Regioselective Thiol-yne Reaction of Thiol with ((Methyl-d3)sulfonyl)ethyne: Synthesis of (2-((Methyl-d3)sulfonyl)vinyl)sulfides.

Herein, we have developed a new method for the synthesis of ((methyl-d3)sulfonyl)ethyne, which is cost-effective and environmentally friendly and can be synthesized at the gram level. As an ideal thiol-yne reagent, it can be reacted with various types of thiols to afford (Z)- and (E)-type vinyl sulfides under different conditions with high selectivity. In addition, it can complete the conformational transition from Z- to E-type products under suitable conditions, and can also carry out further derivatization smoothly. The deuterium content of all products was greater than 99%. The preliminary mechanistic studies support the visible light-mediated radical course, and herein provide a novel and efficient synthetic strategy for the direct introduction of deuterated methyl groups, enriching the methods for the construction of C-S bond-containing compounds.

Manganese-Promoted Cyclization Reaction of Enynones with Tetrasulfides: Synthesis of Multisubstituted Furanmethyl Disulfides.

A tandem cyclization reaction of enynones with tetrasulfides has been developed under manganese-promoted conditions, leading to the high-yield formation of various furanmethyl disulfides. This reaction is characterized by readily available starting materials, mild reaction conditions, and a broad substrate scope, making it attractive and practical. It provides a new strategy for the synthesis of disulfide-containing functionalized furans.

Regioselective 1,4-/1,3-Difunctionalization of 1,3-Enynes with Selenosulfonates in Water.

1,4-/1,3-Regioselective bifunctionalization of 1,3-enynes with selenosulfonates in water under catalyst-free conditions for the construction of sulfonyl allene and 1,3-disulfonyl-conjugated dienes respectively have been developed. The reactions feature mild reaction conditions in aqueous solution and remarkable regioselectivity controlled by substrates.

Nickel-Catalyzed Acid Chlorides with Tetrasulfides for the Synthesis of Thioesters and Acyl Disulfides.

Herein, we report a novel method for the synthesis of thioesters and acyl disulfides via nickel-catalyzed reductive cross-electrophile coupling of acid chlorides with tetrasulfides. This approach for the synthesis of thioesters and acyl disulfides is convenient and practical under mild reaction conditions, relying on easy availability. In addition, a wide range of thioesters and acyl disulfides were obtained in medium to good yields with good functional group tolerance. Moreover, thioesters and acyl disulfides can also be prepared at the gram scale, indicating that they have certain potential for industrial application.

Photoinduced Construction of Thieno[3,4-c]quinolin-4(5H)-ones/Selenopheno[3,4-c]quinolin-4(5H)-ones Using Diphenyl Disulfide or Diphenyl Diselenide as Sulfur or Selenium Sources.

A photocatalytic synthesis of thieno[3,4-c]quinolin-4(5H)-ones/selenopheno[3,4-c]quinolin-4(5H)-ones using diphenyl disulfide or diphenyl diselenide as sulfur or selenium sources was developed. Two C-S/Se bonds and one C-C bond were constructed simultaneously without transition metals and other additives.

Elevated serum FGF21 is an independent predictor for adverse events in hemodialysis patients from two large centers: a prospective cohort study.

Introduction: We explored the relationship and the predictive value of serum fibroblast growth factor 21 (FGF21) with all-cause mortality, major adverse cardiovascular events (MACEs) and pneumonia in hemodialysis (HD) patients.Methods: A total of 388 Chinese HD patients from two HD centers were finally enrolled in this prospective cohort study (registration number: ChiCTR 1900028249) between January 2018 and December 2018. Serum FGF21 was detected. Patients were followed up with a median period of 47 months to record the MACEs and pneumonia until death or 31 December 2022.Results: The incidence of all-cause mortality, MACEs and pneumonia in HD patients were 20.6%, 29.6%, and 34.8%, respectively. The optimal cutoffs for FGF21 to predict all-cause mortality, MACEs and pneumonia were 437.57 pg/mL, 216.99 pg/mL and 112.79 pg/mL. Multivariate Cox regression analyses showed that FGF21, as a categorical variable, was an independent predictor for all-cause mortality, MACEs and pneumonia (HR, 3.357, 95% CI, 2.128-5.295, p < 0.001; HR, 1.575, 95% CI, 1.046-2.371, p = 0.029; HR, 1.784; 95% CI, 1.124-2.830; p = 0.014, respectively). The survival nomogram, MACEs-free survival nomogram and pneumonia-free survival nomogram based on FGF21 constructed for individualized assessment of HD patients had a high C-index with 0.841, 0.706 and 0.734.Conclusion: Higher serum FGF21 is an independent predictor of all-cause mortality, MACEs and pneumonia in HD patients.

A Heteromodal Word-Meaning Binding Site in the Visual Word Form Area under Top-Down Frontoparietal Control.

The integral capacity of human language together with semantic memory drives the linkage of words and their meaning, which theoretically is subject to cognitive control. However, it remains unknown whether, across different language modalities and input/output formats, there is a shared system in the human brain for word-meaning binding and how this system interacts with cognitive control. Here, we conducted a functional magnetic resonance imaging experiment based on a large cohort of subjects (50 females, 50 males) to comprehensively measure the brain responses evoked by semantic processing in spoken and written word comprehension and production tasks (listening, speaking, reading, and writing). We found that heteromodal word input and output tasks involved distributed brain regions within a frontal-parietal-temporal network and focally coactivated the anterior lateral visual word form area (VWFA), which is located in the basal occipitotemporal area. Directed connectivity analysis revealed that the VWFA was invariably under significant top-down modulation of the frontoparietal control network and interacts with regions related to attention and semantic representation. This study reveals that the VWFA is a key site subserving general semantic processes linking words and meaning, challenging the predominant emphasis on this area's specific role in reading or more general visual processes. Our findings also suggest that the dynamics between semantic memory and cognitive control mechanisms during word processing are largely independent of the modalities of input or output.SIGNIFICANCE STATEMENT Binding words and their meaning into a coherent whole during retrieval requires accessing semantic memory and cognitive control, allowing our thoughts to be expressed and comprehended through mind-external tokens in multiple modalities, such as written or spoken forms. However, it is still unknown whether multimodal language comprehension and production share a common word-meaning binding system in human brains and how this system is connected to a cognitive control mechanism. By systematically measuring brain activity evoked by spoken and written verbal input and output tasks tagging word-meaning binding processes, we demonstrate a general word-meaning binding site within the visual word form area (VWFA) and how this site is modulated by the frontal-parietal control network.

Informed MEG/EEG source imaging reveals the locations of interictal spikes missed by SEEG.

Determining the accurate locations of interictal spikes has been fundamental in the presurgical evaluation of epilepsy surgery. Stereo-electroencephalography (SEEG) is able to directly record cortical activity and localize interictal spikes. However, the main caveat of SEEG techniques is that they have limited spatial sampling (covering <5% of the whole brain), which may lead to missed spikes originating from brain regions that were not covered by SEEG. To address this problem, we propose a SEEG-informed minimum-norm estimates (SIMNE) method by combining SEEG with magnetoencephalography (MEG) or EEG. Specifically, the spike locations determined by SEEG offer as a priori information to guide MEG source reconstruction. Both computer simulations and experiments using data from five epilepsy patients were conducted to evaluate the performance of SIMNE. Our results demonstrate that SIMNE generates more accurate source estimation than a traditional minimum-norm estimates method and reveals the locations of spikes missed by SEEG, which would improve presurgical evaluation of the epileptogenic zone.

Cortical electrophysiological evidence for individual-specific temporal organization of brain functional networks.

The human brain has been demonstrated to rapidly and continuously form and dissolve networks on a subsecond timescale, offering effective and essential substrates for cognitive processes. Understanding how the dynamic organization of brain functional networks on a subsecond level varies across individuals is, therefore, of great interest for personalized neuroscience. However, it remains unclear whether features of such rapid network organization are reliably unique and stable in single subjects and, therefore, can be used in characterizing individual networks. Here, we used two sets of 5-min magnetoencephalography (MEG) resting data from 39 healthy subjects over two consecutive days and modeled the spontaneous brain activity as recurring networks fast shifting between each other in a coordinated manner. MEG cortical maps were obtained through source reconstruction using the beamformer method and subjects' temporal structure of recurring networks was obtained via the Hidden Markov Model. Individual organization of dynamic brain activity was quantified with the features of the network-switching pattern (i.e., transition probability and mean interval time) and the time-allocation mode (i.e., fractional occupancy and mean lifetime). Using these features, we were able to identify subjects from the group with significant accuracies (~40% on average in 0.5-48 Hz). Notably, the default mode network displayed a distinguishable pattern, being the least frequently visited network with the longest duration for each visit. Together, we provide initial evidence suggesting that the rapid dynamic temporal organization of brain networks achieved in electrophysiology is intrinsic and subject specific.

Protective effect of dabrafenib on renal ischemia-reperfusion injury in vivo and in vitro.

AIMS: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which can lead to poor outcome and increased risk of mortality. Dabrafenib (DAB) is an approved cancer treatment. Little is known about the effect of DAB in prevention or treatment of renal IRI. METHODS: For in vivo experiments, C57BL/6 mice were divided into four groups: sham (no IRI, no DAB), IRI, DAB, and DAB + IRI. IRI was induced by clamping of bilateral renal pedicles for 30 min. For in vitro experiments, HK-2 cells were used to establish the hypoxia/reoxygenation (H/R) injury model, with four groups: control (no H/R, no DAB), H/R, DAB, and DAB + H/R. Renal function and renal histological changes were recorded. Expression of NGAL and KIM-1 proteins and mRNAs were determined by western blotting and qRT-PCR; secretion of inflammatory cytokines (IL-6 and TNF- α) was determined by qRT-PCR; Cell death was determined using the TUNEL assay, measurement of cleaved caspase-3, and flow cytometry. Necroptosis-related proteins were determined by western blotting. RESULTS: In mice, DAB pretreatment improved renal function and also reduced histological injury, inflammation, cell death, and expression of necroptosis-associated proteins. In HK-2 cells, DAB significantly decreased the levels of NGAL and KIM-1, inflammatory cytokines, cell death, and necroptosis-related proteins. CONCLUSION: Our in vitro and in vivo experiments indicated that DAB appears to alleviate renal IRI by suppressing cell death and inhibiting inflammatory responses. DAB has potential use for the clinical prevention and treatment of AKI-induced IRI.

[Paclitaxel liposome for the treatment of castration-resistant prostate cancer].

OBJECTIVE: To investigate the effect and safety of the 3-week paclitaxel liposome protocol in the treatment of castration-resistant prostate cancer (CRPC). METHODS: This retrospective study included 40 cases of CRPC treated by the 3-week paclitaxel liposome protocol from February 2014 to February 2019, which involved intravenous injection of 10 mg dexamethasone in 100 ml normal saline on the first day and that of metoclopramide and panxi tora azole on the second day, followed by about 3 hours of intravenous drip of paclitaxel liposome at 135 mg/m2 for a course of 3 weeks. During the follow-up period, the patients received detection of the serum PSA level before treatment and chest x-ray and whole-body bone scan every six months. After two courses of treatment, the patients were observed for the changes in the serum PSA level, relief of bone pain, quality of survival, overall survival rate, overall survival time and toxic reactions. The protocol was continued unless the patient underwent progression, refused for unacceptable toxicity, or died. RESULTS: The patients were aged 59 to 79 (mean 68.80±5.67) years old, with the serum PSA level of (28.05 ± 3.22) µg/L at the baseline and (4.12 ± 0.23) µg/L after treatment. Thirty-eight of the patients were followed up for 3 to 33 (mean 12.2) months. PSA-based evaluation showed therapeutic effectiveness in 14 cases (35%), stable condition in 21 (52.5 %) and progression in 5 (12.5 %). Of the 18 patients with bone metastasis and pain, 16 (88.9 %) experienced relief of the symptoms and reduced the use of painkillers, with the bone pain scores of 5.20 ± 1.22 vs 2.79 ± 0.57 before and after treatment. By the end of the follow-up, the overall survival rate was 55.0% (22/40) and the median survival time was 17 months (95% CI: 13.4－24.6). During the treatment, no obvious adverse reactions were observed except for anemia in 1 case and hair loss in another. CONCLUSIONS: For the treatment of CRPC in China, the 3-week paclitaxel liposome protocol has the advantages of desirable safety, low toxicity, acceptable drug tolerance and improved quality of survival, but its curative effect needs to be verified with more randomized clinical trials with larger samples and longer follow-ups.

Highly efficient generation of 0.2 mJ terahertz pulses in lithium niobate at room temperature with sub-50 fs chirped Ti:sapphire laser pulses.

We demonstrate generation of 0.2 mJ terahertz (THz) pulses in lithium niobate driven by Ti:sapphire laser pulses at room temperature. Employing tilted pulse front technique, the 800 nm-to-THz energy conversion efficiency has been optimized to 0.3% through chirping the sub-50 fs pump laser pulses to overcome multi-photon absorption and to extend effective interaction length for phase matching. Our approach paves the way for mJ-level THz generation via optical rectification using existing Ti:sapphire laser systems which can deliver Joule-level pulse energy with sub-50 fs pulse duration.

Psychological distress among re-education through labour camp detainees in Guangxi Autonomous Region, China.

BACKGROUND: There is currently no information about the prevalence of, and factors contributing to psychological distress experienced by re-education through labour camp detainees in China. METHODS: A cross-sectional face-to-face survey was conducted in three labour camps in Guangxi, China. The questionnaire covered socio-demographic characteristics; sexually transmissible infections (STIs); drug use; psychological distress (K-10); and health service usage and access inside the labour camps. K-10 scores were categorised as ≤30 (low to moderate distress) and >30 or more (highly distressed). Univariate and multivariate logistic regression models identified factors independently associated with high K-10 scores for men and women separately. RESULTS: In total, 755 detainees, 576 (76%) men and 179 (24%) women, participated in the health survey. The study found 11.6% men versus 11.2% women detainees experienced high psychological distress, but no significant gender differences were observed (p> 0.05). Multivariate logistic regression showed that multiple physical health problems were significantly associated with high psychological distress among men. CONCLUSION: Drug treatment and forensic mental health services need to be established in detention centres in China to treat more than 10% of detainees with drug use and mental health disorders.

Structural plasticity of green fluorescent protein to amino acid deletions and fluorescence rescue by folding-enhancing mutations.

BACKGROUND: Green fluorescent protein (GFP) and its derivative fluorescent proteins (FPs) are among the most commonly used reporter systems for studying gene expression and protein interaction in biomedical research. Most commercially available FPs have been optimized for their oligomerization state to prevent potential structural constraints that may interfere with the native function of fused proteins. Other approach to reducing structural constraints may include minimizing the structure of GFPs. Previous studies in an enhanced GFP variant (EGFP) identified a series of deletions that can retain GFP fluorescence. In this study, we interrogated the structural plasticity of a UV-optimized GFP variant (GFP(UV)) to amino acid deletions, characterized the effects of deletions and explored the feasibility of rescuing the fluorescence of deletion mutants using folding-enhancing mutations. METHODS: Transposon mutagenesis was used to screen amino acid deletions in GFP that led to fluorescent and nonfluorescent phenotypes. The fluorescent GFP mutants were characterized for their whole-cell fluorescence and fraction soluble. Fluorescent GFP mutants with internal deletions were purified and characterized for their spectral and folding properties. Folding-ehancing mutations were introduced to deletion mutants to rescue their compromised fluorescence. RESULTS: We identified twelve amino acid deletions that can retain the fluorescence of GFP(UV). Seven of these deletions are either at the N- or C- terminus, while the other five are located at internal helices or strands. Further analysis suggested that the five internal deletions diminished the efficiency of protein folding and chromophore maturation. Protein expression under hypothermic condition or incorporation of folding-enhancing mutations could rescue the compromised fluorescence of deletion mutants. In addition, we generated dual deletion mutants that can retain GFP fluorescence. CONCLUSION: Our results suggested that a "size-minimized" GFP may be developed by iterative incorporation of amino acid deletions, followed by fluorescence rescue with folding-enhancing mutations.

Intraoral Digital Impression Technique: A Review.

With the techniques of computer-aided design and computer-aided manufacturing (CAD/CAM) being applied in the field of prosthodontics, a concept of intraoral digital impressions was put forward in the early 1980s. It has drawn comprehensive attention from dentists and has been used for dental prosthesis fabrication in a number of cases. This new digital impression technique is expected to bring about absolute digitization to the mode of prosthodontics. A few published articles have indicated that dental prostheses fabricated from intraoral digital impressions have exhibited remarkable advantages over those from conventional impressions in several respects. The present review discusses intraoral digital impression techniques in terms of the following aspects: (1) categories and principles of intraoral digital impression devices currently available; (2) operating characteristics of the devices; and (3) comparison of the manipulation, accuracy, and repeatability between intraoral digital impression and conventional impression.

Copper-Catalyzed Chemoselective Coupling of N-Dithiophthalimides and Alkyl Halides: Synthesis of Unsymmetrical Disulfides and Sulfides.

In this paper, we report an unprecedented copper-catalyzed disulfides or sulfides coupling reaction involving unactivated alkyl halides and N-dithiophthalimides. This reaction can be conducted under mild conditions using low-cost metal catalysts and exhibits high chemical selectivity and functional group compatibility, enabling the efficient assembly of various sulfides and disulfides.

Copper(0)-Catalyzed Reductive Coupling of Disulfurating Reagents and (Hetero)aryl/Alkyl Halides.

Herein, we reported a copper(0)-catalyzed reductive coupling of disulfurating reagents and (hetero)aryl/alkyl halides. Copper(0) can be directly inserted into tetrasulfide and then undergoes reductive coupling with (hetero)aryl Iodides to construct disulfide. The method features the unprecedented use of copper(0)-catalyzed disulfurating reagents (tetrasulfides) in cross-coupling chemistry and is convenient with broad substrate scopes, even applicable to different halogenated hydrocarbons. It is worth noting that the methodology is practical with the late-stage modification of bioactive scaffolds of pharmaceuticals. In the meantime, the synthesis of disulfides is successfully achieved on a gram scale, indicating the approach is highly valuable.

Visible Light-Catalyzed Reactions of Polysulfide (DBSPS) with Aryldiazonium.

A visible light-catalyzed radical coupling reaction of polysulfide reagents with aryldiazonium was developed, which gave thiosulfonates under mild conditions. In this reaction, the thiosulfonates were isolated in good yields with a broad tolerance to functional groups. And the synthesis of diaryl monosulfides were achieved through a step-by-step reaction of two molecular aryldiazonium with DBSPS, where the sulfur source was provided by DBSPS. It was worth noting that the reaction of this monosulfides could also be achieved by a one pot two-step process. The described polysulfide reagents were able to produce three new radicals: sulfonyl radicals, sulfur-sulfonyl radicals and sulfur-sulfur-sulfonyl radicals.

Signaling mechanism underlying α2A -adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats.

Stimulation of α2A -adrenoceptors (ARs) in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. A previous study in our laboratory showed that α2A -AR stimulation suppresses excitatory synaptic transmission in layer V-VI pyramidal cells of the rat medial PFC (mPFC). However, the intracellular mechanism underlying the α2A -AR suppression remains unclear. In the present study, we recorded evoked excitatory postsynaptic current (eEPSC) in layer V-VI pyramidal cells of the mPFC, using whole-cell patch-clamp recording. We found that the α2A -AR agonist guanfacine significantly suppresses eEPSC in mPFC pyramidal cells. The α2A -AR inhibition is mediated by the Gi-cAMP-PKA-PP1-CaMKII-AMPAR signaling pathway, as such inhibition no longer exists when each step of this pathway is blocked with NF023, Rp-cAMP, PKI5-24 or H89, tautomycin, and KN-62 or KN-93, respectively.

Simultaneous Preparation of Sulfides/Selenides and Sulfones via Synergistic Nickel-Catalyzed Reductive Coupling and SN2 Reaction.

Sulfone compounds and thioether compounds are two highly valuable classes of compounds, but it is challenging to prepare sulfone and thioether compounds simultaneously and efficiently. Here we report that sulfides/selenides and sulfones can be obtained simultaneously using allyl bromide/benzyl bromide-activated alkyl bromides and thiosulfonates/selenosulfonates using a nickel-catalyzed reductive coupling and SN2 synergistic strategy, which is characterized by excellent atom and step economy, mild reaction conditions, broad functional group compatibility, and excellent yields.