Deletions of singular U1 snRNA gene significantly interfere with transcription and 3'-end mRNA formation.

Small nuclear RNAs (snRNAs) are structural and functional cores of the spliceosome. In metazoan genomes, each snRNA has multiple copies/variants, up to hundreds in mammals. However, the expressions and functions of each copy/variant in one organism have not been systematically studied. Focus on U1 snRNA genes, we investigated all five copies in Drosophila melanogaster using two series of constructed strains. Analyses of transgenic flies that each have a U1 promoter-driven gfp revealed that U1:21D is the major and ubiquitously expressed copy, and the other four copies have specificities in developmental stages and tissues. Mutant strains that each have a precisely deleted copy of U1-gene exhibited various extents of defects in fly morphology or mobility, especially deletion of U1:82Eb. Interestingly, splicing was changed at limited levels in the deletion strains, while large amounts of differentially-expressed genes and alternative polyadenylation events were identified, showing preferences in the down-regulation of genes with 1-2 introns and selection of proximal sites for 3'-end polyadenylation. In vitro assays suggested that Drosophila U1 variants pulled down fewer SmD2 proteins compared to the canonical U1. This study demonstrates that all five U1-genes in Drosophila have physiological functions in development and play regulatory roles in transcription and 3'-end formation.

Sex-lethal regulates back-splicing and generation of the sex-differentially expressed circular RNAs.

Conversely to canonical splicing, back-splicing connects the upstream 3' splice site (SS) with a downstream 5'SS and generates exonic circular RNAs (circRNAs) that are widely identified and have regulatory functions in eukaryotic gene expression. However, sex-specific back-splicing in Drosophila has not been investigated and its regulation remains unclear. Here, we performed multiple RNA analyses of a variety sex-specific Drosophila samples and identified over ten thousand circular RNAs, in which hundreds are sex-differentially and -specifically back-spliced. Intriguingly, we found that expression of SXL, an RNA-binding protein encoded by Sex-lethal (Sxl), the master Drosophila sex-determination gene that is only spliced into functional proteins in females, promoted back-splicing of many female-differential circRNAs in the male S2 cells, whereas expression of a SXL mutant (SXLRRM) did not promote those events. Using a monoclonal antibody, we further obtained the transcriptome-wide RNA-binding sites of SXL through PAR-CLIP. After splicing assay of mini-genes with mutations in the SXL-binding sites, we revealed that SXL-binding on flanking exons and introns of pre-mRNAs facilitates back-splicing, whereas SXL-binding on the circRNA exons inhibits back-splicing. This study provides strong evidence that SXL has a regulatory role in back-splicing to generate sex-specific and -differential circRNAs, as well as in the initiation of sex-determination cascade through canonical forward-splicing.

Functional Upgrading of an Organo-Ir(III) Complex to an Organo-Ir(III) Prodrug as a DNA Damage-Responsive Autophagic Inducer for Hypoxic Lung Cancer Therapy.

The efficiency of nitrogen mustards (NMs), among the first chemotherapeutic agents against cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time. Prodrug IrCpNM could upregulate the level of catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the hypoxia-inducible factor (HIF-1α) to relieve hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under hypoxia, as simultaneous ROS promotion and glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.

Dual depletion of myeloid-derived suppressor cells and tumor cells with self-assembled gemcitabine-celecoxib nano-twin drug for cancer chemoimmunotherapy.

Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.

Sihler's staining technique: How to and guidance for botulinum neurotoxin injection in human muscles.

The Sihler's stain is a whole-mount nerve staining technique that allows visualization of the nerve distribution and permits mapping of the entire nerve supply patterns of the organs, skeletal muscles, mucosa, skin, and other structures that contain myelinated nerve fibers. Unlike conventional approaches, this technique does not require extensive dissection or slide preparation. To date, the Sihler's stain is the best tool for demonstrating the precise intramuscular branching and distribution patterns of skeletal muscles. The intramuscular neural distribution is used as a guidance tool for the application of botulinum neurotoxin injections. In this review, we have identified and summarized the ideal botulinum neurotoxin injection points for several human tissues.

[Treatment of chronic prostatitis with Xiongji Formula based on the concept of "brain-heart-kidney-essence chamber" axis of medication].

Chronic prostatitis is a process of kidney deficiency and blood stasis mixed with various pathological factors involving the essence chamber, which is manifested as kidney deficiency and blood stasis. Based on the concept of the "brain-heart-kidney-essence chamber" axis of medication, Xiongji Formula is applied to the treatment of chronic prostatitis, due to its "simultaneous holistic and local action" and effects of tonifying the kidney yang and assisting the systemic yang, acting on the brain, heart and kidney as a whole, and meanwhile activating blood circulation, eliminating blood stasis and restoring the function of the essence chamber. This paper discusses the etiology and pathogenesis of chronic prostatitis with kidney deficiency and blood stasis in Chinese medicine, expounds the significance of "brain-heart-kidney-essence chamber" axis of medication, and explores the specific value and clinical application of Xiongji Formula.

Surface Lattice Modulation Enables Stable Cycling of High-Loading All-solid-state Batteries at High Voltages.

Halide solid electrolytes, known for their high ionic conductivity at room temperature and good oxidative stability, face notable challenges in all-solid-state Li-ion batteries (ASSBs), especially with unstable cathode/solid electrolyte (SE) interface and increasing interfacial resistance during cycling. In this work, we have developed an Al3+-doped, cation-disordered epitaxial nanolayer on the LiCoO2 surface by reacting it with an artificially constructed AlPO4 nanoshell; this lithium-deficient layer featuring a rock-salt-like phase effectively suppresses oxidative decomposition of Li3InCl6 electrolyte and stabilizes the cathode/SE interface at 4.5 V. The ASSBs with the halide electrolyte Li3InCl6 and a high-loading LiCoO2 cathode demonstrated high discharge capacity and long cycling life from 3 to 4.5 V. Our findings emphasize the importance of specialized cathode surface modification in preventing SE degradation and achieving stable cycling of halide-based ASSBs at high voltages.

Surface Lattice Modulation through Chemical Delithiation toward a Stable Nickel-Rich Layered Oxide Cathode.

Nickel-rich layered oxides (NLOs) are considered as one of the most promising cathode materials for next-generation high-energy lithium-ion batteries (LIBs), yet their practical applications are currently challenged by the unsatisfactory cyclability and reliability owing to their inherent interfacial and structural instability. Herein, we demonstrate an approach to reverse the unstable nature of NLOs through surface solid reaction, by which the reconstructed surface lattice turns stable and robust against both side reactions and chemophysical breakdown, resulting in improved cycling performance. Specifically, conformal La(OH)3 nanoshells are built with their thicknesses controlled at nanometer accuracy, which act as a Li+ capturer and induce controlled reaction with the NLO surface lattices, thereby transforming the particle crust into an epitaxial layer with localized Ni/Li disordering, where lithium deficiency and nickel stabilization are both achieved by transforming oxidative Ni3+ into stable Ni2+. An optimized balance between surface stabilization and charge transfer is demonstrated by a representative NLO material, namely, LiNi0.83Co0.07Mn0.1O2, whose surface engineering leads to a highly improved capacity retention and excellent rate capability with a strong capability to inhibit the crack of NLO particles. Our study highlights the importance of surface chemistry in determining chemical and structural behaviors and paves a research avenue in controlling the surface lattice for the stabilization of NLOs toward reliable high-energy LIBs.

Pseudogene TDGF1P3 regulates the proliferation and metastasis of colorectal cancer cells via the miR-338-3p-PKM2 axis.

Research in the past decade has revealed significant roles of pseudogenes in colorectal cancer (CRC). Here, the role of teratocarcinoma-derived growth factor 1 pseudogene 3 (TDGF1P3) in regulating the proliferation and invasion of CRC cells was investigated; in addition, its downstream targets were analyzed, and the underlying mechanisms were elucidated. TDGF1P3 was determined to be upregulated in CRC cells and tissues. Silencing TDGF1P3 substantially repressed cell proliferation, migration, and invasion in vitro. Similarly, in vivo assays showed that TDGF1P3 knockdown attenuated tumor growth in nude mice. Mechanistic investigations revealed that TDGF1P3 directly bound to miR-338-3p, thereby preventing miR-338-3p from binding to its target mRNA pyruvate kinase M2 (PKM2). Functional rescue tests indicated that TDGF1P3 regulates CRC cell proliferation and invasion by restraining the miR-338-3p-PKM2 axis. Thus, these data illustrated that TDGF1P3 exerts its oncogenic activity by upregulating PKM2 via competitively binding miR-338-3p, which may be a therapeutic target for CRC.

Medical students' academic satisfaction: Social cognitive factors matter.

PURPOSE: Academic satisfaction (AS)-the extent to which people enjoy their role or experiences as medical students-has important implications for well-being and career development. This study explores the relationships between social cognitive factors and AS in a Chinese medical education context. METHOD: The social cognitive model of academic satisfaction (SCMAS) was adopted as the theoretical framework. Within this model, AS is assumed to be related to social cognitive factors-environmental supports, outcome expectations, perceived goal progress and self-efficacy. Demographic variables, financial pressure, college entrance examination scores and social cognitive constructs in SCMAS were collected. To explore the relationships between medical students' social cognitive factors and AS, hierarchical multiple regression analyses were performed. RESULTS: The final sampled data consisted of 127 042 medical students from 119 medical institutions. Demographic variables, financial pressure and college entrance examination scores were first entered in Model 1, explaining 4% of the variance in AS. Social cognitive factors were entered in Model 2, explaining an additional 39% of the variance. Medical students would report higher levels of AS when they (a) held strong confidence in their skills needed for success in studying medicine (ß = 0.20, p < 0.05), (b) had optimistic beliefs about the outcome of studying medicine (ß = 0.40, p < 0.05), (c) felt that they were making good progress in studying medicine (ß = 0.06, p < 0.05) and (d) believed that they received adequate environmental support (ß = 0.25, p < 0.05). The outcome expectations showed the strongest correlation with AS, and each 1-point increase was associated with 0.39 points on the AS score, controlling for all other factors in the model. CONCLUSIONS: Social cognitive factors play an important role in medical students' AS. Intervention programmes or courses aiming to improve medical students' AS are advised to consider social cognitive factors.

Opioids increase the risk of delirium in critically ill patients: A propensity score analysis.

BACKGROUND: Medications are biologically plausible and potentially modifiable risk factors for delirium. Therapies for delirium might involve more specific strategies such as avoiding the use of delirium-inducing drugs to reduce the incidence of delirium. The association between opioid exposure within 24 hours prior to delirium assessment and the risk of delirium was studied. MATERIALS AND METHODS: Using three large databases, the MIMIC III v1.4, MIMIC-IV v0.4 and eICU Collaborative Research, we performed a multicenter, observational cohort study with two cohorts to estimate the relative risks of outcomes among patients administered opioids within 24 hours prior to delirium assessment. Propensity score matching was performed to generate a balanced 1 : 1 matched cohort and to identify potential prognostic factors. The outcomes included mortality, length of intensive care unit (ICU) stay, length of hospitalization, and odds of being discharged home. RESULTS: Propensity matching successfully balanced the covariates for the 9,529 patients in each group. Opioid use was associated with a significantly higher risk for delirium than not using opioids (p < 0.001). Additionally, treatment with opioids was associated with higher mortality and a longer ICU stay (p < 0.001) than treatment without opioids. However, patients treated with opioids were more likely to be discharged home (p < 0.001). CONCLUSION: Opioids may be an independent risk factor for delirium in critically ill patients.

The local coupling and telecoupling of urbanization and ecological environment quality based on multisource remote sensing data.

Coordinating the relationship between urbanization and ecological environment quality (EEQ) is crucial to achieving sustainable development. With the development of globalization, the pattern of remote interaction between urbanization and EEQ has gradually increased. However, the current study on the coupling of urbanization and EEQ lacks a remote perspective, and the remote sensing ecological index (RSEI) model has not yet considered the environmental pollution caused by population agglomeration. For these reasons, this study proposes the remote sensing ecological environment index (RSEEI) model and measures the local coupling and telecoupling coordination degree (LTCCD) of urbanization and EEQ in China from 2000 to 2020. According to the results, the rate of change of EEQ in China was -0.00011a-1. RSEEI widens the gap between the east and west of EEQ, differentiated by the Heihe-Tengchong Line. China's urbanization is growing at a 0.0008a-1 rate, with a spatially driven radiation potential with Beijing, Shanghai, Hong Kong, and Macao as the core. LTCCD follows an increasing trend from inland to coastal and west to east. Over 70% of provinces experienced a shift in adjacent LTCCD levels, and 14 provinces moved from disorder to coordination after 2010. The telecoupling strengthens the correlation between urbanization and EEQ among regions compared with traditional coupling. In addition, the eastern coastal areas, the northern and central-south inland areas, and the northwest face different coordination problems.

Oxycodone-acetaminophen versus celecoxib for postoperative pain in knee osteoarthritis patients after total knee arthroplasty: a randomized, controlled study.

PURPOSE: Oxycodone-acetaminophen is a synergic combination of semisynthetic opioid agonis and analgesic/antipyretic agent, which improves analgesic efficacy. This randomized, controlled study intended to evaluate the analgesic efficacy and tolerance of oxycodone-acetaminophen compared to celecoxib alone in post-total knee arthroplasty (TKA) knee osteoarthritis patients. METHODS: One hundred and six knee osteoarthritis patients were randomized into oxycodone-acetaminophen group (N = 54) and celecoxib group (N = 52) at a 1:1 ratio. Each patient orally received oxycodone-acetaminophen (5 mg/325 mg, four times per day) or celecoxib (200 mg, twice per day) from 2 h to day (D) 3 after TKA; meanwhile, each patient received 2-day patient-controlled analgesia (PCA). The primary outcome was pain visual analog scale (VAS) score at rest; other assessments were the secondary outcomes. RESULTS: Pain VAS scores at rest at D1, D2, D3, and pain VAS scores at flexion at D0.5, D1, D2, D3 were lower in oxycodone-acetaminophen group compared to celecoxib group (all P < 0.050). Besides, extra (P < 0.001) and total (P < 0.001) PCA consumption were declined in oxycodone-acetaminophen group compared with celecoxib group. Furthermore, patients' satisfaction score at D3 (P = 0.012) and D7 (P = 0.043) was higher in oxycodone-acetaminophen group versus celecoxib group. Hospital for special surgery knee score (HSS) at preoperation, M1, and M3 did not differ between the two groups (all P > 0.050). The incidences of all adverse events were not varied between oxycodone-acetaminophen and celecoxib groups (all P > 0.050). CONCLUSION: Oxycodone-acetaminophen exerts superior analgesic efficacy, patients' satisfaction, and similar tolerance compared to celecoxib in post-TKA knee osteoarthritis patients.

Guidance in botulinum neurotoxin injection for lower extremity spasticity: Sihler's staining technique.

Spasticity is a motor disease characterized by a velocity-dependent acceleration in muscle tone or tonic stretch reflexes linked to hypertonia. Lower limb spasticity has been successfully treated with botulinum neurotoxin; however, the injection sites have not been generalized. Sihler's stain has been used to visualize intramuscular nerve distribution to guide botulinum neurotoxin injection. Sihler staining is a whole-mount nerve staining technique that allows visualization of nerve distribution and mapping of entire nerve supply patterns in skeletal muscle with hematoxylin-stained myelinated nerve fibers. This study reviewed and summarized previous lower extremity spasticity studies to determine the ideal injection site for botulinum neurotoxin.

Intramuscular neural distribution of the obturator internus muscle regarding injective treatment.

INTRODUCTION: The obturator internus muscle is frequently targeted for injective treatments such as botulinum toxin injections in the management of pain syndromes. However, there are controversies over injective method delivering injection to the muscle. METHOD: A method called modified Sihler's method was used to stain the OI muscle in 16 specimens to reveal the intramuscular neural distribution of the muscle. RESULT: The greatest intramuscular neural distribution was located on the 2/10-4/10 of the muscle in the medial edge of the obturator foramen (0/0) to the greater trochanter of the femur (10/10). CONCLUSION: The result suggests that botulinum neurotoxin should be delivered in the intrapelvic portion of the obturator internus muscle. As most of the extrapelvic portion of the obturator muscle is composed of a tendinous portion, it should be considered unsuitable as an injection site by medical professionals.

Sonoanatomy of the platysmal bands: What causes the platysmal band?

BACKGROUND: The platysmal band is created by the platysma muscle, a thin superficial muscle that covers the entire neck and the lower part of the face. The platysmal band appears at the anterior and posterior borders of the muscle. To date, no definite pathophysiology has been established. Here, we observed a lack of knowledge of the anatomy of the platysma muscle using ultrasonography in this study. METHODS: We conducted a descriptive, prospective study observing the platysmal band in resting and contraction states to reveal muscle changes. Twenty-four participants (aged 23-57 years) with anterior and posterior neck bands underwent ultrasonography in resting and contracted states. Ten cadavers were studied aged 67-85 years to measure the thickness of the platysma muscle at 12 points: horizontally (medial, middle, lateral) and vertically (inferior mandibular margin, hyoid bone, cricoid cartilage, superior margin of clavicle). RESULTS: The anterior and posterior borders of the platysma muscle were thicker than the middle of the platysma muscle when in a contracted state, and the muscle also had a convex shape when contracted. The thickness of the platysma muscle was not significantly different over 12 points in the resting state. During contraction, the platysma muscles contracted in the medial and lateral margins of the muscle, which was more significant in the posterior bands. CONCLUSION: The anterior and posterior platysmal bands are related to muscle thickness during contraction. These observations support the change in platysmal band treatment only at the anterior and posterior border of the muscle.

Bayesian semiparametric joint model of multivariate longitudinal and survival data with dependent censoring.

We consider a novel class of semiparametric joint models for multivariate longitudinal and survival data with dependent censoring. In these models, unknown-fashion cumulative baseline hazard functions are fitted by a novel class of penalized-splines (P-splines) with linear constraints. The dependence between the failure time of interest and censoring time is accommodated by a normal transformation model, where both nonparametric marginal survival function and censoring function are transformed to standard normal random variables with bivariate normal joint distribution. Based on a hybrid algorithm together with the Metropolis-Hastings algorithm within the Gibbs sampler, we propose a feasible Bayesian method to simultaneously estimate unknown parameters of interest, and to fit baseline survival and censoring functions. Intensive simulation studies are conducted to assess the performance of the proposed method. The use of the proposed method is also illustrated in the analysis of a data set from the International Breast Cancer Study Group.

Focal Segmental Glomerulosclerosis Followed by Acute Hepatitis A Infection: Case Report.

Background and Objectives: Chronic viral hepatitis such as hepatitis B or hepatitis C is frequently related to nephropathies, yet acute hepatitis A virus (HAV) infection is an exception. Materials and Methods: A 43-year-old male presented with jaundice accompanied by nausea and vomiting. The patient was diagnosed with acute HAV infection. Although the liver function improved after conservative treatment, various symptoms such as proteinuria, hypoalbuminemia, generalized edema and pleural effusion persisted. Due to nephrotic syndrome, the patient was referred to the clinic of the nephrology department and a renal biopsy was performed. Results: The result of the renal biopsy was focal segmental glomerulosclerosis (FSGS) based on histology, electron microscopy and immunohistochemistry. Therefore, based on the clinical history and biopsy results, the patient was diagnosed as having FSGS aggravated by acute HAV infection. Proteinuria, hypoalbuminemia and generalized edema were improved after prednisolone treatment. Conclusions: Although less common, acute HAV infection can also present with an extrahepatic manifestation, for example, FSGS. Hence, clinical attention is required if proteinuria or hypoalbuminemia persists in patients with acute HAV infection.

Shape Control of Carbon Nanoparticles via a Simple Anion-Directed Strategy for Precise Endoplasmic Reticulum-Targeted Imaging.

Herein, small-sized fluorescent carbon nanoparticles (CNs) with tunable shapes ranging from spheres to various rods with aspect ratios (ARs) of 1.00, 1.51, 1.89, and 2.85 are prepared using a simple anion-directed strategy for the first time. Based on comprehensive morphological and structural characteristics of CNs, along with theoretical calculations of density functional theory and molecular dynamics simulations, their shape-control mechanism is attributed to interionic interactions-induced self-assembly, followed by carbonization. The endoplasmic reticulum-targeting accuracy of CNs is gradually enhanced as their shape changes from spherical to higher-AR rods, accompanied by a Pearson's correlation coefficient up to 0.90. This work presents a facile approach to control the shape of CNs and reveals the relationship between the shape and organelle-targeting abilities of CNs, thereby providing a novel idea to synthesize CNs that serve as precise organelle-targeted fluorescent probes.

Coordination-Assisted Precise Construction of Metal Oxide Nanofilms for High-Performance Solid-State Batteries.

The application of solid-state batteries (SSBs) is challenged by the inherently poor interfacial contact between the solid-state electrolyte (SSE) and the electrodes, typically a metallic lithium anode. Building artificial intermediate nanofilms is effective in tackling this roadblock, but their implementation largely relies on vapor-based techniques such as atomic layer deposition, which are expensive, energy-intensive, and time-consuming due to the monolayer deposited per cycle. Herein, an easy and low-cost wet-chemistry fabrication process is used to engineer the anode/solid electrolyte interface in SSBs with nanoscale precision. This coordination-assisted deposition is initiated with polyacrylate acid as a functional polymer to control the surface reaction, which modulates the distribution and decomposition of metal precursors to reliably form a uniform crack-free and flexible nanofilm of a large variety of metal oxides. For demonstration, artificial Al2O3 interfacial nanofilms were deposited on a ceramic SSE, typically garnet-structured Li6.5La3Zr1.5Ta0.5O12 (LLZT), that led to a significant decrease in the Li/LLZT interfacial resistance (from 2079.5 to 8.4 Ω cm2) as well as extraordinarily long cycle life of the assembled SSBs. This strategy enables the use of a nickel-rich LiNi0.83Co0.07Mn0.1O2 cathode to deliver a reversible capacity of 201.5 mAh g-1 at a considerable loading of 4.8 mg cm-2, featuring performance metrics for an SSB that is competitive with those of traditional Li-ion systems. Our study demonstrates the potential of solution-based routes as an affordable and scalable manufacturing alternative to vapor-based deposition techniques that can accelerate the development of SSBs for practical applications.