Asymmetric 1,n-Remote Aminoacetoxylation of Unactivated Internal Alkenes Enabled by Palladium Catalysis.

A palladium-catalyzed asymmetric 1,n-remote aminoacetoxylation of cis-alkenes has been developed using PhI(OAc)2 as an oxidant, providing the acetoxylated lactams with excellent enantioselectivities under mild reaction conditions. The sterically hindered pyridine-oxazoline (Pyox) L3 with a tert-butyl group in oxazoline ring and propyl group in C6 position of pyridinyl is vital for the reaction, where the former is good for asymmetric aminopalladation step and the latter for the chain walking process. The enantioenriched lactam products were proven to be good building blocks for the synthesis of azabicycles.

Palladium-Catalyzed Remote Hydrosulfonamidation of Alkenes: Access to Primary N-Alkyl Sulfamides by the SuFEx Reaction.

Herein, we establish a remote hydrosulfonamidation (HSA) of alkenes using palladium catalysis, where N-fluoro-N-(fluoro-sulfonyl)-carbamate with a sulfur(VI) fluoride moiety is demonstrated as a good amidation reagent. The anti-Markovnikov HSA reaction of terminal alkenes and the remote HSA of internal alkenes are achieved to efficiently yield primary N-alkyl-N-(fluorosulfonyl)-carbamates. In addition, this protocol enables the high-value utilization of alkane by combining the dehydrogenation process. The generated N-alkyl products exhibit a unique reactivity of sulfur(VI) fluorides, which can be directly transferred to N-alkyl sulfamides or amines via the sulfur(VI) fluoride exchange reaction, thereby streamlining their synthesis. Moreover, a (pyridyl) benzazole-type ligand proved to be vital for the excellent chemo- and regioselectivities.

MSI-DTI: predicting drug-target interaction based on multi-source information and multi-head self-attention.

Identifying drug-target interactions (DTIs) holds significant importance in drug discovery and development, playing a crucial role in various areas such as virtual screening, drug repurposing and identification of potential drug side effects. However, existing methods commonly exploit only a single type of feature from drugs and targets, suffering from miscellaneous challenges such as high sparsity and cold-start problems. We propose a novel framework called MSI-DTI (Multi-Source Information-based Drug-Target Interaction Prediction) to enhance prediction performance, which obtains feature representations from different views by integrating biometric features and knowledge graph representations from multi-source information. Our approach involves constructing a Drug-Target Knowledge Graph (DTKG), obtaining multiple feature representations from diverse information sources for SMILES sequences and amino acid sequences, incorporating network features from DTKG and performing an effective multi-source information fusion. Subsequently, we employ a multi-head self-attention mechanism coupled with residual connections to capture higher-order interaction information between sparse features while preserving lower-order information. Experimental results on DTKG and two benchmark datasets demonstrate that our MSI-DTI outperforms several state-of-the-art DTIs prediction methods, yielding more accurate and robust predictions. The source codes and datasets are publicly accessible at https://github.com/KEAML-JLU/MSI-DTI.

The clinical features of severe COVID-19 with respiratory failure: A Chinese single-center retrospective study.

The global pandemic of COVID-19, caused by the novel coronavirus SARS-CoV-2, has resulted in widespread alterations to public health measures worldwide. This observational study aimed to assess the clinical features and results of respiratory failure in patients with severe COVID-19. A single-center observational study was performed at a Chinese hospital between November 1, 2022, and February 31, 2023. All 182 enrolled patients were diagnosed with respiratory failure, 84 patients were infected with COVID-19, and the other 98 patients were not infected. A review of available medical records at admission and discharge, including neuroimaging, laboratory values at admission, mortality, length of hospitalization, and hospital costs, was conducted during the COVID-19 pandemic. All 182 eligible patients completed the follow-up. There was no significant difference in baseline characteristics between respiratory failure combined with COVID-19 (P > .05). Respiratory failure combined with COVID-19 infection may lead to higher 30-day mortality (16.36% vs 7.14%, P = .005), longer hospital stays (22.5 ±â€…5.9 vs 12.8 ±â€…4.2, P < .001), larger hospitalization costs (P < .001), and increased hospitalization complications, such as pulmonary embolism (10.30% vs 4.76%, P = .039), deep vein thrombosis (33.33% vs 18.57%, P = .001), incidence of 7-day delirium (69.70% vs 46.19%, P < .001), and respiratory failure (38.18% vs 24.77%, P = .005). If respiratory failure occurs while the patient is infected with COVID-19, treatment and prognosis worsen. Our understanding of COVID-19 and the care we provide to patients with respiratory failure is crucial to better prepare for a potential pandemic.

Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease.

The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.

Site-Selective sp2 C-H Cyanation of Allenes via Copper-Catalyzed Radical Relay.

Compared with the extensively reported hydrogen atom transfer (HAT) at sp3 C-H, abstraction of hydrogen atoms at the sp2 carbon is extremely rare. Here, we communicate the site-selective cyanation of the sp2 C-H bond of allenes using the strategy of copper-catalyzed radical relay. The reactions afford various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. These reactions exhibit excellent site-selectivity toward sp2 C-H, which can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical. The favorable HAT on sp2 C-H is due to crucial hydrogen bonding between the fluoride bonded to the Cu(II) center and the hydrogen atom at the allylic position. These features enable the late-stage functionalization of druglike bioactive molecules containing an allene motif.

Effects of DJ­1 on apoptosis and mitophagy of glomerular podocytes.

By studying the effects of DJ-1 overexpression and silencing on the morphological structure and mitophagy of glomerular podocytes, the present study aimed to identify the effects of DJ-1 on glomerular podocyte apoptosis and mitophagy. MPC5 mouse glomerular podocytes were cultured in vitro and divided into four groups: Control, DJ-1 overexpression, empty vector and DJ-1 silencing. DJ-1 gene overexpression and silencing models were prepared, the morphological structures of podocytes and mitochondria in each group were observed, and podocyte apoptosis and DJ-1/PTEN expression were subsequently detected in each group. The experimental results showed reduced volume, retracted foot processes, loosened intercellular connections, presence of dead cells, increased apoptotic rate, increased expression of PTEN, and swollen mitochondria due to the number of vacuoles and autophagosomes in podocytes in the DJ-1 silencing group. The surface areas of podocytes in the DJ-1 overexpression group were greater than those in the control group. Moreover, the structure of the foot processes was more obvious, the number of cells was greater, the intercellular connections were closer, the apoptotic rate was reduced, the expression of PTEN was decreased, the mitochondrial structure was more obvious and the mitochondrial cristae were more whole. Notably, there were no differences between the empty vector and control groups. In conclusion, these results indicated that DJ-1 may regulate podocyte apoptosis and mitophagy through the DJ-1/PTEN pathway, and could maintain the stability of the normal morphology, structure and function of glomerular podocytes.

Fungal small RNAs ride in extracellular vesicles to enter plant cells through clathrin-mediated endocytosis.

Small RNAs (sRNAs) of the fungal pathogen Botrytis cinerea can enter plant cells and hijack host Argonaute protein 1 (AGO1) to silence host immunity genes. However, the mechanism by which these fungal sRNAs are secreted and enter host cells remains unclear. Here, we demonstrate that B. cinerea utilizes extracellular vesicles (EVs) to secrete Bc-sRNAs, which are then internalized by plant cells through clathrin-mediated endocytosis (CME). The B. cinerea tetraspanin protein, Punchless 1 (BcPLS1), serves as an EV biomarker and plays an essential role in fungal pathogenicity. We observe numerous Arabidopsis clathrin-coated vesicles (CCVs) around B. cinerea infection sites and the colocalization of B. cinerea EV marker BcPLS1 and Arabidopsis CLATHRIN LIGHT CHAIN 1, one of the core components of CCV. Meanwhile, BcPLS1 and the B. cinerea-secreted sRNAs are detected in purified CCVs after infection. Arabidopsis knockout mutants and inducible dominant-negative mutants of key components of CME pathway exhibit increased resistance to B. cinerea infection. Furthermore, Bc-sRNA loading into Arabidopsis AGO1 and host target gene suppression are attenuated in those CME mutants. Together, our results demonstrate that fungi secrete sRNAs via EVs, which then enter host plant cells mainly through CME.

Fungal small RNAs ride in extracellular vesicles to enter plant cells through clathrin-mediated endocytosis.

Small RNAs (sRNAs) of the fungal pathogen Botrytis cinerea can enter plant cells and hijack host Argonaute protein 1 (AGO1) to silence host immunity genes. However, the mechanism by which these fungal sRNAs are secreted and enter host cells remains unclear. Here, we demonstrate that B. cinerea utilizes extracellular vesicles (EVs) to secrete Bc-sRNAs, which are then internalized by plant cells through clathrin-mediated endocytosis (CME). The B. cinerea tetraspanin protein, Punchless 1 (BcPLS1), serves as an EV biomarker and plays an essential role in fungal pathogenicity. We observe numerous Arabidopsis clathrin-coated vesicles (CCVs) around B. cinerea infection sites and the colocalization of B. cinerea EV marker BcPLS1 and Arabidopsis CLATHRIN LIGHT CHAIN 1, one of the core components of CCV. Meanwhile, BcPLS1 and the B. cinerea-secreted sRNAs are detected in purified CCVs after infection. Arabidopsis knockout mutants and inducible dominant-negative mutants of key components of the CME pathway exhibit increased resistance to B. cinerea infection. Furthermore, Bc-sRNA loading into Arabidopsis AGO1 and host target gene suppression are attenuated in those CME mutants. Together, our results demonstrate that fungi secrete sRNAs via EVs, which then enter host plant cells mainly through CME.

[Analgesic effect of buccal acupuncture on patients after lumbar spinal fusion: a randomized controlled trial].

OBJECTIVE: To observe the effect of buccal acupuncture on pain after lumbar spinal fusion. METHODS: Sixty patients undergoing lumbar spinal fusion were randomly divided into an observation group (30 cases, 1 case dropped off) and a control group (30 cases, 1 case was eliminated). The patients in the control group were treated with routine anesthesia. On the basis of the control group, the patients in the observation group were treated with buccal acupuncture at bilateral back point, waist point, and sacral point for 30 min per treatment. The first acupuncture was given before anesthesia induction, and then once a day postoperation for two days, totally 3 treatments. The dosage of sufentanil, the number of remedial analgesia, and the incidence of nausea and vomiting within 48 h after surgery were compared between the two groups; rest and motion visual analogue scale (VAS) scores at 2 (T1), 8 (T2), 12 (T3), 24 (T4), and 48 (T5) h after surgery were observed; the quality of recovery-15 scale (QoR-15) at 24 and 48 h after surgery were evaluated. RESULTS: The dosage of sufentanil and the number of remedial analgesia within 48 h after surgery in the observation group were lower than those in the control group (P<0.01). There was no significant statistically difference in rest and motion VAS scores between the two groups in T1, T2, T3, T4 and T5 (P>0.05). The QoR-15 scores in the observation group at 24 and 48 h after surgery were higher than those in the control group (P<0.01). The incidence of nausea in the observation group was lower than that in the control group (P<0.05). CONCLUSION: Buccal acupuncture could reduce the amount of postoperative analgesic drugs of patients after lumbar spinal fusion, and promote early postoperative recovery.

Copper-Catalyzed Asymmetric Functionalization of Vinyl Radicals for the Access to Vinylarene Atropisomers.

A novel asymmetric radical strategy for the straightforward synthesis of atropisomerically chiral vinyl arenes has been established herein, proceeding through copper-catalyzed atroposelective cyanation/azidation of aryl-substituted vinyl radicals. Critical to the success of the radical relay process is the atroposelective capture of the highly reactive vinyl radicals with chiral L*Cu(II) cyanide or azide species. Moreover, these axially chiral vinylarene products can be easily transformed into atropisomerically enriched amides and amines, enantiomerically enriched benzyl nitriles via an axis-to-center chirality transfer process, and an atropisomerically pure organocatalyst for the chemo-, diastereo-, and enantioselective (4 + 2) cyclization reaction.

Regio- and enantioselective remote dioxygenation of internal alkenes.

Methods for the enantioselective direct oxygenation of internal alkenes have provided chemists with versatile and powerful toolboxes for the synthesis of optically pure alcohols, one of the most privileged structural motifs. Regioselectivity, however, remains a formidable challenge in the functionalization of internal alkenes. Here we report a palladium-catalysed highly regio- and enantioselective remote 1,n-dioxygenation (n ≥ 4) of internal alkenes with engineered pyridine-oxazoline (Pyox) ligands. The reactions proceed efficiently and exhibit a broad substrate scope with excellent regio- and enantioselectivity, affording optically pure 1,n-diol acetates as the key synthons for important bioactive molecules. Experimental studies and density functional theory calculations provide evidence that the regioselectivity is governed by the reactivity disparity of two allylic C-H bonds, where the oxypalladation is reversible and the first palladium migration step proves to be the regioselectivity-determining step, enabled by the modified phenyl-substituted Pyox ligands.

Correlation of ABO blood groups with treatment response and efficacy in infants with persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide.

OBJECTIVE: Not all infants with persistent pulmonary hypertension of the newborn (PPHN) respond to inhaled nitric oxide (iNO) therapy, as it is known to improve oxygenation in only 50% to 60% of cases. In this study, we investigated whether ABO blood groups were a relevant factor affecting the improvement of oxygenation by nitric oxide (NO) therapy in infants with PPHN. METHODS: This study was a retrospective, multicenter, and cohort-controlled trial that involved 37 medical units. Infants with PPHN who met the inclusion criteria and were treated with NO (a vasodilator) alone from July 1, 2015, to June 30, 2020, were selected and assigned into three groups: blood type A, blood type B, and blood type O (there were only 7 cases of blood type AB, with a small number of cases, and therefore, blood type AB was excluded for further analysis). The response to iNO therapy was defined as an increase in the ratio of the partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) > 20% from the basal value after treatment. Oxygenation was assessed mainly based on the two values, oxygenation index (OI) and PaO2/FiO2. The correlation of ABO blood groups with responses to iNO therapy and their influence on the efficacy of iNO therapy was analyzed based on the collected data. RESULTS: The highest proportion of infants with PPHN who eventually responded to iNO therapy was infants with blood type O. Infants with blood type O more readily responded to iNO therapy than infants with blood type B. Oxygenation after iNO treatment group was optimal in the blood type O group and was the worst in the blood type A group among the three groups. Infants with blood type O showed better efficacy than those with blood types A and B. CONCLUSION: ABO blood groups are correlated with responses to iNO therapy in infants with PPHN, and different blood groups also affect the efficacy of NO therapy in infants with PPHN. Specifically, infants with blood type O have a better response and experience the best efficacy to iNO therapy.

ATG13 is involved in immune response of pathogen invasion in blood clam Tegillarca granosa.

Mammalian autophagy-related gene 13 (ATG13) is a vital component of the ATG1 autophagy initiation complex which plays an essential role in autophagy. However, the molecular function of ATG13 in pathogen defense in invertebrates is still poorly understood. In this study, the full-length cDNA sequence of blood clam Tegillarca granosa ATG13 (TgATG13) was obtained, which was 1,918 bp in length, including 283 bp 5' UTR, 252 bp 3' UTR and 1,383 bp open reading frame (ORF) encoding 460 amino acids. Phylogenetic analysis revealed that TgATG13 had the closest relationship with that of Crassostrea Virginica. Quantitative real-time PCR results showed that the transcript of TgATG13 was universally expressed in various tissues of blood clam, with the highest expression level in hemocytes. The expression level of TgATG13 was robustly increased after exposure of both Vibrio alginolyticus and LPS. Fluorescence confocal microscopy further showed that TgATG13 promoted the production of autophagosome. In summary, our study demonstrated that TgATG13 was involved in the immune regulation of blood clam during pathogen invasion, deepening our understanding of the innate immune mechanism of blood clam.

Enantioselective cyanation of propargylic C-H bonds via cooperative photoredox and copper catalysis.

Herein, we report an enantioselective cyanation of propargylic C-H bonds by combining photoredox catalysis with a copper-catalyzed radical relay in which the propargylic radical was generated by an intramolecular 1,5-HAT process. This reaction provides easy access to optically pure propargyl nitrile compounds under mild conditions.

Serum Anion Gap Level Predicts All-Cause Mortality in Septic Patients: A Retrospective Study Based on the MIMIC III Database.

PURPOSE: Sepsis is a significant threat in the intensive care unit (ICU) worldwide because it has high morbidity and mortality rates. Early recognition and diagnosis of sepsis are essential for the prevention of adverse outcomes. The present study aimed to quantitatively assess the association between serum anion gap (AG) levels and 30- and 90-day all-cause mortality among sepsis patients. METHODS: Clinical data of patients diagnosed with sepsis were extracted from the Medical Information Mart for Intensive Care III (MIMIC III) database. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association between serum AG levels and all-cause mortality. A receiver operating characteristic (ROC) curve was drawn to quantify the efficacy of using the serum AG level to predict all-cause mortality. RESULTS: A total of 3811 patients were included in the study. The Kaplan-Meier curves showed that patients with higher serum AG levels had a shorter survival time than those with lower levels. Serum AG levels were found to be highly effective in predicting all-cause mortality secondary to sepsis (30-day: AUROC = 0.703; 90-day: AUROC = 0.696). The Cox regression model further indicated that the serum AG level was an independent risk factor for 30- and 90-day mortality in sepsis (HR 3.44, 95% CI 2.97-3.99 for 30-day; HR 3.17, 95% CI 2.76-3.65 for 90-day, P < 0.001 for both). CONCLUSIONS: High serum AG may be considered as an alternative parameter for predicting the death risk in sepsis when other variables are not immediately available. Prospective large-scale studies are needed to support its predictive value in the clinic.

Palladium-Catalyzed Remote Hydro-Oxygenation of Internal Alkenes: An Efficient Access to Primary Alcohols.

As a general method for the synthesis of alcohols, the direct oxygenation of alkenes is difficult to afford linear alcohols. Herein, we communicate the remote hydro-oxygenation of alkenes under palladium catalysis, in which both terminal and internal alkenes are suitable to yield the corresponding linear alcohols efficiently. A compatible SelectFluor/silane redox system plays an essential role for the excellent chemo- and regioselectivities. The reaction features a broad substrate scope and excellent functional group compatibility.

Apgar scores correlate with survival rate at discharge in extremely preterm infants with gestational age of 25-27 weeks.

Low Apgar score is associated with increased risk of death in preterm or full-term infants. However, the use of Apgar score to assess extremely preterm (EP) infants is controversial. In this study, we characterized the distribution of Apgar scores in EP infants with gestational age between 25 and 27 weeks, and investigated the association of Apgar score with survival rate at discharge by analyzing the clinical data of the EP infants discharged between January 2008 and December 2017 from 26 neonatal intensive care units in Guangdong Province, China. A total of 1567 infants with gestational age of 26.84±0.79 weeks and birth weight of 951±169 grams were involved in our study. The Apgar score increased with gestational age from 25 to 27 weeks and with time from birth from 1 to 10 min. The survival rate increased with a higher Apgar score, but no significant difference was found for 1-min Apgar score and the survival rate between infants with 25 or 26 weeks of gestation or 5-min Apgar score in infants with 25 weeks of gestation. The Apgar score is associated with survival of EP infants.

Electrophotocatalytic Decoupled Radical Relay Enables Highly Efficient and Enantioselective Benzylic C-H Functionalization.

Asymmetric sp3 C-H functionalization has been demonstrated to substantially expedite target molecule synthesis, spanning from feedstocks upgradation to late-stage modification of complex molecules. Herein, we report a highly efficient and sustainable method for enantioselective benzylic C-H cyanation by merging electrophoto- and copper catalysis. A novel catalytic system allows one to independently regulate the hydrogen atom transfer step for benzylic radical formation and speciation of Cu(II)/Cu(I) to effectively capture the transient radical intermediate, through tuning the electronic property of anthraquinone-type photocatalyst and simply modulating the applied current, respectively. Such decoupled radical relay catalysis enables a unified approach for enantioselective benzylic C-H cyanation of diverse alkylarenes, many of which are much less reactive or even unreactive using the existing method relying on coupled radical relay. Moreover, the current protocol is also amenable to late-stage functionalization of bioactive molecules, including natural products and drugs.

Usnic Acid extends healthspan and improves the neurodegeneration diseases via mTOR/PHA-4 signaling pathway in Caenorhabditis elegans.

The Mammalian/mechanistic target of rapamycin (mTOR) played a central role in cellular survival and aging. Inhibition of mTOR had been proposed as a reasonable strategy to promote lifespan and delay age-related diseases in evolutionarily diverse organisms. The study showed that lifespan extension and age-related diseases improvement could be achieved by targeting evolutionarily conserved mTOR pathways and mechanisms using pharmacological interventions. Using this approach in Caenorhabditis elegans, We found that 2 µM Usnic Acid significantly extended the healthy lifespan in wild-type animals. Furthermore, via genetic screen, we showed that Usnic Acid acted on mTOR, which was followed by the activation of PHA-4/Foxa to extend the healthy lifespan. Intriguingly, Usnic Acid also delayed neurodegeneration diseases such as Alzheimer's and polyglutamine disease through mTOR-dependent manner. Our work suggested that Usnic Acid might be a viable candidate for the prevention and treatment of aging and age-related diseases.