Stereoselective Synthesis of Tri- and Tetrasubstituted Allylsilanes via Copper-Catalyzed Decarboxylative Silylation of Vinylethylene Carbonates.

Herein, a stereoselective copper-catalyzed decarboxylative silylation of readily available vinylethylene carbonates (VECs) with PhMe2Si-Bpin is reported, affording a wide range of tri- and tetrasubstituted allylsilanes in moderate to high yields with E-selectivity. This protocol was characterized by high stereoselectivity, broad substrate scope, operational simplicity, and mild reaction conditions, which were amenable to diverse derivatizations and gram-scale synthesis.

Dithiolation of Alkenyl Sulfonium Salts with Arylthiols to Access 1,2-Dithioalkanes.

A dithiolation of alkenyl sulfonium salts with arylthiols is described, affording a series of 1,2-dithioalkanes in high yields. This protocol features mild and catalyst-free conditions and involves the formation of two C-S bonds sequentially via the regioselective addition of an arylthiol to the unsaturated C═C bonds, followed by the attack of another arylthiol to form 1,2-dithioalkanes exclusively.

Prevalence of depressive and anxiety symptoms among Chinese older adults during the COVID-19 pandemic: A systematic review and meta-analysis.

Background: Estimating the prevalence of depressive and anxiety symptoms among older adults with different health conditions can inform mental health services for this population during the corona virus disease-2019 (COVID-19) pandemic. Method: A search of 12 scientific databases identified 17 studies with 11,237 Chinese older adults who were infected by COVID-19, were generally healthy, or had chronic illnesses. Meta-analysis was used to estimate the overall prevalence of depressive and anxiety symptoms in these three groups. Assessment criteria, region, and time phase of the pandemic were tested as sources of heterogeneity. Results: With an average risk of bias score of 6.71 (range = 6-8), the majority of included studies employed appropriate statistical methods, used validated measurement tools, and had adequate response rates; however, they might have deficiencies in sample frame, sampling method, and sample size. Within the COVID-19, general, and chronic illness groups, the prevalence of depressive symptoms was 27%, 26%, and 61%, respectively, and the prevalence of anxiety symptoms was 14%, 23%, and 85%, respectively. Among generally healthy older adults, anxiety was more prevalent during the Phase 2 (March-April 2020) of the pandemic compared with other time phases. Conclusions: The results have implications for addressing the mental health problems of Chinese older adults, especially those with chronic illnesses, during the COVID-19 pandemic.

Repurposing CRISPR/Cas9 for in situ functional assays.

RNAi combined with next-generation sequencing has proven to be a powerful and cost-effective genetic screening platform in mammalian cells. Still, this technology has its limitations and is incompatible with in situ mutagenesis screens on a genome-wide scale. Using p53 as a proof-of-principle target, we readapted the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR associated 9) genome-editing system to demonstrate the feasibility of this methodology for targeted gene disruption positive selection assays. By using novel "all-in-one" lentiviral and retroviral delivery vectors heterologously expressing both a codon-optimized Cas9 and its synthetic guide RNA (sgRNA), we show robust selection for the CRISPR-modified Trp53 locus following drug treatment. Furthermore, by linking Cas9 expression to GFP fluorescence, we use an "all-in-one" system to track disrupted Trp53 in chemoresistant lymphomas in the Eµ-myc mouse model. Deep sequencing analysis of the tumor-derived endogenous Cas9-modified Trp53 locus revealed a wide spectrum of mutants that were enriched with seemingly limited off-target effects. Taken together, these results establish Cas9 genome editing as a powerful and practical approach for positive in situ genetic screens.

The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides.

MicroRNAs (miRNAs) are ribonucleic acids (RNAs) of ∼21 nucleotides that interfere with the translation of messenger RNAs (mRNAs) and play significant roles in development and diseases. In bilaterian animals, the specificity of miRNA targeting is determined by sequence complementarity involving the seed. However, the role of the remaining nucleotides (non-seed) is only vaguely defined, impacting negatively on our ability to efficiently use miRNAs exogenously to control gene expression. Here, using reporter assays, we deciphered the role of the base pairs formed between the non-seed region and target mRNA. We used molecular modeling to reveal that this mechanism corresponds to the formation of base pairs mediated by ordered motions of the miRNA-induced silencing complex. Subsequently, we developed an algorithm based on this distinctive recognition to predict from sequence the levels of mRNA downregulation with high accuracy (r2 > 0.5, P-value < 10-12). Overall, our discovery improves the design of miRNA-guide sequences used to simultaneously downregulate the expression of multiple predetermined target genes.

Structural Parameters Optimization of Elastic Cell in a Near-Bit Drilling Engineering Parameters Measurement Sub.

The downhole engineering parameters measurement sub is a key component of the rotary steerable drilling system. To enable a measurement sub to serve reliably under downhole complex conditions, the structural parameters optimization of its key but weak elastic cell is systematically studied. First, the multiple relations among measurement sensitivities, structural stiffnesses, and strength during structural parameters design are summarized. Second, the selection of the structural parameters of the elastic cell is characterized as a multi-objective optimization model, which is solved using the non-dominated sorting genetic algorithm II (NSGA-II). Furthermore, the finite element method (FEM) is used to verify the measurement performance and static strength of the proposed structure. Finally, transient dynamics analysis is applied to investigate the dynamic strength of the designed structure. The results show that the proposed parameters optimization strategy can quickly obtain the database for the structural parameters design of an elastic cell. The static analysis results based on the FEM further verify the effectiveness of the proposed method. Transient dynamic analysis also reveals the relative rigor of the proposed methodology framework to some extent. This work has practical significance for improving the drilling efficiency and reducing drilling risks. In addition, this proposed methodology has good extensibility.

Palladium-catalyzed regio- and stereo-selective phosphination of cyclic biarylsulfonium salts to access atropoisomeric phosphines.

A palladium-catalyzed regio- and stereo-selective phosphination of cyclic biarylsulfonium salts (racemic) with HPAr3Ar4 for straightforward synthesis of atropoisomeric phosphines (P,S-ligands) bearing a stereogenic axis or both a stereogenic axis and a P-stereogenic center is reported. The high reactivity and regio- and stereo-selectivity originate from the torsional strain release and palladium catalysis, and the construction of a P-stereogenic center is enabled by an efficient dynamic kinetic resolution. The high performance of the nascent P,S-ligands has been demonstrated in palladium-catalyzed asymmetric allylic substitutions, indicating the great potential of the present methodology.

Highly Diastereo- and Enantioselective Synthesis of Chiral Cyclohexylphosphines by Cu-Catalyzed Phosphination-Aldol Cyclization of Ketone-Enamides.

A highly diastereo- and enantioselective phosphinative cyclization of ketone-enamides with secondary diarylphosphines enabled by copper catalysis is reported, providing a range of chiral tertiary cyclohexylphosphines bearing three contiguous stereogenic centers in high yields. This asymmetric phosphination-aldol cyclization protocol can also be extended to desymmetrization of dione-enamides to create four contiguous stereogenic centers in a highly selective manner.

Regiodivergent Remote C-H Functionalization by Tuning Template Geometry.

For transition-metal-catalyzed C-H functionalization, precise differentiation between remote adjacent C(sp2)-H bonds remains a long-standing challenge. Here, the template structure-directivity relationship on remote C-H functionalization of arenes was experimentally and computationally studied. By using geometry-tunable templates, Pd-catalyzed remote meta- and para-C-H activation of benzoic acids was achieved with high site selectivity.

HiChIP-based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 that Confers Genetic Susceptibility to Gastroesophageal Cancer.

Genome-wide association studies (GWAS) have identified more than a hundred single nucleotide variants (SNVs) associated with the risk of gastroesophageal cancer (GEC). The majority of the identified SNVs map to noncoding regions of the genome. Uncovering the causal SNVs and the genes they modulate could help improve GEC prevention and treatment. Here, we used HiChIP against histone 3 lysine 27 acetylation (H3K27ac) to simultaneously annotate active promoters and enhancers, identify the interactions between them, and detect nucleosome free regions (NFRs) harboring potential causal SNVs in a single assay. Application of H3K27Ac HiChIP in GEC relevant models identified 61 potential functional SNVs that reside in NFRs and interact with 49 genes at 17 loci. The approach led to a 67% reduction in the number of SNVs in linkage disequilibrium at these 17 loci, and at seven loci a single putative causal SNV was identified. One SNV, rs147518036, located within the promoter of the UDP-glucuronate decarboxylase 1 (UXS1) gene appeared to underlie the GEC risk association captured by the rs75460256 index SNV. The rs147518036 SNV creates a GABPA DNA recognition motif, resulting in increased promoter activity, and CRISPR-mediated inhibition of the UXS1 promoter reduced viability of GEC cells. These findings provide a framework that simplifies the identification of potentially functional regulatory SNVs and target genes underlying risk-associated loci. In addition, the study implicates increased expression of the enzyme UXS1 and activation of its metabolic pathway as a predisposition to gastric cancer, which highlights potential therapeutic avenues to treat this disease.

RNA-level unscrambling of fragmented genes in Diplonema mitochondria.

We previously reported a unique genome with systematically fragmented genes and gene pieces dispersed across numerous circular chromosomes, occurring in mitochondria of diplonemids. Genes are split into up to 12 short fragments (modules), which are separately transcribed and joined in a way that differs from known trans-splicing. Further, cox1 mRNA includes six non-encoded uridines indicating RNA editing. In the absence of recognizable cis-elements, we postulated that trans-splicing and RNA editing are directed by trans-acting molecules. Here, we provide insight into the post-transcriptional processes by investigating transcription, RNA processing, trans-splicing and RNA editing in cox1 and at a newly discovered site in cob. We show that module precursor transcripts are up to several thousand nt long and processed accurately at their 5' and 3' termini to yield the short coding-only regions. Processing at 5' and 3' ends occurs independently, and a processed terminus engages in trans-splicing even if the module's other terminus is yet unprocessed. Moreover, only cognate module transcripts join, though without directionality. In contrast, module transcripts requiring RNA editing only trans-splice when editing is completed. Finally, experimental and computational analyses suggest the existence of RNA trans-factors with the potential for guiding both trans-splicing and RNA editing.

Suicide before and during the COVID-19 Pandemic: A Systematic Review with Meta-Analysis.

Synthesizing evidence to examine changes in suicide-related outcomes before and during the pandemic can inform suicide management during the COVID-19 crisis. We searched 13 databases as of December 2022 for studies reporting both the pre- and peri-pandemic prevalence of suicidal ideation, suicide attempts, or rate of death by suicide. A random-effects model was used to pool the ratio of peri- and pre-pandemic prevalence of suicidal ideation and attempt (Prevalence Ratio-PR) and rate of death by suicide (Rate Ratio; RR). We identified 51, 55, and 25 samples for suicidal ideation, attempt, and death by suicide. The prevalence of suicidal ideation increased significantly among non-clinical (PR = 1.142; 95% CI: 1.018-1.282; p = 0.024; k = 28) and clinical (PR = 1.134; 95% CI: 1.048-1.227; p = 0.002; k = 23) samples, and pooled estimates differed by population and study design. Suicide attempts were more prevalent during the pandemic among non-clinical (PR = 1.14; 95% CI: 1.053-1.233; p = 0.001; k = 30) and clinical (PR = 1.32; 95% CI: 1.17-1.489; p = 0.000; k = 25) participants. The pooled RR for death by suicide was 0.923 (95% CI: 0.84-1.01; p = 0.092; k = 25), indicating a nonsignificant downward trend. An upward trend of suicidal ideation and suicide attempts was observed during the COVID-19 pandemic, despite suicide rate remaining stable. Our findings suggest that timely prevention and intervention programs are highly needed for non-clinical adult population and clinical patients. Monitoring the real-time and long-run suicide risk as the pandemic evolves is warranted.

Highly Regioselective Dichalcogenation of Alkenyl Sulfonium Salts to Access 1,1-Dichalcogenalkenes.

An unprecedented geminal olefinic dichalcogenation of alkenyl sulfonium salts with dichalcogenides ArYYAr (Y = S, Se, Te) is reported, providing various trisubstituted 1,1-dichalcogenalkenes [Ar1CH = C(YAr2)2] in a highly selective manner under mild and catalyst-free conditions. The key process involves the formation of two geminal olefinic C-Y bonds via sequential C-Y cross-coupling and C-H chalcogenation. A mechanistic rationale is further supported by control experiments and density functional theory calculations.

CCT-Unet: A U-Shaped Network Based on Convolution Coupled Transformer for Segmentation of Peripheral and Transition Zones in Prostate MRI.

The accurate segmentation of prostate region in magnetic resonance imaging (MRI) can provide reliable basis for artificially intelligent diagnosis of prostate cancer. Transformer-based models have been increasingly used in image analysis due to their ability to acquire long-term global contextual features. Although Transformer can provide feature representations of the overall appearance and contour representations at long distance, it does not perform well on small-scale datasets of prostate MRI due to its insensitivity to local variation such as the heterogeneity of the grayscale intensities in the peripheral zone and transition zone across patients; meanwhile, the convolutional neural network (CNN) could retain these local features well. Therefore, a robust prostate segmentation model that can aggregate the characteristics of CNN and Transformer is desired. In this work, a U-shaped network based on the convolution coupled Transformer is proposed for segmentation of peripheral and transition zones in prostate MRI, named the convolution coupled Transformer U-Net (CCT-Unet). The convolutional embedding block is first designed for encoding high-resolution input to retain the edge detail of the image. Then the convolution coupled Transformer block is proposed to enhance the ability of local feature extraction and capture long-term correlation that encompass anatomical information. The feature conversion module is also proposed to alleviate the semantic gap in the process of jumping connection. Extensive experiments have been conducted to compare our CCT-Unet with several state-of-the-art methods on both the ProstateX open dataset and the self-bulit Huashan dataset, and the results have consistently shown the accuracy and robustness of our CCT-Unet in MRI prostate segmentation.

Predicting visual acuity with machine learning in treated ocular trauma patients.

AIM: To predict best-corrected visual acuity (BCVA) by machine learning in patients with ocular trauma who were treated for at least 6mo. METHODS: The internal dataset consisted of 850 patients with 1589 eyes and an average age of 44.29y. The initial visual acuity was 0.99 logMAR. The test dataset consisted of 60 patients with 100 eyes collected while the model was optimized. Four different machine-learning algorithms (Extreme Gradient Boosting, support vector regression, Bayesian ridge, and random forest regressor) were used to predict BCVA, and four algorithms (Extreme Gradient Boosting, support vector machine, logistic regression, and random forest classifier) were used to classify BCVA in patients with ocular trauma after treatment for 6mo or longer. Clinical features were obtained from outpatient records, and ocular parameters were extracted from optical coherence tomography images and fundus photographs. These features were put into different machine-learning models, and the obtained predicted values were compared with the actual BCVA values. The best-performing model and the best variable selected were further evaluated in the test dataset. RESULTS: There was a significant correlation between the predicted and actual values [all Pearson correlation coefficient (PCC)>0.6]. Considering only the data from the traumatic group (group A) into account, the lowest mean absolute error (MAE) and root mean square error (RMSE) were 0.30 and 0.40 logMAR, respectively. In the traumatic and healthy groups (group B), the lowest MAE and RMSE were 0.20 and 0.33 logMAR, respectively. The sensitivity was always higher than the specificity in group A, in contrast to the results in group B. The classification accuracy and precision were above 0.80 in both groups. The MAE, RMSE, and PCC of the test dataset were 0.20, 0.29, and 0.96, respectively. The sensitivity, precision, specificity, and accuracy of the test dataset were 0.83, 0.92, 0.95, and 0.90, respectively. CONCLUSION: Predicting BCVA using machine-learning models in patients with treated ocular trauma is accurate and helpful in the identification of visual dysfunction.

Group I-intron trans-splicing and mRNA editing in the mitochondria of placozoan animals.

Placozoa - the simplest known free-living animals - have been considered primitive, early diverging metazoans based on mitochondrial genome structure and phylogeny. Here we reanalyze placozoan mitochondrial DNAs, reported to include a highly unorthodox, fragmented and incomplete cox1 gene. We discover overlooked exons and split group I introns that mediate trans-splicing of the discontinuous placozoan cox1. Furthermore, we find that cox1 expression involves U-to-C editing, reconstituting an otherwise invariant, essential histidine involved in copper binding. These atypical features qualify placozoan mitochondrial gene and genome organization as derived rather than primitive. Whether the Placozoa diverged early or late during metazoan evolution remains unresolved by mitochondrial phylogeny.

Four-quadrant fast compressive tracking of breast ultrasound videos for computer-aided response evaluation of neoadjuvant chemotherapy in mice.

BACKGROUND AND OBJECTIVE: Neoadjuvant chemotherapy (NAC) is a valuable treatment approach for locally advanced breast cancer. Contrast-enhanced ultrasound (CEUS) potentially enables the assessment of therapeutic response to NAC. In order to evaluate the response accurately, quantitatively and objectively, a method that can effectively compensate motions of breast cancer in CEUS videos is urgently needed. METHODS: We proposed the four-quadrant fast compressive tracking (FQFCT) approach to automatically perform CEUS video tracking and compensation for mice undergoing NAC. The FQFCT divided a tracking window into four smaller windows at four quadrants of a breast lesion and formulated the tracking at each quadrant as a binary classification task. After the FQFCT of breast cancer videos, the quantitative features of CEUS including the mean transit time (MTT) were computed. All mice showed a pathological response to NAC. The features between pre- (day 1) and post-treatment (day 3 and day 5) in these responders were statistically compared. RESULTS: When we tracked the CEUS videos of mice with the FQFCT, the average tracking error of FQFCT was 0.65 mm, reduced by 46.72% compared with the classic fast compressive tracking method (1.22 mm). After compensation with the FQFCT, the MTT on day 5 of the NAC was significantly different from the MTT before NAC (day 1) (p = 0.013). CONCLUSIONS: The FQFCT improves the accuracy of CEUS video tracking and contributes to the computer-aided response evaluation of NAC for breast cancer in mice.

US FDA-approved therapeutic antibodies with high-concentration formulation: summaries and perspectives.

Thirty four (34) of the total US FDA approved 103 therapeutic antibody drugs, accounts for one third of the total approved mAbs, are formulated with high protein concentration (100 mg/mL or above) which are the focus of this article. The highest protein concentration of these approved mAbs is 200 mg/mL. The dominant administration route is subcutaneous (76%). Our analysis indicates that it may be rational to implement a platform formulation containing polysorbate, histidine and sucrose to accelerate high concentration formulation development for antibody drugs. Since 2015, the FDA approval numbers are significantly increased which account for 76% of the total approval numbers, i.e., 26 out of 34 highly concentrated antibodies. Thus, we believe that the high concentration formulations of antibody drugs will be the future trend of therapeutic antibody formulation development, regardless of the challenges of highly concentrated protein formulations.

[Corrigendum] Connexin 43 reduces susceptibility to sympathetic atrial fibrillation.

Following the publication of the above article, the authors have realized that the data shown in Fig. 3B were published previously in Fig 1A of following publication, on which several of were co­authors [Shu C, Huang W, Zeng Z, He Y, Luo B, Liu H, Li J and Xu J: Connexin 43 is involved in the sympathetic atrial fibrillation in canine and canine atrial myocytes. Anatol J Cardiol 18: 3­9, 2017]. This error arose inadvertently; the corrected version of Fig. 3, also containing the correct data for Fig. 3B, is shown opposite. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum, and stress that this error did not significantly influence either the results or the conclusions of the paper. Furthermore, the authors apologize to the readership for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 42: 1125-1133, 2018; DOI: 10.3892/ijmm.2018.3648].

The effects of acceptance and commitment therapy on the psychological and physical outcomes among cancer patients: A meta-analysis with trial sequential analysis.

OBJECTIVE: The current study used meta-analysis and trial sequential analysis to estimate the effects of Acceptance and Commitment Therapy (ACT) on the psychological and physical distress of cancer patients, and to identify potential moderators in this body of research. METHODS: A search of multiple databases in February 2020 identified 25 independent trials (17 randomized controlled trials, 8 non-randomized controlled trials; 2256 participants) on the effects of ACT among cancer patients. Trial sequential analysis (TSA) was used to determine whether the available evidence is sufficient to draw strong conclusions. RESULTS: ACT significantly reduced cancer patients' psychological distress (g = 0.88), and improved psychological flexibility (g = 0.58), quality of life (g = 1.19), and sense of hope (g = 2.17). TSA showed that there was sufficient evidence to obtain stable estimates of the effect of ACT on psychological distress and quality of life. Effect sizes for psychological distress were larger in studies conducted in eastern countries, in younger samples, and when therapy was of longer duration. CONCLUSION: Acceptance and Commitment Therapy can effectively improve the mental health of cancer patients, and can be applied to clinical practice as an effective psychological intervention. Researchers are encouraged to take into account stage and trajectory of cancer in future studies.