long-term intervention were better than short-term intervention.