Copper-Catalyzed Aromatization-Driven Ring-Opening Amination and Oxygenation of Spiro Dihydroquinazolinones.

Mild and inexpensive copper-catalyzed aromatization-driven ring-opening amination and oxygenation of spiro dihydroquinazolinones are presented, respectively. These protocols provide facile and atom-economical access to the aminated and the carbonyl-containing quinazolin-4(3H)-ones in good yields with good functional group compatibility, which are difficult to obtain by conventional methods. Remarkably, a telescoped procedure involving the condensation and the ring-opening/functionalization for simple cycloalkanone was found to be accessible. Mechanistic studies suggest a radical pathway for this transformation.

Evaluating the clinical efficacy of the anterolateral thigh flap in lower limb reconstruction surgeries: a systematic review and meta-analysis.

OBJECTIVE: To comprehensively assess the clinical efficacy of the anterolateral thigh flap in lower limb reconstruction (LLR) surgeries and explore its application value via a meta-analysis. METHODS: Published articles on the efficacy of anterolateral thigh flap in LLR were retrieved in English databases such as PubMed, Web of Science, Embase, and The Cochrane Library, which were searched from their inception to November 2023. The search terms included "anterolateral thigh flaps", "lower extremity", "free muscle" and "reconstruction". Subsequently, data extraction of eligible studies was carried out, and data analysis was conducted using RevMan 5.3 software. RESULTS: The final selection comprised 12 appropriate studies, encompassing a total of 577 patients. Meta-analysis demonstrated that negligible differences existed in the length of hospital stay among patients treated with different types of flaps (mean difference (MD) =-0.10, 95% confidence interval (CI) =-0.400.20, P>0.05). Additionally, the occurrence of complications differed slightly (Risk difference (RD) =-0.02, 95% CI=-0.090.05, P>0.05). The incidence of secondary surgeries also demonstrated non-significant differences (RD=-0.04, 95% CI=-0.11-0.04, P>0.05). Nevertheless, patients who underwent anterolateral thigh flap transplantation exhibited a drastic decrease in donor site morbidity (Odds ratio (OR) =0.22, 95% CI=0.10-0.49, P<0.05). CONCLUSION: The clinical efficacy of the anterolateral thigh flap in LLR surgeries shows no significant differences in hospital stay, complication rates, or the need for secondary surgeries compared to other flaps. However, using anterolateral thigh flap in LLR significantly reduces donor site morbidity.

A fluorescence-enhanced method specific for furfural determination in Chinese Baijiu based on luminescent carbon dots and direct surface reaction.

Detecting the furfural concentration in Baijiu can be used to assess the quality of Baijiu, allowing for the optimization of processing techniques and the enhancement of overall quality. In this paper, a fluorescence-enhanced method based on carbon dots (o-CDs) is developed for the furfural determination in Chinese Baijiu. In an environment full-filled with ·SO4- and ·OH, furfural undergone a direct surface reaction with the ortho-diamino groups at o-CDs. The created furan-based imidazole increased the surface electron density, leading an emission enhancement and color changes from orange to green. Thereby, a linear fluorescence response of o-CDs-TA to furfural is established in water with a detection limit of 30.5 nM. Finally, after ethanol correction it is used to determine furfural in Chinese Baijiu with high precision and reproducibility, providing a new strategy with low-cost and high sensitivity. In particular, the idea of covalently connecting target molecule to the CDs surface via the assistance of free radical opens a new avenue to merge the nanoscale and molecular realms through implementing chemical role into carbon nanostructures.

Molecular and cellular dynamics of the developing human neocortex at single-cell resolution.

The development of the human neocortex is a highly dynamic process and involves complex cellular trajectories controlled by cell-type-specific gene regulation 1 . Here, we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence. In parallel, we performed spatial transcriptomic analysis on a subset of the samples to illustrate spatial organization and intercellular communication. This atlas enables us to catalog cell type-, age-, and area-specific gene regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification, and lineage-tracing experiments, we have untangled the complex lineage relationships among progenitor subtypes during the transition from neurogenesis to gliogenesis in the human neocortex. We identified a tripotential intermediate progenitor subtype, termed Tri-IPC, responsible for the local production of GABAergic neurons, oligodendrocyte precursor cells, and astrocytes. Remarkably, most glioblastoma cells resemble Tri-IPCs at the transcriptomic level, suggesting that cancer cells hijack developmental processes to enhance growth and heterogeneity. Furthermore, by integrating our atlas data with large-scale GWAS data, we created a disease-risk map highlighting enriched ASD risk in second-trimester intratelencephalic projection neurons. Our study sheds light on the gene regulatory landscape and cellular dynamics of the developing human neocortex.

Photoredox-Catalyzed Sequential Decarboxylative/Defluorinative Aminoalkylation of CF3-Alkenes with N-Arylglycines.

A photoredox-catalyzed sequential decarboxylative/defluorinative aminoalkylation of CF3-alkenes with N-arylglycines is described. This metal-free and redox-neutral protocol provided efficient access to the monofluoroalkenyl-1,5-diamines in good yields with excellent functional group compatibility. Mechanistic studies revealed that the reaction proceeds via a radical pathway with the gem-difluoroalkenyl amine as an intermediate.

Deficiency of ValRS-m Causes Male Infertility in Drosophila melanogaster.

Drosophila spermatogenesis involves the renewal of germline stem cells, meiosis of spermatocytes, and morphological transformation of spermatids into mature sperm. We previously demonstrated that Ocnus (ocn) plays an essential role in spermatogenesis. The ValRS-m (Valyl-tRNA synthetase, mitochondrial) gene was down-regulated in ocn RNAi testes. Here, we found that ValRS-m-knockdown induced complete sterility in male flies. The depletion of ValRS-m blocked mitochondrial behavior and ATP synthesis, thus inhibiting the transition from spermatogonia to spermatocytes, and eventually, inducing the accumulation of spermatogonia during spermatogenesis. To understand the intrinsic reason for this, we further conducted transcriptome-sequencing analysis for control and ValRS-m-knockdown testes. The differentially expressed genes (DEGs) between these two groups were selected with a fold change of ≥2 or ≤1/2. Compared with the control group, 4725 genes were down-regulated (dDEGs) and 2985 genes were up-regulated (uDEGs) in the ValRS-m RNAi group. The dDEGs were mainly concentrated in the glycolytic pathway and pyruvate metabolic pathway, and the uDEGs were primarily related to ribosomal biogenesis. A total of 28 DEGs associated with mitochondria and 6 meiosis-related genes were verified to be suppressed when ValRS-m was deficient. Overall, these results suggest that ValRS-m plays a wide and vital role in mitochondrial behavior and spermatogonia differentiation in Drosophila.

Modular and Regioselective Synthesis of Benzo-Fused Five-Membered Rings Enabled by Co/Ti Synergism.

The regiocontrol in constructing benzo-fused five-membered rings by C-H cyclization remains an important challenge. We report a highly general and regioselective methodology to access such heterocycles and indenones, where under the catalysis of CoBr2/bipyridine, aryl titanates, alkynes and EX2 (E = NR, S(O), RP(O), R2Si, CO, etc.) were assembled to various heterocycles and indenones in a modular manner. Unprecedented 1,2-Co/Ti heterobimetallic arylene and benzotitanole intermediates have played crucial roles in these syntheses.

Metal-free, photoredox-catalyzed aromatization-driven deconstructive functionalization of spiro-dihydroquinazolinones with α-CF3 alkenes.

Metal-free, photoredox-catalyzed aromatization-driven deconstructive functionalization of spiro-dihydroquinazolinones with α-CF3 alkenes is presented. The readily available spiro-dihydroquinazolinones reacted efficiently with α-CF3 alkenes during photocatalysis to give the gem-difluoroallylated and the CF3-containing quinazolin-4(3H)-ones in good yields with excellent chemoselectivity. The selectivity depends on the electron effect of substituents in α-CF3 alkenes. A wide range of four-, five-, six-, seven-, eight- and twelve-membered spiro-dihydroquinazolinones were compatible with this transformation. The protocol is also characterized by the mild and redox-neutral reaction conditions, good functional group compatibility and excellent atom economy. Mechanistic studies revealed that the reaction proceeds via a radical pathway.

Random forest predictive modeling of prolonged hospital length of stay in elderly hip fracture patients.

Background: In elderly individuals suffering from hip fractures, a prolonged hospital length of stay (PLOS) not only heightens the probability of patient complications but also amplifies mortality risks. Yet, most elderly hip fracture patients present compromised baseline health conditions. Additionally, PLOS leads to increased expenses for patient treatment and care, while also diminishing hospital turnover rates. This, in turn, jeopardizes the prompt allocation of beds for urgent cases. Methods: A retrospective study was carried out from October 2021 to November 2023 on 360 elderly hip fracture patients who underwent surgical treatment at West China Hospital. The 75th percentile of the total patient cohort's hospital stay duration, which was 12 days, was used to define prolonged hospital length of stay (PLOS). The cohort was divided into training and testing datasets with a 70:30 split. A predictive model was developed using the random forest algorithm, and its performance was validated and compared with the Lasso regression model. Results: Out of 360 patients, 103 (28.61%) experienced PLOS. A Random Forest classification model was developed using the training dataset, identifying 10 essential variables. The Random Forest model achieved perfect performance in the training set, with an area under the curve (AUC), balanced accuracy, Kappa value, and F1 score of 1.000. In the testing set, the model's performance was assessed with an AUC of 0.846, balanced accuracy of 0.7294, Kappa value of 0.4325, and F1 score of 0.6061. Conclusion: This study aims to develop a prognostic model for predicting delayed discharge in elderly patients with hip fractures, thereby improving the accuracy of predicting PLOS in this population. By utilizing machine learning models, clinicians can optimize the allocation of medical resources and devise effective rehabilitation strategies for geriatric hip fracture patients. Additionally, this method can potentially improve hospital bed turnover rates, providing latent benefits for the healthcare system.

Computational Studies of Reactions of 1,2,4,5-Tetrazines with Enamines in MeOH and HFIP.

The reaction between 1,2,4,5-tetrazines and alkenes in polar solvents proceeds through a Diels-Alder cycloaddition along the C-C axis (C3/C6 cycloaddition) of the tetrazine, followed by dinitrogen loss. By contrast, the reactions of 1,2,4,5-tetrazines with enamines in hexafluoroisopropanol (HFIP) give 1,2,4-triazine products stemming from a formal Diels-Alder addition across the N-N axis (N1/N4 cycloaddition). We explored the mechanism of this interesting solvent effect through DFT calculations in detail and revealed a novel reaction pathway characterized by C-N bond formation, deprotonation, and a 3,3-sigmatropic rearrangement. The participation of an HFIP molecule was found to be crucial to the N1/N4 selectivity over C3/C6 due to the more favored initial C-N bond formation than C-C bond formation.

Lewis Acid-Catalyzed Formal [2π+2σ] Cycloaddition of Bicyclobutanes with Quinoxalin-2(1H)-ones: Access to Quinoxaline-Fused Aza-Bicyclo[2.1.1]hexanes.

An efficient synthesis of quinoxaline-fused aza-bicyclo[2.1.1]hexanes bearing multiple quaternary carbon centers via the intermolecular [2π+2σ] cycloaddition of bicyclo[1.1.0]butanes and quinoxalin-2(1H)-ones, facilitated by Lewis acid catalysis, is presented. This reaction is carried out under mild conditions and exhibits a broad substrate scope and excellent functional group tolerance.

A case of scrub typhus with meningitis as the onset: Case report and literature review.

RATIONALE: Scrub typhus is a naturally occurring acute febrile disease caused by Orientia tsutsugamushi. Although it can cause multiple organ dysfunction, central nervous system infections are uncommon. PATIENT CONCERNS: A 17-year-old male presented with a 5-day history of fever and headaches. The MRI of the head revealed thickness and enhancement of the left temporal lobe and tentorium cerebelli, indicating potential inflammation. DIAGNOSES: The patient was diagnosed with a central nervous system infection. INTERVENTIONS: Ceftriaxone and acyclovir were administered intravenously to treat the infection, reduce fever, restore acid-base balance, and manage electrolyte disorders. OUTCOMES: Despite receiving ceftriaxone and acyclovir as infection therapy, there was no improvement. Additional multipathogen metagenomic testing indicated the presence of O tsutsugamushi infection, and an eschar was identified in the left axilla. The diagnosis was changed to scrub typhus with meningitis and the therapy was modified to intravenous doxycycline. Following a 2-day therapy, the body temperature normalized, and the fever subsided. CONCLUSIONS: The patient was diagnosed with scrub typhus accompanied by meningitis, and doxycycline treatment was effective. LESSION: Rarely reported cases of scrub typhus with meningitis and the lack of identifiable symptoms increase the chance of misdiagnosis or oversight. Patients with central nervous system infections presenting with fever and headache unresponsive to conventional antibacterial and antiviral treatment should be considered for scrub typhus with meningitis. Prompt multipathogen metagenomic testing is recommended to confirm the diagnosis and modify the treatment accordingly.

Aromatization-driven deconstructive functionalization of spiro dihydroquinazolinones via dual photoredox/nickel catalysis.

Aromatization-driven deconstruction and functionalization of spiro dihydroquinazolinones via dual photoredox/nickel catalysis is developed. The aromatization effect was introduced to synergistically drive unstrained cyclic C-C bond cleavage, with the aim of overcoming the ring-size limitation of nitrogen-centered radical induced deconstruction of carbocycles. Herein, we demonstrate the synergistic photoredox/nickel catalyzed deconstructive cross-coupling of spiro dihydroquinazolinones with organic halides. Remarkably, structurally diverse organic halides including aryl, alkenyl, alkynyl, and alkyl bromides were compatible for the coupling. In addition, this protocol is also characterized by its mild and redox-neutral conditions, excellent functional group compatibility, high atom economy, and easy scalability. A telescoped procedure involving condensation and ring-opening/coupling was found to be accessible. This work provides a complementary strategy to the existing radical-mediated C-C bond cleavage of unstrained carbocycles.

Role of calcineurin in regulating renal potassium (K+) excretion: Mechanisms of calcineurin inhibitor-induced hyperkalemia.

Calcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium-dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na+ and K+ transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting-related-receptor-with-A-type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2. Calcineurin also participates in regulating thiazide-sensitive NaCl-cotransporter (NCC) in the distal convoluted tubule. The mechanisms by which calcineurin regulates NCC include directly dephosphorylation of NCC, regulating Kelch-like-3/CUL3 E3 ubiquitin-ligase complex, which is responsible for WNK (with-no-lysin-kinases) ubiquitination, and inhibiting Kir4.1/Kir5.1, which determines NCC expression/activity. Finally, calcineurin is also involved in regulating ROMK (Kir1.1) channels in the cortical collecting duct and Cyp11 2 expression in adrenal zona glomerulosa. In summary, calcineurin is involved in the regulation of NKCC2, NCC, and inwardly rectifying K+ channels in the kidney, and it also plays a role in modulating aldosterone synthesis in adrenal gland, which regulates epithelial-Na+-channel expression/activity. Thus, application of calcineurin inhibitors (CNIs) is expected to abrupt calcineurin-mediated regulation of transepithelial Na+ and K+ transport in the kidney. Consequently, CNIs cause hypertension, compromise renal K+ excretion, and induce hyperkalemia.

Perivascular neurons instruct 3D vascular lattice formation via neurovascular contact.

The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.

Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration.

Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We found that OPTN C-terminus truncation (OPTN∆C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a striking decrease of axonal mitochondria. Surprisingly, we discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C-terminus dependent manner. Encouragingly, overexpressing OPTN/TRAK1/KIF5B reverses not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes striking ON regeneration. Therefore, in addition to generating new animal models for NTG and ALS, our results establish OPTN as a novel facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.

A review of biomacromolecule-based 3D bioprinting strategies for structure-function integrated repair of skin tissues.

When skin is damaged or affected by diseases, it often undergoes irreversible scar formation, leading to aesthetic concerns and psychological distress for patients. In cases of extensive skin defects, the patient's life can be severely compromised. In recent years, 3D printing technology has emerged as a groundbreaking approach to skin tissue engineering, offering promising solutions to various skin-related conditions. 3D bioprinting technology enables the precise fabrication of structures by programming the spatial arrangement of cells within the skin tissue and subsequently printing skin replacements either in a 3D bioprinter or directly at the site of the defect. This study provides a comprehensive overview of various biopolymer-based inks, with a particular emphasis on chitosan (CS), starch, alginate, agarose, cellulose, and fibronectin, all of which are natural polymers belonging to the category of biomacromolecules. Additionally, it summarizes artificially synthesized polymers capable of enhancing the performance of these biomacromolecule-based bioinks, thereby composing hybrid biopolymer inks aimed at better application in skin tissue engineering endeavors. This review paper examines the recent advancements, characteristics, benefits, and limitations of biological 3D bioprinting techniques for skin tissue engineering. By utilizing bioinks containing seed cells, hydrogels with bioactive factors, and biomaterials, complex structures resembling natural skin can be accurately fabricated in a layer-by-layer manner. The importance of biological scaffolds in promoting skin wound healing and the role of 3D bioprinting in skin tissue regeneration processes is discussed. Additionally, this paper addresses the challenges and constraints associated with current 3D bioprinting technologies for skin tissue and presents future perspectives. These include advancements in bioink formulations, full-thickness skin bioprinting, vascularization strategies, and skin appendages bioprinting.

Photoredox-catalyzed alkylarylation of activated alkenes via a ring-opening/Truce-Smiles rearrangement cascade.

A photoredox-catalyzed alkylarylation of activated alkenes via a radical C-C bond cleavage/Truce-Smiles rearrangement cascade is developed. The protocol features mild and redox-neutral conditions, broad substrate scope and excellent functional group compatibility, providing a facile and efficient approach to the long-chain distal keto-amides with all-carbon quaternary centers at the alpha position.