A Nationwide Study on the Risks of Complications and Healthcare Costs of Snakebite Envenomation in Taiwan.

In Taiwan, six medically important venomous snakes, Trimeresurus stejnegeri stejnegeri, Protobothrops mucrosquamatus, Deinagkistrodon acutus, Daboia siamensis, Naja atra, and Bungarus multicinctus, are found. However, comprehensive research on the complications and associated healthcare costs of snakebite envenomation (SBE) is lacking. We retrospectively analyzed pertinent information from the Taiwan National Health Insurance Research Database dated January 2002 to December 2014. We investigated the risk factors for complications and their impact on healthcare costs. Among the 12,542 patients with SBE, those from N. atra or B. multicinctus were more likely to experience wound infections and neurological complications than were those from T. s. stejnegeri or P. mucrosquamatus. In addition, being female, being elderly, and having a Charlson Comorbidity Index equal to or greater than 3 points were associated with an increased likelihood of wound infections and psychological complications. The annual national economic burden averaged US$1,083,624, with an average healthcare cost of US$1,129 per SBE. Snakebite envenomations from N. atra or B. multicinctus, as well as various complications, resulted in significantly higher costs. It is crucial to comprehend the risk factors for complications and their role in increasing expenses to provide insight for tailored healthcare interventions, mitigate complications, and reduce the economic burdens associated with SBEs.

Detection of α-Synuclein in Oral Mucosa by Seed Amplification Assay in Synucleinopathies and Isolated REM Sleep Behavior Disorder.

OBJECTIVE: Evidence of abnormal α-synuclein (α-Syn) deposition in the brain is required for definitive diagnosis of synucleinopathies, which remains challenging. The seed amplification assay (SAA) is an innovative technique that can detect the seeding activity of misfolded α-Syn, enabling the amplification and detection of minute quantities of pathogenic α-Syn aggregates. This study aimed to evaluate oral mucosa α-Syn SAA as possible diagnostic and prodromal biomarkers for synucleinopathies. METHODS: A total of 107 Parkinson's disease (PD) patients, 99 multiple system atrophy (MSA) patients, 33 patients with isolated rapid eye movement sleep behavior disorder (iRBD) and 103 healthy controls (HC) were included. The SAA was applied to detect the seeding activity of α-Syn from oral mucosa. A combination of morphological, biochemical, and biophysical methods was also used to analyze the fibrils generated from the oral mucosa α-Syn SAA. RESULTS: Structured illumination microscopy images revealed the increased α-Syn species in oral mucosa of PD, MSA, and iRBD patients than in HCs. Oral mucosa α-Syn SAA distinguished patients with PD from HC with 67.3% sensitivity and 90.3% specificity. Oral mucosa was α-Syn SAA positive in 53.5% MSA patients and 63.6% iRBD patients. Furthermore, the α-Syn fibrils generated from MSA demonstrated greater resistance to proteinase K digestion and exhibited stronger cytotoxicity compared to those from PD patients. CONCLUSION: Oral mucosa α-Syn seeding activity may serve as novel non-invasive diagnostic and prodromal biomarkers for synucleinopathies. The α-Syn aggregates amplified from the oral mucosa of PD and MSA exhibited distinct biochemical and biophysical properties. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Epidemic Features and Megagenomic Analysis of Childhood Mycoplasma Pneumoniae post COVID-19 Pandemic: A 6-year Study in Southern China.

With the atypical rise of Mycoplasma pneumoniae infection (MPI) in 2023, prompt studies are needed to determine the current epidemic features and risk factors with emerging trends of MPI to furnish a framework for subsequent investigations. This multicentre, retrospective study was designed to analyse the epidemic patterns of MPI before and after the COVID-19 pandemic, as well as genotypes and the macrolide resistance-associated mutations in MP sampled from pediatric patients in Southern China. Clinical data was collected from 133674 patients admitted into investigational hospitals from June 1, 2017, to November 30, 2023. Metagenomic next-generation sequencing (mNGS) data were retrieved based on MP sequence positive samples from 299 pediatric patients for macrolide resistance-associated mutations analysis. Pearson's chi-squared test was used to compare categorical variables between different time frames. The monthly average cases of pediatric common respiratory infection diseases were increased without enhanced public health measures after the pandemic, especially for influenza, respiratory syncytial virus infection, and MPI. The contribution of MPI to pneumoniae was similar to that in the outbreak in 2019. Compared mNGS data between 2019-2022 and 2023, the severity of MP did not grow stronger despite higher rates of macrolide-resistance hypervariable sites, including loci 2063 and 2064, were detected in childhood MP samples of 2023. Our findings indicated ongoing surveillance is necessary to understand the impact of post pandemic on MP transmission disruption on epidemic season and severity of clinical outcomes in different scenarios.

Impacts of medication adherence and home healthcare on the associations between polypharmacy and the risk of severe hypoglycemia among elderly diabetic patients in Taiwan from 2002 to 2012: A nationwide case-crossover study.

AIM: To assess how medication adherence and home healthcare support influence the role of polypharmacy in induced hypoglycemia events among elderly diabetic patients. METHODS: This case-crossover study retrieved records on diabetic patients >=65 years with severe hypoglycemia from 2002 to 2012 in Taiwan. Case period defined as 1-3 days before severe hypoglycemia was compared with a preceding control period of the same length, with an all-washout period of 30 days. Moreover, the modifiable effects of medication adherence and home healthcare service use were evaluated by stratified analysis. RESULTS: Totally 2,237 patients were identified. Polypharmacy use was associated with the risk of severe hypoglycemia. Patients receiving polypharmacy without home healthcare services (aOR: 1.34; 95 % CI: 1.16-1.54) and those with poor adherence to anti-diabetic medications (aOR: 1.48; 95 % CI: 1.24-1.77) were significantly associated with an elevated risk of severe hypoglycemia. In patients with good adherence, non-home healthcare users being prescribed with polypharmacy had a higher risk of severe hypoglycemia. In the group that received home healthcare services, patients with poor adherence using polypharmacy had a higher risk of severe hypoglycemia. CONCLUSIONS: Good adherence and receiving home healthcare services were associated with a decreased odds of severe hypoglycemic events in elderly diabetic patients, regardless of the fact whether they were prescribed with polypharmacy.

The risk of sexual dysfunction in Chinese women with recurrent pregnancy loss and the associated factors: a multicenter cross-sectional study.

Background: Recurrent pregnancy loss (RPL) is a severe traumatic event for women of childbearing age. However, the association between RPL and female sexual dysfunction was unknown. Aim: The study sought to investigate the association between RPL and sexual dysfunction, and to explore the risk factors of sexual dysfunction for RPL patients. Methods: A multicenter cross-sectional study involving both RPL patients and healthy women was performed in 3 different hospitals in West China from May 2021 to January 2023. Baseline information including sociodemographic data and disease histories were collected. The Female Sexual Function Index (FSFI) was used to assess the sexual function of participants. Outcomes: The main outcome was the proportion of women at increased risk of sexual dysfunction (total FSFI scores <26.55), and the secondary outcome was risk factors of sexual dysfunction in RPL patients. Results: A total of 233 RPL patients and 185 healthy women were included in this study. RPL patients had significantly lower total FSFI scores (median 31.7 [interquartile range, 26.6-33.5] vs 33.0 [interquartile range, 31.2-34.1]; P < .001) and a significantly higher risk of sexual dysfunction than healthy women (24.9% vs 8.6%; P < .001). Body mass index >24 kg/m2 (adjusted odds ratio [OR], 4.132; 95% confidence interval [CI], 1.902-8.976, P < .001), working >8 h/d (adjusted OR, 2.111; 95% CI, 1.020-4.369, P = .044), and unexplained RPL (adjusted OR, 3.785; 95% CI, 1.967-7.280, P < .001) were independent risk factors of sexual dysfunction for RPL patients. Clinical Implications: RPL patients, especially those patients with the previously mentioned risk factors, should be focused on the risk of sexual dysfunction, and appropriate preventions could be applied. Strength and Limitations: We explored the association between RPL and sexual dysfunction and explored the risk factors of sexual dysfunction among RPL patients for the first time, and the multicenter data increased the generalizability of results. However, the cross-sectional design did not provide an exact causal relationship between RPL and sexual dysfunction, and potential risk factors related to mental health were not investigated. Conclusion: RPL patients were at an increased risk of sexual dysfunction. Overweight, fatigue caused by work, and unexplained RPL were risk factors of sexual dysfunction for RPL patients.

Enhancing resistance, but not virulence attributed to the high mortality caused by carbapenem-resistant Klebsiella pneumoniae.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a global threat due to its high mortality in clinical patients. However, the specific mechanisms underlying this increased mortality remain unclear. The objective of this study is to investigate how the development of a resistance phenotype contributes to the significantly higher mortality associated with this pathogen. To achieve this, a collection of isogeneic strains was generated. The clinical carbapenem-susceptible K. pneumoniae (CSKP) strain HKU3 served as the control isolate, while HKU3-KPC was created through conjugation with a blaKPC-2-bearing plasmid and served as clinical CRKP strain. Using a sepsis model, it was demonstrated that both HKU3 and HKU3-KPC exhibited similar levels of virulence. Flow cytometry, RNA-seq, and ELISA analysis were employed to assess immune cell response, M1 macrophage polarization, and cytokine storm induction, revealing that both strains elicited comparable types and levels of these immune responses. Subsequently, meropenem was utilized to treat K. pneumoniae infection, and it was found that meropenem effectively reduced bacterial load, inhibited M1 macrophage polarization, and suppressed serum cytokine production during HKU3 (CSKP) infection. However, these effects were not observed in the case of HKU3-KPC (CRKP) infection. These findings provide evidence that the high mortality associated with CRKP is attributed to its enhanced survival within the host during antibiotic treatment, resulting in a cytokine storm and subsequent host death. The development of an effective therapy for CRKP infections could significantly reduce the mortality caused by this pathogen.

Sterile inflammation of peritoneal membrane caused by peritoneal dialysis: focus on the communication between immune cells and peritoneal stroma.

Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the failure of this therapy. This deterioration is primarily caused by infectious and sterile inflammation. Sterile inflammation, which is inflammation without infection, is particularly concerning as it can be subtle and often goes unnoticed. The onset of sterile inflammation involves various pathological processes. Peritoneal cells detect signals that promote inflammation and release substances that attract immune cells from the bloodstream. These immune cells contribute to the initiation and escalation of the inflammatory response. The existing literature extensively covers the involvement of different cell types in the sterile inflammation, including mesothelial cells, fibroblasts, endothelial cells, and adipocytes, as well as immune cells such as macrophages, lymphocytes, and mast cells. These cells work together to promote the occurrence and progression of sterile inflammation, although the exact mechanisms are not fully understood. This review aims to provide a comprehensive overview of the signals from both stromal cells and components of immune system, as well as the reciprocal interactions between cellular components, during the initiation of sterile inflammation. By understanding the cellular and molecular mechanisms underlying sterile inflammation, we may potentially develop therapeutic interventions to counteract peritoneal membrane damage and restore normal function.

Physical immune escape: Weakened mechanical communication leads to escape of metastatic colorectal carcinoma cells from macrophages.

The significance of biochemical cues in the tumor immune microenvironment in affecting cancer metastasis is well established, but the role of physical factors in the microenvironment remains largely unexplored. In this article, we investigated how the mechanical interaction between cancer cells and immune cells, mediated by extracellular matrix (ECM), influences immune escape of cancer cells. We focus on the mechanical regulation of macrophages' targeting ability on two distinct types of colorectal carcinoma (CRC) cells with different metastatic potentials. Our results show that macrophages can effectively target CRC cells with low metastatic potential, due to the strong contraction exhibited by the cancer cells on the ECM, and that cancer cells with high metastatic potential demonstrated weakened contractions on the ECM and can thus evade macrophage attack to achieve immune escape. Our findings regarding the intricate mechanical interactions between immune cells and cancer cells can serve as a crucial reference for further exploration of cancer immunotherapy strategies.

Osteocyte ferroptosis induced by ATF3/TFR1 contributes to cortical bone loss during ageing.

Cortical bone loss is intricately associated with ageing and coincides with iron accumulation. The precise role of ferroptosis, characterized by iron overload and lipid peroxidation, in senescent osteocytes remains elusive. We found that ferroptosis was a crucial mode of osteocyte death in cortical bone during ageing. Using a single-cell transcriptome analysis, we identified activating transcription factor 3 (ATF3) as a critical driver of osteocyte ferroptosis. Elevated ATF3 expression in senescent osteocytes promotes iron uptake by upregulating transferrin receptor 1 while simultaneously inhibiting solute carrier family 7-member 11-mediated cystine import. This process leads to an iron overload and lipid peroxidation, culminating in ferroptosis. Importantly, ATF3 inhibition in aged mice effectively alleviated ferroptosis in the cortical bone and mitigated cortical bone mass loss. Taken together, our findings establish a pivotal role of ferroptosis in cortical bone loss in older adults, providing promising prevention and treatment strategies for osteoporosis and fractures.

Discovery of acetophenone/piperazin-2-one hybrids as selective anti-TNBC cancer agents by causing DNA damage.

Twenty-five acetophenone/piperazin-2-one (APPA) hybrids were designed and synthesized based on key pharmacophores found in anti-breast cancer drugs Neratinib, Palbociclib, and Olaparib. Compound 1j exhibited good in vitro antiproliferative activity (IC50 = 6.50 µM) and high selectivity (SI = 9.2 vs HER2-positive breast cancer cells SKBr3; SI = 7.3 vs normal breast cells MCF-10A) against triple negative breast cancer (TNBC) cells MDA-MB-468. In addition, 1j could selectively cause DNA damage, inducing the accumulation of γH2AX and P53 in MDA-MB-468 cells. It also reduced the phosphorylation level of P38 and the expression of HSP70, which further prevented the repair of DNA damage and caused cells S/G2-arrest leading to MDA-MB-468 cells death.

Endoscopic Cryoablation Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: Cryoablation is a traditional antitumor therapy with good prospects for development. The efficacy of endoscopic management as a kidney-sparing surgery for high-risk upper tract urothelial carcinoma (UTUC) remains controversial. Our aim was to evaluate the impact of endoscopic cryoablation (ECA) versus radical nephroureterectomy (RNU) on survival outcomes, renal function, and complications. METHODS: We retrospectively analyzed data for 116 patients with newly diagnosed high-risk UTUC who underwent either ECA (n = 13) or RNU (n = 103) from March 25, 2019 to December 8, 2021. Propensity score matching (1:4) using the nearest neighbor method was performed before analysis. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), intravesical recurrence-free survival (RFS), the change in renal function, and treatment-emergent adverse events (TEAEs). KEY FINDINGS AND LIMITATIONS: At median follow-up of 28.2 mo for the ECA group and 27.6 mo for the RNU group, 2-yr OS (82% vs 84%), PFS (73% vs 71%), and intravesical RFS (81% vs 83%) rates after matching did not significantly differ. A decline in renal function was observed after RNU, but not after ECA. Five (41.7%) patients in the ECA group reported six TEAEs, and 17 patients (35.4%) in the RNU group reported 20 TEAEs. CONCLUSIONS AND CLINICAL IMPLICATIONS: In comparison to RNU, ECA for UTUC resulted in noninferior oncological outcomes and superior preservation of renal function. PATIENT SUMMARY: Our study suggests that a treatment called endoscopic cryoablation for high-risk cancer in the upper urinary tract can help in preserving kidney function, with similar survival outcomes to those after more extensive surgery. This option can be considered for selected patients with a strong preference for kidney preservation.

Research on the facile regeneration of degraded cathode materials from spent LiNi0.5Co0.2Mn0.3O2 lithium-ion batteries.

Rational reusing the waste materials in spent batteries play a key role in the sustainable development for the future lithium-ion batteries. In this work, we propose an effective and facile solid-state-calcination strategy for the recycling and regeneration of the cathode materials in spent LiNi0.5Co0.2Mn0.3O2 (NCM523) ternary lithium-ion batteries. By systemic physicochemical characterizations, the stoichiometry, phase purity and elemental composition of the regenerated material were deeply investigated. The electrochemical tests confirm that the material characteristics and performances got recovered after the regeneration process. The optimal material was proved to exhibit the excellent capacity with a discharge capacity of 147.9 mAh g-1 at 1 C and an outstanding capacity retention of 86% after 500 cycles at 1 C, which were comparable to those of commercial NCM materials.

Trilaciclib dosage in Chinese patients with extensive-stage small cell lung cancer: a pooled pharmacometrics analysis.

This study aimed to analyze potential ethnic disparities in the dose-exposure-response relationships of trilaciclib, a first-in-class intravenous cyclin-dependent kinase 4/6 inhibitor for treating chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (ES-SCLC). This investigation focused on characterizing these relationships in both Chinese and non-Chinese patients to further refine the dosing regimen for trilaciclib in Chinese patients with ES-SCLC. Population pharmacokinetic (PopPK) and exposure-response (E-R) analyses were conducted using pooled data from four randomized phase 2/3 trials involving Chinese and non-Chinese patients with ES-SCLC. PopPK analysis revealed that trilaciclib clearance in Chinese patients was approximately 17% higher than that in non-Chinese patients with ES-SCLC. Sex and body surface area influenced trilaciclib pharmacokinetics in both populations but did not exert a significant clinical impact. E-R analysis demonstrated that trilaciclib exposure increased with a dosage escalation from 200 to 280 mg/m2, without notable changes in myeloprotective or antitumor efficacy. However, the incidence of infusion site reactions, headaches, and phlebitis/thrombophlebitis rose with increasing trilaciclib exposure in both Chinese and non-Chinese patients with ES-SCLC. These findings suggest no substantial ethnic disparities in the dose-exposure-response relationship between Chinese and non-Chinese patients. They support the adoption of a 240-mg/m2 intravenous 3-day or 5-day dosing regimen for trilaciclib in Chinese patients with ES-SCLC.

Molecular beacon-based detection of circulating microRNA-containing extracellular vesicle as an α-synucleinopathy biomarker.

Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate microRNA-containing extracellular vesicles (EVs) in plasma. We recruited 1203 participants including healthy controls (HCs) and patients with isolated REM sleep behavior disorder (iRBD), α-synucleinopathies, or non-α-synucleinopathies from eight centers across China. Plasma miR-44438-containing EV levels were significantly increased in α-synucleinopathies, including those in the prodromal stage (e.g., iRBD), compared to both non-α-synucleinopathy patients and HCs. However, there are no significant differences between Parkinson's disease (PD) and multiple system atrophy. The miR-44438-containing EV levels negatively correlated with age and the Hoehn and Yahr stage of PD patients, suggesting a potential association with disease progression. Furthermore, a longitudinal analysis over 16.3 months demonstrated a significant decline in miR-44438-containing EV levels in patients with PD. These results highlight the potential of plasma miR-44438-containing EV as a biomarker for early detection and progress monitoring of α-synucleinopathies.

Superconducting Two-Dimensional FeSe Grown on the Fe-Enriched Interface.

Two-dimensional (2D) tetragonal FeSe has sparked extensive research interest owing to its tunable superconductivity, providing valuable insights into the design of high-temperature superconductors. Currently, the intricate Fe-Se phase diagram poses a challenge to the controlled synthesis of superconducting 2D FeSe in a pure tetragonal phase. Here, we exploit the ion-exchange property of fluorophlogopite mica to devise a straightforward approach for the phase-controlled synthesis of tetragonal FeSe on an Fe-enriched mica surface within a molten salt environment. This method successfully produces highly crystalline FeSe in a pure tetragonal phase with adjustable thickness. We investigated the surface composition of the postgrowth mica substrate using various microscopic and spectroscopic characterizations to highlight the importance of the Fe-enriched growth interface in the phase-selective synthesis of 2D tetragonal FeSe. The obtained 2D FeSe exhibited 2D superconductivity, comparable to that of FeSe mechanically exfoliated from bulk crystals, confirming the high quality of our samples. Beyond tetragonal FeSe, 2D antiferromagnetic FeTe and superconducting FeSxSeyTe1-x-y have been phase-selectively synthesized via this approach. Our study elucidates the significance of the growth interface on the phase-selective synthesis of 2D materials and presents potential opportunities for the phase-controlled synthesis of 2D multiphase materials via the rational design of the growth interface.

Poly(ethylene oxide)- and Polyzwitterion-Based Thermoplastic Elastomers for Solid Electrolytes.

In this article, ABA triblock copolymer (tri-BCP) thermoplastic elastomers with poly(ethylene oxide) (PEO) middle block and polyzwitterionic poly(4-vinylpyridine) propane-1-sulfonate (PVPS) outer blocks were synthesized. The PVPS-b-PEO-b-PVPS tri-BCPs were doped with lithium bis-(trifluoromethane-sulfonyl) imide (LiTFSI) and used as solid polyelectrolytes (SPEs). The thermal properties and microphase separation behavior of the tri-BCP/LiTFSI hybrids were studied. Small-angle X-ray scattering (SAXS) results revealed that all tri-BCPs formed asymmetric lamellar structures in the range of PVPS volume fractions from 12.9% to 26.1%. The microphase separation strength was enhanced with increasing the PVPS fraction (fPVPS) but was weakened as the doping ratio increased, which affected the thermal properties of the hybrids, such as melting temperature and glass transition temperature, to some extent. As compared with the PEO/LiTFSI hybrids, the PVPS-b-PEO-b-PVPS/LiTFSI hybrids could achieve both higher modulus and higher ionic conductivity, which were attributed to the physical crosslinking and the assistance in dissociation of Li+ ions by the PVPS blocks, respectively. On the basis of excellent electrical and mechanical performances, the PVPS-b-PEO-b-PVPS/LiTFSI hybrids can potentially be used as solid electrolytes in lithium-ion batteries.

Patients with chronic ankle instability exhibit increased sensorimotor cortex activation and correlation with poorer lateral balance control ability during single-leg stance: a FNIRS study.

Introduction: Chronic Ankle Instability (CAI) is a musculoskeletal condition that evolves from acute ankle sprains, and its underlying mechanisms have yet to reach a consensus. Mounting evidence suggests that neuroplastic changes in the brain following ankle injuries play a pivotal role in the development of CAI. Balance deficits are a significant risk factor associated with CAI, yet there is a scarcity of evidence regarding the sensorimotor cortical plasticity related to balance control in affected individuals. This study aims to evaluate the differences in cortical activity and balance abilities between patients with CAI and uninjured individuals during a single-leg stance, as well as the correlation between these factors, in order to elucidate the neurophysiological alterations in balance control among patients with CAI. Methods: The study enrolled 24 patients with CAI and 24 uninjured participants. During single-leg stance, cortical activity was measured using a functional near-infrared spectroscopy (fNIRS) system, which included assessments of the pre-motor cortex (PMC), supplementary motor area (SMA), primary motor cortex (M1), and primary somatosensory cortex (S1). Concurrently, balance parameters were tested utilizing a three-dimensional force platform. Results: Independent sample t-tests revealed that, compared with the uninjured individuals, the patients with CAI exhibited a significant increase in the changes of oxyhemoglobin concentration (ΔHbO) during single-leg stance within the left S1 at Channel 5 (t = 2.101, p = 0.041, Cohen's d = 0.607), left M1 at Channel 6 (t = 2.363, p = 0.022, Cohen's d = 0.682), right M1 at Channel 15 (t = 2.273, p = 0.029, Cohen's d = 0.656), and right PMC/SMA at Channel 11 (t = 2.467, p = 0.018, Cohen's d = 0.712). Additionally, the center of pressure root mean square (COP-RMS) in the mediolateral (ML) direction was significantly greater (t = 2.630, p = 0.012, Cohen's d = 0.759) in the patients with CAI. Furthermore, a moderate positive correlation was found between ML direction COP-RMS and ΔHbO2 in the M1 (r = 0.436; p = 0.033) and PMC/SMA (r = 0.488, p = 0.016), as well as between anteroposterior (AP) direction COP-RMS and ΔHbO in the M1 (r = 0.483, p = 0.017). Conclusion: Patients with CAI demonstrate increased cortical activation in the bilateral M1, ipsilateral PMC/SMA, and contralateral S1. This suggests that patients with CAI may require additional brain resources to maintain balance during single-leg stance, representing a compensatory mechanism to uphold task performance amidst diminished lateral balance ability in the ankle joint.

CuCS/Cur composite wound dressings promote neuralized skin regeneration by rebuilding the nerve cell "factory" in deep skin burns.

Regenerating skin nerves in deep burn wounds poses a significant clinical challenge. In this study, we designed an electrospun wound dressing called CuCS/Cur, which incorporates copper-doped calcium silicate (CuCS) and curcumin (Cur). The unique wound dressing releases a bioactive Cu2+-Cur chelate that plays a crucial role in addressing this challenge. By rebuilding the "factory" (hair follicle) responsible for producing nerve cells, CuCS/Cur induces a high expression of nerve-related factors within the hair follicle cells and promotes an abundant source of nerves for burn wounds. Moreover, the Cu2+-Cur chelate activates the differentiation of nerve cells into a mature nerve cell network, thereby efficiently promoting the reconstruction of the neural network in burn wounds. Additionally, the Cu2+-Cur chelate significantly stimulates angiogenesis in the burn area, ensuring ample nutrients for burn wound repair, hair follicle regeneration, and nerve regeneration. This study confirms the crucial role of chelation synergy between bioactive ions and flavonoids in promoting the regeneration of neuralized skin through wound dressings, providing valuable insights for the development of new biomaterials aimed at enhancing neural repair.

PAMless SpRY exhibits a preference for the seed region for efficient targeting.

Protospacer-adjacent motif (PAM) recognition licenses Cas nucleases for genome engineering applications, thereby restricting gene targeting to PAM-containing regions. Protein engineering has led to PAM-relaxed SpCas9 variants like SpG and SpRY. Given the evolved role of PAMs in facilitating target-searching kinetics, it remains unclear how these variants quickly locate their targets. We show that SpG and SpRY exhibit a preference for the seed region. To compensate for the relaxed PAM recognition, SpRY has evolved a sequence preference for the seed region through interactions with A61R and A1322R. Furthermore, SpCas9 exhibits a significant decrease in target search kinetics on high-PAM-density DNA, slowing down up to three orders of magnitude compared to low-PAM-density DNA, suggesting the necessity for sequence recognition even in PAM-relaxed variants. This underscores the importance of considering Cas9 target-searching kinetics in SpCas9 PAMless engineering, providing valuable insights for further PAMless Cas9 protein engineering efforts.