UCF101 Rescues against Diabetes-Evoked Cardiac Remodeling and Contractile Anomalies through AMPK-Mediated Induction of Mitophagy.

BACKGROUND: Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury although its impact on diabetic cardiomyopathy remains elusive. METHOD: Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanism involved. Adult mice were made diabetic using streptozotocin (STZ) while receiving UCF101 (7.15 mg/kg, i.p.) for 6 consecutive days. RESULT: STZ evidently evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin1, elevated p62), mitophagy (FUNDC1 and Parkin with elevated TOM20), increased left ventricular (LV) end systolic diameter, dampened fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/relengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effect from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMPK (Thr172) and cell survival molecule GSK3ß, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, mitophagy inhibitor liensinine and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C. CONCLUSION: These findings denote that UCF101 rescues diabetes-instigated alterations in cardiac structure and contraction, likely through AMPK-mediated regulation of mitophagy.

Combination of Losartan and Platinum Nanoparticles with Photothermal Therapy Induces Immunogenic Cell Death Effective Against Neuroblastoma.

Introduction: Photothermal therapy (PTT) is a promising therapeutic procedure with minimal side effects, which can not only kill tumor directly but also cause immunogenic cell death (ICD). However, most solid tumors, including neuroblastoma, are abundant in fibroblasts, which limit the penetration and delivery of nanoparticles. Losartan is an antihypertensive drug approved by the FDA, and it has been proved to have the effect of breaking down excessive ECM network. Methods: In this study, we investigated the application and potential mechanism of the combination of mesoporous platinum nanoparticles (MPNs) and losartan in the PTT of neuroblastoma by establishing neuroblastoma models in vitro and in vivo. Results: Compared to the MPNs group without 808 nm laser irradiation, Neuro-2a cells pretreated with PTT and losartan showed lower survival rates, increased surface calreticulin, and higher release of HMGB1 and ATP. The group also exhibited the highest anti-tumor efficacy in vivo, with a tumor suppression ratio of approximately 80%. Meanwhile, we found that CD3+ T cells, CD4+ T cells and CD8+ T cells from the peripheral blood of experimental group mice were significantly higher than control groups, and CD8+PD-1+ cells were significantly lower than those in MPNs + Los group and Los + laser group. And the expression of PD-1 and α-SMA in Neuro-2a tumors tissue was reduced. Furthermore, losartan could reduce damage of liver function caused by MPNs and laser treatment. Conclusion: This study demonstrated that losartan-induced fibroblasts ablation increased the penetration of MPNs into tumors. Enhanced penetration allowed PTT to kill more tumor cells and synergistically activate immune cells, leading to ICD, indicating the great promise of the strategy for treating neuroblastoma in vivo.

Placental growth factor alleviates hyperglycemia-induced trophoblast pyroptosis by regulating mitophagy.

INTRODUCTION: Hyperglycemia is closely related to trophoblast dysfunction during pregnancy and results in suppressed invasion, migration, and pro-inflammatory cell death of trophoblasts. Hyperglycemia is a dependent risk factor for gestational hypertension accompanied by decreased placental growth factor (PLGF), which is important for maternal and fetal development. However, there is currently a lack of evidence to support whether PLGF can alleviate trophoblast cell dysfunction caused by high blood sugar. Here, we aim to clarify the effect of hyperglycemia on trophoblast dysfunction and determine how PLGF affects this process. METHODS: The changes in placental tissue histomorphology from gestational diabetes mellitus (GDM) patients were compared with those of normal placentas. HTR8/SVneo cells were cultured in different amounts of glucose to examine cellular pyroptosis, migration, and invasion as well as PLGF levels. Furthermore, the levels of pyroptosis-related proteins (NLRP3, pro-caspase1, caspase1, IL-1ß, and Gasdermin D [GSDMD]) as well as autophagy-related proteins (LC3-II, Beclin1, and p62) were examined by Western blotting. The GFP-mRFP-LC3-II system and transmission electron microscopy were used to detect mitophagy levels, and small interfering RNAs targeting BCL2 Interacting Protein 3 (siBNIP3) and PTEN-induced kinase 1 (siPINK1) were used to determine the role of mitophagy in pyroptotic death of HTR-8/SVneo cells. RESULTS: Our results show that hyperglycemia upregulates NLRP3, pro-caspase1, caspase1, IL-1ß at the protein level in GDM patients. High glucose (HG, 25 mM) inhibits viability, invasion, and migration of trophoblast cells while suppressing superoxide dismutase levels and promoting malondialdehyde production, thus leading to a senescence associated beta-gal-positive cell burst. PLGF levels in nucleus and the cytosol are also inhibited by HG, whereas PLGF treatment inhibited pyroptosis-related protein levels of NLRP3, pro-caspase1, caspase1, IL-1ß, and GSDMD, Gasdermin D N-terminal domain (GSDMD-N). HG-induced mitochondrial dysfunction and BNIP3 and PINK1/Parkin expression. Knocking down BINP3 and PINK1 abolished the protective role of PLGF by preventing mitophagy. CONCLUSION: PLGF inhibited hyperglycemia, while PLGF reversed hyperglycemic injury by promoting mitophagy via the BNIP3/PINK1/Parkin pathway. Altogether, these results suggest that PLGF may protect against trophoblast dysfunction in diabetes.

Analysis of metastasis­related risk factors and clinical relevance in adult soft­tissue sarcoma.

Metastasis occurs in nearly 50% of cases of adult soft-tissue sarcoma (ASTS), leading to a dismal prognosis, with a 2-year survival rate of ~30%. Consequently, a prognostic model that incorporates metastatic characteristics may be instrumental in predicting survival time and in crafting optimal personalized therapeutic strategies for patients with ASTS. In the present study, a prognostic prediction model for ASTS was developed by examining genes that are differentially expressed between non-metastatic and metastatic patients in the Gene Expression Omnibus dataset. The prognostic model, which includes five featured genes [actin γ2 (ACTG2), apolipoprotein D, coatomer protein complex subunit γ2 imprinted transcript 1, collagen type VI α6 chain and osteomodulin], was further validated in patients with ASTS from the Cancer Genome Atlas dataset. Based on these five-gene signatures, patients were categorized into high- and low-risk groups. Functional and pathway analyses revealed disparities in stemness, extracellular matrix and cell adhesion-related pathways between the two risk groups, particularly noting the activation of the PI3K-Akt pathway in high-risk cases. Analysis of immune infiltration also revealed variations in immune microenvironment changes between the two risk groups. Immunohistochemical staining substantiated the prognostic significance of these gene signatures in a specific sarcoma subtype. Additionally, wound-healing and Transwell assays demonstrated that inhibition of ACTG2 by shRNAs curbed cell migration and invasion in a sarcoma HOS cell line, underscoring its role in sarcoma metastasis. In conclusion, the present study successfully developed and validated a metastasis-based prognosis prediction model. This model not only reliably forecasts the survival of patients with ASTS, but also may pave the way for further investigation into the processes underlying sarcoma metastasis, ultimately aiding in the design of tailored therapeutic regimens.

PlWRKY47 Coordinates With Cytosolic Glyceraldehyde-3-Phosphate Dehydrogenase 2 Gene to Improve Thermotolerance Through Inhibiting Reactive Oxygen Species Generation in Herbaceous Peony.

Although WRKY transcription factors play crucial roles in plant responses to high-temperature stress, little is known about Group IIb WRKY family members. Here, we identified the WRKY-IIb protein PlWRKY47 from herbaceous peony (Paeonia lactiflora Pall.), which functioned as a nuclear-localized transcriptional activator. The expression level of PlWRKY47 was positively correlated with high-temperature tolerance. Silencing of PlWRKY47 in P. lactiflora resulted in the decreased tolerance to high-temperature stress by accumulating reactive oxygen species (ROS). Overexpression of PlWRKY47 improved plant high-temperature tolerance through decreasing ROS accumulation. Moreover, PlWRKY47 directly bound to the promoter of cytosolic glyceraldehyde-3-phosphate dehydrogenase 2 (PlGAPC2) gene and activated its transcription. PlGAPC2 was also positively regulated high-temperature tolerance in P. lactiflora by increasing NAD+ content to inhibit ROS generation. Additionally, PlWRKY47 physically interacted with itself to form a homodimer, and PlWRKY47 could also interact with one Group IIb WRKY family member PlWRKY72 to form a heterodimer, they all promoted PlWRKY47 to bind to and activate PlGAPC2. These data support that the PlWRKY47-PlWRKY47 homodimer and PlWRKY72-PlWRKY47 heterodimer can directly activate PlGAPC2 expression to improve high-temperature tolerance by inhibiting ROS generation in P. lactiflora. These results will provide important insights into the plant high-temperature stress response by WRKY-IIb transcription factors.

Clinical application of a modified wiltse approach in middle and lower thoracic vertebrae: a case-control study of thoracic fracture patients.

BACKGROUND: The Wiltse approach has been extensively employed in thoracolumbar surgeries due to its minimal muscle damage. However, in the middle and lower thoracic spine, the conventional Wiltse approach necessitates the severance of the latissimus dorsi and trapezius muscles, potentially leading to muscular injury. Consequently, we propose a modified Wiltse approach for the middle and lower thoracic vertebrae, which may further mitigate muscular damage. METHODS: From May 2018 to April 2022, 60 patients with spinal fractures in the middle and lower thoracic vertebrae (T5-12) were enrolled in this study. Thirty patients underwent surgery using the modified Wiltse approach (Group A), while the remaining 30 patients received traditional posterior surgery (Group B). The observation indices included operation time, intraoperative blood loss, incision length, number of C-arm exposures, postoperative drainage, postoperative ambulation time, discharge time, as well as preoperative and postoperative Cobb's angle, percentage of anterior vertebral body height (PAVBH), visual analog scale (VAS) Score, and Oswestry disability index (ODI). RESULTS: Compared to the traditional posterior approach, the modified Wiltse approach demonstrated significant advantages in operation time, intraoperative blood loss, length of incision, postoperative ambulation time, postoperative drainage, and discharge time, as well as postoperative VAS and ODI scores. No significant differences were observed between the two groups in terms of number of C-arm exposures, postoperative Cobb's angle, or postoperative PAVBH. CONCLUSION: We propose a modification of the Wiltse approach for the middle and lower thoracic vertebral regions, which may further minimize muscular damage and facilitate the recovery of patients who have undergone surgery in the middle and lower thoracic vertebrae.

Diagnosis and treatment of anterior cruciate ligament injuries: Consensus of Chinese experts part II: Graft selection and clinical outcome evaluation.

Background: In the recent decade, there has been substantial progress in the technologies and philosophies associated with diagnosing and treating anterior cruciate ligament (ACL) injuries in China. The therapeutic efficacy of ACL reconstruction in re-establishing the stability of the knee joint has garnered widespread acknowledgment. However, the path toward standardizing diagnostic and treatment protocols remains to be further developed and refined. Objective: In this context, the Chinese Association of Orthopaedic Surgeons (CAOS) and the Chinese Society of Sports Medicine (CSSM) collaboratively developed an expert consensus on diagnosing and treating ACL injury, aiming to enhance medical quality through refining professional standards. Methods: The consensus drafting team invited experts across the Greater China region, including the mainland, Hong Kong, Macau, and Taiwan, to formulate and review the consensus using a modified Delphi method as a standardization approach. As members of the CSSM Lower Limb Study Group and the CAOS Arthroscopy and Sports Medicine Study Group, invited experts concentrated on two pivotal issues: "Graft Selection" and "Clinical Outcome Evaluation" during the second part of the consensus development. Results: This focused discussion ultimately led to a strong consensus on nine specific consensus terms. Conclusion: The consensus clearly states that ACL reconstruction has no definitive "gold standard" graft choice. Autografts have advantages in healing capability but are limited in availability and have potential donor site morbidities; allografts reduce surgical trauma but incur additional costs, and there are concerns about slow healing, quality control issues, and a higher failure rate in young athletes; synthetic ligaments allow for early rehabilitation and fast return to sport, but the surgery is technically demanding and incurs additional costs. When choosing a graft, one should comprehensively consider the graft's characteristics, the doctor's technical ability, and the patient's needs. When evaluating clinical outcomes, it is essential to ensure an adequate sample size and follow-up rate, and the research should include patient subjective scoring, joint function and stability, complications, surgical failure, and the return to sport results. Medium and long-term follow-ups should not overlook the assessment of knee osteoarthritis.

PlPOD45 positively regulates high-temperature tolerance of herbaceous peony by scavenging reactive oxygen species.

Herbaceous peony (Paeonia lactiflora Pall.) is a widely used famous traditional flower in China. It prefers cold and cool climate, but is not resistant to high temperature during summer in the middle and lower reaches of the Yangtze River. Previously, we found peroxidase (POD) is an important antioxidant enzyme that played an important role in high-temperature tolerance of P. lactiflora. The present study isolated the candidate gene PlPOD45 and verified its function in resisting high-temperature stress. And the results showed that PlPOD45 had an open reading frame of 978 bp that encoded 325 amino acids. Its protein was localized to the cell membrane and cytoplasm. High-temperature stress induced PlPOD45 expression. Heterologous overexpression of PlPOD45 improved plant tolerance to high-temperature stress, decreased reactive oxygen species (ROS) accumulation, relative electrical conductivity and malondialdehyde content, and increased the ratio of variable fluorescence to highest fluorescence and POD activity. Conversely, silencing PlPOD45 in P. lactiflora could decrease POD activity, ROS scavenging capability and cell membrane stability when these plants were exposed to high-temperature stress. These results suggest that PlPOD45 positively regulates high-temperature tolerance through ROS scavenging, which would provide a theoretical basis for improving high-temperature tolerance in P. lactiflora. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01505-x.

The chest CT perspective on sarcopenia: Exploring reference values for muscle mass quantity/quality and its application in old adults.

OBJECTIVE: To determine reference values for diagnosing sarcopenia through chest CT scans and evaluate their suitability for use among the Chinese old population. METHODS: Chest CT scans were obtained from 500 healthy individuals aged 19-39. Skeletal muscle mass was assessed on chest CT at the level of T4 by the skeletal muscle area (T4SMA), skeletal muscle index (T4SMI), T12 erector spinae muscle area (T12ESMA), and T12 skeletal muscle index (T12SMI), as well as skeletal muscle density (SMD) at T4 and T12 levels. The diagnostic threshold for sarcopenia was defined as a gender-specific value below 2 SD of the mean value in the young group. These cutoff values were then applied to a group of older adults aged 65 and over. RESULTS: Diagnostic thresholds for low skeletal muscle in men were 110.05 cm², 36.01 cm²/m², 29.56 cm², and 9.65 cm²/m² for T4SMA, T4SMI, T12ESMA, and T12SMI, respectively. For women, the thresholds were: 69.93 cm², 26.51 cm²/m², 17.84 cm²/m², and 6.87 cm²/m², respectively. Diagnostic thresholds for low SMD were 38.63HU in men, 34.74 HU for women at T4 level. At T12 level, the cutoff values were 40.94 HU for men and 36.63 HU for women. Sarcopenia prevalence in men, defined by T4SMA, T4SMI, T12ESMA, and T12SMI cutoffs, was 35.6%, 18.9%, 36.7%, and 23.7%, respectively. In women, sarcopenia prevalence was 5.1%, 3.2%, 3.2%, and 1.9%, respectively. CONCLUSION: This study established reference values for sarcopenia diagnosis through chest CT scans among the Chinese population, highlighting the importance of utilizing chest CT scans for sarcopenia detection and muscle health monitoring in older adults.

Long-term outcomes in rapamycin on renal allograft function: a 30-year follow-up from a single-center experience.

OBJECTIVES: To evaluate long-term renal graft prognosis and the role of rapamycin from a single-center in China over a 30-year follow-up. METHODS: This study enrolled a total of 654 patients who underwent kidney transplantation between 1989 and 2020. The basic characteristics of the included patients were collected. Graft survival was described and compared using Kaplan-Meier curves (K-M curves). Both continuous and categorical variables were included in a multivariate Cox proportional-hazards model. Patients were divided into rapamycin-based quadruple immunosuppression regimen group (rapa group, n = 41) and conventional tacrolimus-based triple immunosuppression regimen group (control group, n = 218). The indication biopsy results of the two groups were further reviewed to compare the incidence of rejection, acute rejection, and banff score. RESULTS: The overall 5, 10, 15, 20-year graft survival rate of our center is 87.5%, 62.4%, 46.4% and 20.9%, respectively. The median survival time after surgery is 14 years. Multiple Cox regression analysis identified BMI (p = 0.035), dialysis type (p < 0.001), immunosuppressants (p < 0.01), urine albumen (p < 0.001), globulin (p = 0.041), and blood glucose (p = 0.002) as risk factors. The 20-year, 10-year and 5-year AUC is 0.78, 0.75 and 0.75. The combination of FK506 and rapamycin was further suggested by the model to effectively improve the graft prognosis (p < 0.01, HR = 0.763). The K-M curve showed that the long-term survival rate of renal grafts in the rapa group was significantly better than that in the conventional group (p < 0.001). In addition, indication biopsy records revealed a lower possibility of immune rejection in the rapa group than that in the conventional group (p < 0.001). Banff score indicated that rapa group had less vascular inflammation in the transplanted kidney. CONCLUSIONS: In this study, a 30-year follow-up was performed in a single center, and a total graft 20-year survival rate of 20.9% was reported. The prognostic model and subgroup analysis suggested that FK506 combined with rapamycin could effectively improve the prognosis of renal transplantation, which could be explained by reduced acute rejection and less vascular inflammation.

Perspectives on a peer-driven intervention to promote pre-exposure prophylaxis (PrEP) uptake among men who have sex with men in southern New England: a qualitative study.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is a highly effective pharmaceutical intervention that prevents HIV infection, but PrEP uptake across the US has been slow among men who have sex with men (MSM), especially among Black/African American (B/AA) and Hispanic /Latino (H/L) MSM. This study investigates the acceptability and essential components of a peer-driven intervention (PDI) for promoting PrEP uptake among MSM, with a specific focus on B/AA and H/L communities. METHODS: We conducted 28 semi-structured, qualitative interviews with MSM in southern New England to explore the components of a PDI, including attitudes, content, and effective communication methods. A purposive sampling strategy was used to recruit diverse participants who reflect the communities with the highest burden of HIV infection. RESULTS: Of 28 study participants, the median age was 28 years (interquartile range [IQR]: 25, 35). The sample comprised B/AA (39%, n = 11) and H/L (50%, n = 14) individuals. Notably, nearly half of the participants (46%) were current PrEP users. We found that many participants were in favor of using a PDI approach for promoting PrEP. Additionally, several participants showed interest in becoming peer educators themselves. They emphasized the need for strong communication skills to effectively teach others about PrEP. Moreover, participants noted that peer education should cover key topics like how PrEP works, how effective it is, and any possible side effects. CONCLUSIONS: Our study shows that effective PDIs, facilitated by well-trained peers knowledgeable about PrEP, could enhance PrEP uptake among MSM, addressing health disparities and potentially reducing HIV transmission in B/AA and H/L communities.

Functional Characterization of the Paeonia ostii P5CS Gene under Drought Stress.

With persistent elevation in global temperature, water scarcity becomes a major threat to plant growth and development, yield security, agricultural sustainability, and food production. Proline, as a key osmolyte and antioxidant, plays a critical role in regulating drought tolerance in plants, especially its key biosynthetic enzyme, delta-1-pyrroline-5-carboxylate synthase (P5CS), which always positively responds to drought stress. As an important woody oil crop, the expansion of Paeonia ostii cultivation needs to address the issue of plant drought tolerance. Here, we isolated a PoP5CS gene from P. ostii, with an open reading frame of 1842 bp encoding 613 amino acids. PoP5CS expression progressively increased in response to increasing drought stress, and it was localized in the cytoplasm. Silencing of PoP5CS in P. ostii reduced drought tolerance, accompanied by decreased proline content, elevated reactive oxygen species (ROS) accumulation, and increased relative electrical conductivity (REC) and malondialdehyde (MDA) levels. Conversely, overexpression of PoP5CS in Nicotiana tabacum plants enhanced drought resistance, manifested by increased proline levels, reduced ROS accumulation, and lower REC and MDA contents. This study isolates PoP5CS from P. ostii and validates its role in regulating drought tolerance, providing valuable genetic resources and theoretical insights for the development of drought-resistant P. ostii cultivars.

Effect of mutation of phaC on carbon supply, extracellular polysaccharide production, and pathogenicity of Xanthomonas oryzae pv. oryzae.

Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight in rice. Polyhydroxyalkanoates (PHAs) consitute a diverse group of biopolyesters synthesized by bacteria under nutrient-limited conditions. The phaC gene is important for PHA polymerization. We investigated the effects of phaC gene mutagensis in Xoo strain PXO99A. The phaC gene knock-out mutant exhibited reduced swarming ability relative to that of the wild-type. Under conditions where glucose was the sole sugar source, extracellular polysaccharide (EPS) production by ΔphaC declined by 44.8%. ΔphaC showed weak hypersensitive response (HR) induction in the leaves of non-host Nicotiana tabacum, concomitant with downregulation of hpa1 gene expression. When inoculated in rice leaves by the leaf-clipping method, ΔphaC displayed reduced virulence in terms of lesion length compared with the wild-type strain. The complemented strain showed no significant difference from the wild-type strain, suggesting that the deletion of phaC in Xoo induces significant alterations in various physiological and biological processes. These include bacterial swarming ability, EPS production, transcription of hrp genes, and glucose metabolism. These changes are intricately linked to the energy utilization and virulence of Xoo during plant infection. These findings revealed involvement of phaC in Xoo is in the maintaining carbon metabolism by functioning in the PHA metabolic pathway.

Synergistic actions of three MYB transcription factors underpin blotch formation in tree peony.

Blotches in floral organs attract pollinators and promote pollination success. Tree peony (Paeonia suffruticosa Andr.) is an internationally renowned cut flower with extremely high ornamental and economic value. Blotch formation on P. suffruticosa petals is predominantly attributed to anthocyanin accumulation. However, the endogenous regulation of blotch formation in P. suffruticosa remains elusive. Here, we identified the regulatory modules governing anthocyanin-mediated blotch formation in P. suffruticosa petals, which involves the transcription factors PsMYB308, PsMYBPA2, and PsMYB21. PsMYBPA2 activated PsF3H expression to provide sufficient precursor substrate for anthocyanin biosynthesis. PsMYB21 activated both PsF3H and PsFLS expression and promoted flavonol biosynthesis. The significantly high expression of PsMYB21 in non-blotch regions inhibited blotch formation by competing for anthocyanin biosynthesis substrates, while conversely, its low expression in the blotch region promoted blotch formation. PsMYB308 inhibited PsDFR and PsMYBPA2 expression to directly prevent anthocyanin-mediated blotch formation. Notably, a smaller blotch area, decreased anthocyanin content, and inhibition of anthocyanin structural gene expression were observed in PsMYBPA2-silenced petals, while the opposite phenotypes were observed in PsMYB308-silenced and PsMYB21-silenced petals. Additionally, PsMYBPA2 and PsMYB308 interacted with PsbHLH1-3, and their regulatory intensity on target genes was synergistically regulated by the PsMYBPA2-PsbHLH1-3 and PsMYB308-PsbHLH1-3 complexes. PsMYB308 also competitively bound to PsbHLH1-3 with PsMYBPA2 to fine-tune the regulatory network to prevent overaccumulation of anthocyanin in blotch regions. Overall, our study uncovers a complex R2R3-MYB transcriptional regulatory network that governs anthocyanin-mediated blotch formation in P. suffruticosa petals, providing insights into the molecular mechanisms underlying blotch formation in P. suffruticosa.

Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin-2 dephosphorylation and impairing mitochondrial quality control.

BACKGROUND: The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood. METHODS: We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM. RESULTS: Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific Pgam5 knockout (Pgam5cKO) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, Pgam5 depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2S91D) and phospho-defective (Phb2S9A) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing Phb2S91D were resistant to alcohol-induced heart dysfunction. CONCLUSIONS: We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2S91 dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice. HIGHLIGHTS: Pgam5 knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice. Pgam5 KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice. Pgam5 depletion protects mitochondrial function in alcohol-exposed male mouse cardiomyocytes. Pgam5 depletion normalises MQC in ACM. EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91. Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation. Transgenic mice expressing a Ser91 phospho-mimetic Phb2 mutant are resistant to ACM.

Influence of sources and atmospheric processes on metal solubility in PM2.5 in urban Guangzhou, South China.

Water-soluble metals exert a significant influence on human and ecosystem health. In this study, a comprehensive investigation was undertaken to elucidate the solubilities of metals in PM2.5 and potential influencing factors during the dry season of 2019-2020 in urban Guangzhou, South China. The observed average solubility was <20 % for Al, Fe, Sn, and Ti; 20-40 % for V, Cr, Sb, Pb, and Ni; 40-60 % for Ba and Cu; and 60-80 % for Zn, As, Se, Cd, and Mn. Metals (Al, Ti, and Fe) originated from crustal sources (e.g., soil dust) have much lower solubilities than those (Mn, Zn, As, Se, Cd, and Ba) from fossil fuel combustion sources (e.g., traffic emission, coal combustion), suggesting the dominant role the metal sources played on solubility. Enhanced solubilities of Cu, As, Se, Cd, Sn, Sb, and Pb were associated with aerosol acidity, while those of V, Cr, Mn, Ni, Zn, and Ba were linked to organic acid complexation. For the three crustal metals, the solubilities of Al and Ti primarily depended on aerosol acidity, whereas the solubility of Fe depended on both aerosol acidity under pH < 2 conditions and organic acid complexation under pH > 2 conditions. These findings underscore the primary influence of inherent properties of the metals on their solubility and reveal the varying impacts of atmospheric physicochemical processes, with changes in their solubilities being <10 % for Cd, Sn, Sb, and Pb, 10-20 % for Cu, Cr, Mn, Ni, and Ba, and 20-30 % for As, Se, and Zn.

Ultralow Power In-Sensor Neuronal Computing with Oscillatory Retinal Neurons for Frequency-Multiplexed, Parallel Machine Vision.

In-sensor and near-sensor computing architectures enable multiply accumulate operations to be carried out directly at the point of sensing. In-sensor architectures offer dramatic power and speed improvements over traditional von Neumann architectures by eliminating multiple analog-to-digital conversions, data storage, and data movement operations. Current in-sensor processing approaches rely on tunable sensors or additional weighting elements to perform linear functions such as multiply accumulate operations as the sensor acquires data. This work implements in-sensor computing with an oscillatory retinal neuron device that converts incident optical signals into voltage oscillations. A computing scheme is introduced based on the frequency shift of coupled oscillators that enables parallel, frequency multiplexed, nonlinear operations on the inputs. An experimentally implemented 3 × 3 focal plane array of coupled neurons shows that functions approximating edge detection, thresholding, and segmentation occur in parallel. An example of inference on handwritten digits from the MNIST database is also experimentally demonstrated with a 3 × 3 array of coupled neurons feeding into a single hidden layer neural network, approximating a liquid-state machine. Finally, the equivalent energy consumption to carry out image processing operations, including peripherals such as the Fourier transform circuits, is projected to be <20 fJ/OP, possibly reaching as low as 15 aJ/OP.

Electrospinning technology: a promising approach for tendon-bone interface tissue engineering.

The regeneration of tendon-bone interface tissue has become a topic of great interest in recent years. However, the complex nature of this interface has posed challenges in finding suitable solutions. Tissue engineering, with its potential to improve clinical outcomes and play a crucial role in musculoskeletal function, has been increasingly explored for tendon-bone interface regeneration. This review focuses on the research advancements of electrospinning technology in interface tissue engineering. By utilizing electrospinning, researchers have been able to fabricate scaffolds with tailored properties to promote the regeneration and integration of tendon and bone tissues. The review discusses the unique structure and function of the tendon-bone interface, the mechanisms involved in its healing, and the limitations currently faced in achieving successful regeneration. Additionally, it highlights the potential of electrospinning technology in scaffold fabrication and its role in facilitating the development of functional and integrated tendon-bone interface tissues. Overall, this review provides valuable insights into the application of electrospinning technology for tendon-bone interface tissue engineering, emphasizing its significance in addressing the challenges associated with regeneration in this complex interface.

Exploring the therapeutic potential of urine-derived stem cell exosomes in temporomandibular joint osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative ailment that causes slow cartilage degeneration, aberrant bone remodeling, and persistent discomfort, leading to a considerable reduction in the patient's life quality. Current treatment options for TMJOA have limited efficacy. This investigation aimed to explore a potential strategy for halting or reversing the progression of TMJOA through the utilization of exosomes (EXOs) derived from urine-derived stem cells (USCs). The USC-EXOs were obtained through microfiltration and ultrafiltration techniques, followed by their characterization using particle size analysis, electron microscopy, and immunoblotting. Subsequently, an in vivo model of TMJOA induced by mechanical force was established. To assess the changes in the cartilage of TMJOA treated with USC-EXOs, we performed histology analysis using hematoxylin-eosin staining, immunohistochemistry, and histological scoring. Our findings indicate that the utilization of USC-EXOs yields substantial reductions in TMJOA, while concurrently enhancing the structural integrity and smoothness of the compromised condylar cartilage surface. Additionally, USC-EXOs exhibit inhibitory effects on osteoclastogenic activity within the subchondral bone layer of the condylar cartilage, as well as attenuated apoptosis in the rat TMJ in response to mechanical injury. In conclusion, USC-EXOs hold considerable promise as a potential therapeutic intervention for TMJOA.