Arthroscopic debridement, synovectomy and thermal shrinkage for basal joint arthritis.

BACKGROUND: Ligamentous laxity, cartilage wear, and diffuse synovitis are frequently seen in thumb basal joint arthritis. Although these degenerative changes may be mild for the majority, they have the potential to cause discomfort during movement and compromised hand function. This study assesses the long-term outcomes of arthroscopic debridement, synovectomy, and thermal shrinkage in managing early-stage basal joint arthritis. METHODS: We retrospectively reviewed patients with basal joint arthritis who underwent arthroscopic debridement, synovectomy, and thermal shrinkage between November 2010 and January 2021 by a single surgeon at our medical institute. We assessed functional outcomes, thumb range of motion, perioperative nonsteroidal anti-inflammatory drug (NSAID) use, return to work and satisfaction level. RESULTS: A total of 12 patients (13 hands), with a mean follow-up of 72 months, were included in this study. Significant improvements were observed in pain scores and functional outcomes, along with a reduction in postoperative NSAID use. Patients also reported a relatively quick return to work and a high satisfaction level. CONCLUSION: The study highlights the benefits of arthroscopic intervention, providing a minimally invasive approach with favorable long-term outcomes for patients with symptomatic basal joint arthritis.

Mitochondrial GPX4 acetylation is involved in cadmium-induced renal cell ferroptosis.

Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD+-dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3-/- mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.

Prenatal 1-Nitropyrene Exposure Causes Autism-Like Behavior Partially by Altering DNA Hydroxymethylation in Developing Brain.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1-nitropyrene (1-NP), a key component of motor vehicle exhaust, on autism-like behaviors in a mouse model. Three-chamber test finds that prenatal 1-NP exposure causes autism-like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1-NP-exposed weaning pups. Immunofluorescence finds that prenatal 1-NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1-NP exposure retards tangential migration of GAD67-positive interneurons and downregulates interneuron migration-related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1-NP exposure reduces hydroxymethylation of interneuron migration-related genes through inhibiting ten-eleven translocation (TET) activity in fetal forebrain. Supplement with alpha-ketoglutarate (α-KG), a cofactor of TET enzyme, reverses 1-NP-induced hypohydroxymethylation at specific sites of interneuron migration-related genes. Moreover, α-KG supplement alleviates 1-NP-induced migration retardation of interneurons in fetal forebrain. Finally, maternal α-KG supplement improves 1-NP-induced autism-like behaviors in weaning offspring. In conclusion, prenatal 1-NP exposure causes autism-like behavior partially by altering DNA hydroxymethylation of interneuron migration-related genes in developing brain.

Research and Development of a 3D-Printed Dynamic Finger Flexion Orthosis for Finger Extension Stiffness-A Preliminary Study.

Finger extension stiffness is a common post-traumatic complication that results in the hand's functional impairment. In clinical practice, a dynamic splint enables the patient to stretch the affected finger independently. However, current dynamic splints have drawbacks, such as limited stretching efficacy, and interfere with the hand's functional activities. Therefore, this study aimed to develop a dynamic finger flexion orthosis capable of stretching each finger joint using additive manufacturing (AM) technology, thereby enabling hand functional activity, and analyze the clinical improvement in the range of motion (ROM). One subject with a hand fracture was recruited while undergoing a 7-week home-based rehabilitation program for the orthosis. The outcome measurements included the total active motion (TAM), the tip-to-finger distance (TPD), and the score on the Disability of Arm, Shoulder, and Hand (DASH) questionnaire. The results show that the TAM of the participant's fingers increased by 72.7 degrees on average, the TPD decreased by 3.5 cm on average, and the DASH score decreased to 9.5 points. The 7-week home-based rehabilitation program for the orthosis resulted in a 53.6% increase in the TAM on average. The developed orthosis improved hand function and enabled a more complete ROM in finger flexion.

Arsenic exposure causes decline in sperm motility accompanied by energy metabolism disorders in mouse testes.

Arsenic (As) is a notorious environmental toxicant widely present in various natural environments. As exposure has been correlated with the decline in sperm motility. Yet, the mechanism has not been fully elucidated. Adult male C57 mice were given 0, 1, or 15 mg/L NaAsO2 for 10 weeks. The mature seminiferous tubules and sperm count were decreased in As-exposed mice. Sperm motility and several sperm motility parameters, including average path velocity (VAP), straight-line velocity (VSL), curvilinear velocity (VCL), beat-cross frequency (BCF), linearity (LIN), straightness (STR), and amplitude of lateral head displacement (ALH), were declined in As-exposed mice. RNA sequencing and transcriptomics analyses revealed that differentially expressed genes (DEGs) were mainly enriched in metabolic pathways. Untargeted metabolomics analyses indicated that energy metabolism was disrupted in As-exposed mouse testes. Gene set enrichment analysis showed that glycolysis and oxidative phosphorylation were disturbed in As-exposed mouse testes. As-induced disruption of testicular glucose metabolism and oxidative phosphorylation was further validated by RT-PCR and Western blotting. In conclusion, As exposure causes decline in sperm motility accompanied by energy metabolism disorders in mouse testes.

Ulnar carpal translation following palmar locking plate fixation for distal radius fractures: a retrospective analysis.

BACKGROUND: Concomitant injuries to the radiocarpal ligaments may occur during episodes of distal radius fractures, which may not cause acute subluxation or dislocation but can lead to radiocarpal instability and progress over time. This study aimed to analyze the occurrence of ulnar carpal translation (UCT) after open reduction and internal fixation of distal radius fractures and evaluate the associated factors of UCT. METHODS: The retrospective study has been done now and includes patients treated between 2010 and 2020 who had undergone reduction and locking plate fixation of distal radius fractures. We assessed radiographs taken immediately after the operation and at 3 months post-operation, enrolling patients with UCT for evaluation. In addition to demographic data, we evaluated radiographic parameters, including fracture pattern, fragment involvement, and ulnar variance. We also assessed the palmar tilt-lunate (PTL) angle to determine associated rotatory palmar subluxation of the lunate (RPSL). RESULTS: Among the 1,086 wrists, 53 (4.9%) had UCT within 3 months post-operation. The majority of wrists with UCT exhibited normal to minus ulnar variance (49 wrists; mean: -1.1 mm), and 24 patients (45.3%) had concomitant RPSL. Fracture classification was as follows: 19 type A3 (35.8%), 5 type C1 (9.4%), 11 type C2 (20.8%), and 18 type C3 (34.0%). Radial styloid was involved in 20 wrists (37.7%), palmar rim in 18 wrists (34.0%), dorsal rim in 25 wrists (47.2%), and die-punch fractures in 3 wrists (5.7%). Concomitant ulnar styloid fractures were present in 29 wrists (54.7%). CONCLUSION: This study highlights the potential for UCT to occur following reduction and fixation of distal radius fractures, particularly in cases with a more severe fracture pattern and combined with ulnar minus variance. The high incidence of concomitant RPSL provides further evidence for the possibility of associated radiocarpal ligament insufficiency after distal radius fracture.

Co-exposure to 55 endocrine-disrupting chemicals linking diminished sperm quality: Mixture effect, and the role of seminal plasma docosapentaenoic acid.

Isolated effects of single endocrine-disrupting chemicals (EDCs) on male reproductive health have been studied extensively, but their mixture effect remains unelucidated. Previous research has suggested that consuming diet enriched in omega-3 polyunsaturated fatty acids (PUFA) might be beneficial for reproductive health, whether omega-3 PUFA could moderate the effect of EDCs mixture on semen quality remains to be explored. In this study of 155 male recruited from a reproductive health center in China, we used targeted-exposomics to simultaneously measure 55 EDCs in the urine for exposure burden. Regression analyses were restricted to highly detected EDCs (≥55%, n = 34), and those with consistently elevated risk were further screened and brought into mixture effect models (Bisphenol A, ethyl paraben, methyl paraben [MeP], benzophenone-1 [BP1], benzophenone-3, mono(3-carboxypropyl) phthalate [MCPP]). Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation (QGC) models demonstrated that co-exposure to top-ranked EDCs was related to reduced sperm total (ß = -0.18, 95%CI: -0.29 - -0.07, P = 0.002) and progressive motility (ß = -0.27, 95%CI: -0.43 - -0.10, P = 0.002), but not to lower semen volume. BP1, MeP and MCPP were identified as the main effect driver for deteriorated sperm motion parameters using mixture model analyses. Seminal plasma fatty acid profiling showed that high omega-3 PUFA status, notably elevated docosapentaenoic acid (DPA, C22:5n-3) status, moderated the association between MCPP and sperm motion parameters (total motility: ß = 0.26, 95%CI: 0.01 - -0.51, Pinteraction = 0.047; progressive motility: ß = 0.64, 95%CI: 0.23 - 1.05, Pinteraction = 0.003). Co-exposure to a range of EDCs is mainly associated with deteriorated sperm quality, but to a lesser extent on sperm quantity, high seminal plasma DPA status might be protective against the effect. Our work emphasizes the importance of exposomic approach to assess chemical exposures and highlighted a new possible intervention target for mitigating the potential adverse effect of EDCs on semen quality.

Mechanistic insights into the interactions of TAX1BP1 with RB1CC1 and mammalian ATG8 family proteins.

TAX1BP1, a multifunctional autophagy adaptor, plays critical roles in different autophagy processes. As an autophagy receptor, TAX1BP1 can interact with RB1CC1, NAP1, and mammalian ATG8 family proteins to drive selective autophagy for relevant substrates. However, the mechanistic bases underpinning the specific interactions of TAX1BP1 with RB1CC1 and mammalian ATG8 family proteins remain elusive. Here, we find that there are two distinct binding sites between TAX1BP1 and RB1CC1. In addition to the previously reported TAX1BP1 SKICH (skeletal muscle and kidney enriched inositol phosphatase (SKIP) carboxyl homology)/RB1CC1 coiled-coil interaction, the first coiled-coil domain of TAX1BP1 can directly bind to the extreme C-terminal coiled-coil and Claw region of RB1CC1. We determine the crystal structure of the TAX1BP1 SKICH/RB1CC1 coiled-coil complex and unravel the detailed binding mechanism of TAX1BP1 SKICH with RB1CC1. Moreover, we demonstrate that RB1CC1 and NAP1 are competitive in binding to the TAX1BP1 SKICH domain, but the presence of NAP1's FIP200-interacting region (FIR) motif can stabilize the ternary TAX1BP1/NAP1/RB1CC1 complex formation. Finally, we elucidate the molecular mechanism governing the selective interactions of TAX1BP1 with ATG8 family members by solving the structure of GABARAP in complex with the non-canonical LIR (LC3-interacting region) motif of TAX1BP1, which unveils a unique binding mode between LIR and ATG8 family protein. Collectively, our findings provide mechanistic insights into the interactions of TAX1BP1 with RB1CC1 and mammalian ATG8 family proteins and are valuable for further understanding the working mode and function of TAX1BP1 in autophagy.

Environmentally realistic dose of tire-derived metabolite 6PPD-Q exposure causes intestinal jejunum and ileum damage in mice via cannabinoid receptor-activated inflammation.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) is a quinone derivative of a common tire additive 6PPD, whose occurrence has been widely reported both in the environment and human bodies including in adults, pregnant women and children. Yet, knowledge on the potential intestinal toxicity of 6PPD-Q in mammals at environmentally relevant dose remain unknown. In this study, the effects of 6PPD-Q on the intestines of adult ICR mice were evaluated by orally administering environmentally relevant dose or lower levels of 6PPD-Q (0.1, 1, 10, and 100 µg/kg) for 21 days. We found that 6PPD-Q disrupted the integrity of the intestinal barrier, mostly in the jejunum and ileum, but not in the duodenum or colon, in a dose-dependent manner. Moreover, intestinal inflammation manifested with elevated levels of TNF-α, IL-1, and IL-6 mostly observed in doses at 10 and 100 µg/kg. Using reverse target screening technology combining molecular dynamic simulation modeling we identified key cannabinoid receptors including CNR2 activation to be potentially mediating the intestinal inflammation induced by 6PPD-Q. In summary, this study provides novel insights into the toxic effects of emerging contaminant 6PPD-Q on mammalian intestines and that the chemical may be a cannabinoid receptor agonist to modulate inflammation.

Interfacial engineering of POM-stabilized Ni quantum dots on porous titanium mesh for high-rate and stable alkaline hydrogen production.

The development of low-cost, high-efficiency, and stable electrocatalysts for the alkaline hydrogen evolution reaction (HER) is a key challenge because the alkaline HER kinetics is slowed by an additional water dissociation step. Herein, we report an interfacial engineering strategy for polyoxometalate (POM)-stabilized nickel (Ni) quantum dots decorated on the surface of porous titanium mesh (POMs-Ni@PTM) for high-rate and stable alkaline hydrogen production. Benefiting from the strong interfacial interactions among POMs, Ni atoms, and PTM substrates, as well as unique POM-Ni quantum dot structures, the optimized POMs-Ni@PTM electrocatalyst exhibits a remarkable alkaline HER performance with an overpotential (η10) of 30.1 mV to reach a current density of 10 mA cm-2, which is much better than those of bare Ni decorated porous titanium mesh (Ni@PTM) (η10 = 171.1 mV) and POM decorated porous titanium mesh (POMs@PTM) electrocatalysts (η10 = 493.6 mV), comparable to that of the commercial 20 wt% platinum/carbon (20% Pt/C) electrocatalyst (η10 = 20 mV). Moreover, the optimized POMs-Ni@PTM electrocatalyst demonstrates excellent stability under continuous alkaline water-splitting at a current density of ∼100 mA cm-2 for 100 h, demonstrating great potential for its practical application.

Comparing the Outcomes of Suture Anchor Repair and Rein-Type Capsular Suture for Triangular Fibrocartilage Complex Foveal Tears With a Minimum 2-Year Follow-Up.

PURPOSE: Recent biomechanical studies have highlighted the importance of foveal reinsertion when repairing triangular fibrocartilage complex (TFCC) injury with foveal tears. However, clinical studies comparing different repair techniques are scarce. We compared the clinical outcomes of suture anchor repair and rein-type capsular suture in patients with TFCC palmer 1B foveal tears with a minimum of 2-year follow-up. METHODS: This was a single-surgeon, single-center, retrospective, comparative study. We included patients who underwent TFCC repair surgery due to a foveal tear from December 2013 to October 2018 with a minimum follow-up of 24 months. Postoperative Quick Disabilities of Arm, Shoulder, and Hand (QuickDASH) score, Modified Mayo Wrist Score, visual analogue scale for pain, wrist range of motion, and grip strength were compared. We also measured the maximal ulnar head displacement with dynamic ultrasound to quantify distal radioulnar joint stability. RESULTS: In total, 103 patients were in the suture anchor group (group A) and 84 patients in the rein-type capsular suture group (group B). The mean follow-up time exceeded three years for both groups. There was a minimal difference regarding QuickDASH score, visual analogue scale for pain, and grip strength ratio between the two groups. The rein-type group had significantly better Modified Mayo Wrist Score. The suture anchor group showed better distal radioulnar joint stability with dynamic ultrasound, but was more limited in ulnar deviation. However, these differences are most likely clinically insignificant. CONCLUSIONS: Both suture anchor repair and rein-type capsular suture yielded satisfactory results for TFCC 1B foveal tear in a minimum of 2-year follow-up. The functional scores were similar, and no major complications or recurrent instability were noted in either group. TYPE OF STUDY/LEVEL OF EVIDENCE: Retrospective Therapeutic Comparative Investigation IV.

PFASs in Cerebrospinal Fluids and Blood-CSF Barrier Permeability in Patients with Cognitive Impairment.

Attention has been drawn to the associations between PFASs and human cognitive decline. However, knowledge on the occurrence and permeability of PFASs in the brains of patients with cognitive impairment has not been reported. Here, we determined 30 PFASs in paired sera and cerebrospinal fluids (CSFs) from patients with cognitive impairment (n = 41) and controls without cognitive decline (n = 18). We revealed similar serum PFAS levels but different CSF PFAS levels, with lower CSF PFOA (median: 0.125 vs 0.303 ng/mL, p < 0.05), yet higher CSF PFOS (0.100 vs 0.052 ng/mL, p < 0.05) in patients than in controls. Blood-brain transfer rates also showed lower RCSF/Serum values for PFOA and higher RCSF/Serum values for PFOS in patients, implying potential heterogeneous associations with cognitive function. The RCSF/Serum values for C4-C14 perfluoroalkyl carboxylates exhibited a U-shape trend with increasing chain length. Logistic regression analyses demonstrated that CSF PFOS levels were linked to the heightened risk of cognitive impairment [odds ratio: 3.22 (1.18-11.8)] but not for serum PFOS. Toxicity inference results based on the Comparative Toxicogenomics Database suggested that PFOS in CSF may have a greater potential to impair human cognition than other PFASs. Our results contribute to a better understanding of brain PFAS exposure and its potential impact on cognitive function.

Ionomer structure and component transport in the cathode catalyst layer of PEM fuel cells: A molecular dynamics study.

The transport of water and protons in the cathode catalyst layer (CCL) of proton exchange membrane (PEM) fuel cells is critical for cell performance, but the underlying mechanism is still unclear. Herein, the ionomer structure and the distribution/transport characteristics of water and protons in CCLs are investigated via all-atom molecular dynamics simulations. The results show that at low water contents, isolated water clusters form in ionomer pores, while proton transport is mainly via the charged sites of the ionomer side chains and the Grotthuss mechanism. Moreover, with increasing water content, water clusters are interconnected to form continuous water channels, which provide effective paths for proton transfer via the vehicular and Grotthuss mechanisms. Increasing the ionomer mass content can enhance the dense arrangement of the ionomer, which, in turn, increases the density of charge sites and improves the proton transport efficiency. When the ionomer mass content is high, the clustering effect reduces the space for water diffusion, increases the proton transport path, and finally decreases the proton transport efficiency. By providing physics insights into the proton transport mechanism, this study is helpful for the structural design and performance improvement of CCLs of PEM fuel cells.

Proliferation and Differentiation Potential of Bone Marrow-Derived Mesenchymal Stem Cells From Children With Polydactyly and Adults With Basal Joint Arthritis.

This study compared the proliferation and differentiation potential of bone marrow-derived mesenchymal stem cells (BMSCs) derived from infants with polydactyly and adults with basal joint arthritis. The proliferation rate of adult and infant BMSCs was determined by the cell number changes and doubling times. The γH2AX immunofluorescence staining, age-related gene expression, senescence-associated ß-galactosidase (SA-ß-gal) staining were analyzed to determine the senescence state of adult and infant BMSCs. The expression levels of superoxide dismutases (SODs) and genes associated with various types of differentiation were measured using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR). Differentiation levels were evaluated through histochemical and immunohistochemical staining. The results showed that infant BMSCs had a significantly higher increase in cell numbers and faster doubling times compared with adult BMSCs. Infant BMSCs at late stages exhibited reduced γH2AX expression and SA-ß-gal staining, indicating lower levels of senescence. The expression levels of senescence-related genes (p16, p21, and p53) in infant BMSCs were also lower than in adult BMSCs. In addition, infant BMSCs demonstrated higher antioxidative ability with elevated expression of SOD1, SOD2, and SOD3 compared with adult BMSCs. In terms of differentiation potential, infant BMSCs outperformed adult BMSCs in chondrogenesis, as indicated by higher expression levels of chondrogenic genes (SOX9, COL2, and COL10) and positive immunohistochemical staining. Moreover, differentiated cells derived from infant BMSCs exhibited significantly higher expression levels of osteogenic, tenogenic, hepatogenic, and neurogenic genes compared with those derived from adult BMSCs. Histochemical and immunofluorescence staining confirmed these findings. However, adult BMSCs showed lower adipogenic differentiation potential compared with infant BMSCs. Overall, infant BMSCs demonstrated superior characteristics, including higher proliferation rates, enhanced antioxidative activity, and greater differentiation potential into various lineages. They also exhibited reduced cellular senescence. These findings, within the context of cellular differentiation, suggest potential implications for the use of allogeneic BMSC transplantation, emphasizing the need for further in vivo investigation.

Schottky Junction and D-A1 -A2 System Dual Regulation of Covalent Triazine Frameworks for Highly Efficient CO2 Photoreduction.

Covalent triazine frameworks (CTFs) are emerging as a promising molecular platform for photocatalysis. Nevertheless, the construction of highly effective charge transfer pathways in CTFs for oriented delivery of photoexcited electrons to enhance photocatalytic performance remains highly challenging. Herein, a molecular engineering strategy is presented to achieve highly efficient charge separation and transport in both the lateral and vertical directions for solar-to-formate conversion. Specifically, a large π-delocalized and π-stacked Schottky junction (Ru-Th-CTF/RGO) that synergistically knits a rebuilt extended π-delocalized network of the D-A1 -A2 system (multiple donor or acceptor units, Ru-Th-CTF) with reduced graphene oxide (RGO) is developed. It is verified that the single-site Ru units in Ru-Th-CTF/RGO act as effective secondary electron acceptors in the lateral direction for multistage charge separation/transport. Simultaneously, the π-stacked and covalently bonded graphene is regarded as a hole extraction layer, accelerating the separation/transport of the photogenerated charges in the vertical direction over the Ru-Th-CTF/RGO Schottky junction with full use of photogenerated electrons for the reduction reaction. Thus, the obtained photocatalyst has an excellent CO2 -to-formate conversion rate (≈11050 µmol g-1 h-1 ) and selectivity (≈99%), producing a state-of-the-art catalyst for the heterogeneous conversion of CO2 to formate without an extra photosensitizer.

FUNDC1-mediated mitophagy triggered by mitochondrial ROS is partially involved in 1-nitropyrene-evoked placental progesterone synthesis inhibition and intrauterine growth retardation in mice.

Intrauterine growth retardation (IUGR) is a major cause of perinatal morbidity and mortality. Previous studies showed that 1-nitropyrene (1-NP), an atmospheric pollutant, induces placental dysfunction and IUGR, but the exact mechanisms remain uncertain. In this research, we aimed to explore the role of mitophagy on 1-NP-evoked placental progesterone (P4) synthesis inhibition and IUGR in a mouse model. As expected, P4 levels were decreased in 1-NP-exposed mouse placentas and maternal sera. Progesterone synthases, CYP11A1 and 3ßHSD1, were correspondingly declined in 1-NP-exposed mouse placentas and JEG-3 cells. Mitophagy, as determined by LC3B-II elevation and TOM20 reduction, was evoked in 1-NP-exposed JEG-3 cells. Mdivi-1, a specific mitophagy inhibitor, relieved 1-NP-evoked downregulation of progesterone synthases in JEG-3 cells. Additional experiments showed that ULK1/FUNDC1 signaling was activated in 1-NP-exposed JEG-3 cells. ULK1 inhibitor or FUNDC1-targeted siRNA blocked 1-NP-induced mitophagy and progesterone synthase downregulation in JEG-3 cells. Further analysis found that mitochondrial reactive oxygen species (ROS) were increased and GCN2 was activated in 1-NP-exposed JEG-3 cells. GCN2iB, a selective GCN2 inhibitor, and MitoQ, a mitochondria-targeted antioxidant, attenuated GCN2 activation, FUNDC1-mediated mitophagy, and downregulation of progesterone synthases in JEG-3 cells. In vivo, gestational MitoQ supplement alleviated 1-NP-evoked reduction of placental P4 synthesis and IUGR. These results suggest that FUNDC1-mediated mitophagy triggered by mitochondrial ROS may contribute partially to 1-NP-induced placental P4 synthesis inhibition and IUGR.

Molecular Mechanism Biomarkers Predict Diagnosis in Schizophrenia and Schizoaffective Psychosis, with Implications for Treatment.

Diagnostic uncertainty and relapse rates in schizophrenia and schizoaffective disorder are relatively high, indicating the potential involvement of other pathological mechanisms that could serve as diagnostic indicators to be targeted for adjunctive treatment. This study aimed to seek objective evidence of methylenetetrahydrofolate reductase MTHFR C677T genotype-related bio markers in blood and urine. Vitamin and mineral cofactors related to methylation and indolamine-catecholamine metabolism were investigated. Biomarker status for 67 symptomatically well-defined cases and 67 asymptomatic control participants was determined using receiver operating characteristics, Spearman's correlation, and logistic regression. The 5.2%-prevalent MTHFR 677 TT genotype demonstrated a 100% sensitive and specific case-predictive biomarkers of increased riboflavin (vitamin B2) excretion. This was accompanied by low plasma zinc and indicators of a shift from low methylation to high methylation state. The 48.5% prevalent MTHFR 677 CC genotype model demonstrated a low-methylation phenotype with 93% sensitivity and 92% specificity and a negative predictive value of 100%. This model related to lower vitamin cofactors, high histamine, and HPLC urine indicators of lower vitamin B2 and restricted indole-catecholamine metabolism. The 46.3%-prevalent CT genotype achieved high predictive strength for a mixed methylation phenotype. Determination of MTHFR C677T genotype dependent functional biomarker phenotypes can advance diagnostic certainty and inform therapeutic intervention.

Evaluating the Effect of Gestational Exposure to Perfluorohexane Sulfonate on Placental Development in Mice Combining Alternative Splicing and Gene Expression Analyses.

BACKGROUND: Perfluorohexane sulfonate (PFHxS) is a frequently detected per- and polyfluoroalkyl substance in most populations, including in individuals who are pregnant, a period critical for early life development. Despite epidemiological evidence of exposure, developmental toxicity, particularly at realistic human exposures, remains understudied. OBJECTIVES: We evaluated the effect of gestational exposure to human-relevant body burden of PFHxS on fetal and placental development and explored mechanisms of action combining alternative splicing (AS) and gene expression (GE) analyses. METHODS: Pregnant ICR mice were exposed to 0, 0.03, and 0.3µg/kg/day from gestational day 7 to day 17 via oral gavage. Upon euthanasia, PFHxS distribution was measured using liquid chromatography-tandem mass spectrometry. Maternal and fetal phenotypes were recorded, and histopathology was examined for placenta impairment. Multiomics was adopted by combining AS and GE analyses to unveil disruptions in mRNA quality and quantity. The key metabolite transporters were validated by quantitative real-time PCR (qRT-PCR) for quantification and three-dimensional (3D) structural simulation by AlphaFold2. Targeted metabolomics based on liquid chromatography-tandem mass spectrometry was used to detect amino acid and amides levels in the placenta. RESULTS: Pups developmentally exposed to PFHxS exhibited signs of intrauterine growth restriction (IUGR), characterized by smaller fetal weight and body length (p<0.01) compared to control mice. PFHxS concentration in maternal plasma was 5.01±0.54 ng/mL. PFHxS trans-placenta distribution suggested dose-dependent transfer through placental barrier. Histopathology of placenta of exposed dams showed placental dysplasia, manifested with an attenuated labyrinthine layer area and deescalated blood sinus counts and placental vascular development index marker CD34. Combined GE and AS analyses pinpointed differences in genes associated with key biological processes of placental development, proliferation, metabolism, and transport in placenta of exposed dams compared to that of control dams. Further detection of placental key transporter gene expression, protein structure simulation, and amino acid and amide metabolites levels suggested that PFHxS exposure during pregnancy led to impairment of placental amino acid transportation. DISCUSSION: The findings from this study suggest that exposure to human-relevant very-low-dose PFHxS during pregnancy in mice caused IUGR, likely via downregulating of placental amino acid transporters, thereby impairing placental amino acid transportation, resulting in impairment of placental development. Our findings confirm epidemiological findings and call for future attention on the health risk of this persistent yet ubiquitous chemical in the early developmental stage and provide a new approach for understanding gene expression from both quantitative and qualitative omics approaches in toxicological studies. https://doi.org/10.1289/EHP13217.

Chinese herbal medicine compound of flavonoids adjunctive treatment for oral cancer.

Oral cancer is a prevalent global issue, with oral squamous cell carcinoma constituting the majority of cases. Standard treatments like surgery, radiotherapy, and chemotherapy are available but may have adverse effects. Molecular gene therapy, focusing on genetic mutations linked to oral cancer, presents a promising alternative.In this study, we evaluated 27 chemotherapeutic drugs and 63 Chinese herbal medicines for their effectiveness, categorized them by their cellular mechanisms, and identified potential adjuvant therapy candidates for oral cancer. Our findings highlight the impact of natural flavonoids on oral cancer cells, inducing apoptosis, and confirming their potential in molecular genetic analysis. In conclusion, the natural compounds present in Chinese herbal medicine, particularly flavonoids, offer a promising avenue to target specific genetic mutations in oral cancer cells. This approach may reduce the risks associated with oral cancer treatment and pave the way for innovative adjuvant therapies.

Outcomes of radiocarpal pinning to facilitate nerve repair in wrist-level ulnar nerve injuries with defect.

BACKGROUND: The ideal scenario for ulnar nerve repair is primary end-to-end neurorrhaphy in a tension-free environment. However, this could be complicated by soft tissue loss, scarring, and neuroma formation in a delayed injury, creating a nerve defect. With a wrist-level nerve defect, a flexion position can help shorten the nerve gap; however, maintaining the position can be challenging intraoperatively and postoperatively. METHODS: Previously, we proposed our method of using a 1.6-mm K wire for radius-lunate-capitate pinning of the wrist in flexion to minimize the nerve gap, thereby facilitating neuroma excision and end-to-end neurorrhaphy in delayed ulnar nerve injury. In this study, we elaborate our method and present our case series. RESULTS: From October 2018 to July 2020, five patients (mean age: 48.2 years; mean delay from injury to surgery: 84.6 days; mean follow-up: 17.5 months) were retrospectively reviewed. The mean flexion fixation angle was 52°, and the K wire was removed at an average of 5.1 weeks postoperatively. All patients were followed up for a minimum of 12 months. All patients achieved M4 and S3 or S3+ neurologically (according to the criteria of the Nerve Injuries Committee of the British Medical Research Council). The mean disabilities arm, shoulder, and hand score was 14.1. The mean grasp and pinch strengths were, respectively, 76.8% and 63.6% of the contralateral hand. All wrist range of motion returned to normal within 12 weeks. No complications were noted intraoperatively or postoperatively. CONCLUSION: Our study showed that radiocarpal pinning of the wrist in flexion was safe and convenient to minimize the nerve gap and to facilitate end-to-end neurorrhaphy in limited-sized wrist-level ulnar nerve defects.