Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines.

Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version3-5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.

Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase.

The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide--hereafter referred to as necrosulfonamide--that specifically blocks necrosis downstream of RIP3 activation. An affinity probe derived from necrosulfonamide and coimmunoprecipitation using anti-RIP3 antibodies both identified the mixed lineage kinase domain-like protein (MLKL) as the interacting target. MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.

Copper-Catalyzed Enantioconvergent Radical N-Alkylation of Diverse (Hetero)aromatic Amines.

The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.

Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions.

The enantioconvergent C(sp3)-N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N-alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp3)-N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.

Mesenchymal ß-catenin signaling affects palatogenesis by regulating α-actinin-4 and F-actin.

OBJECTIVE: Our previous research have found that mesenchymal ß-catenin may be involved in palatal shelf (PS) elevation by regulating F-actin. Here, we further investigated the exact mechanism of ß-catenin/F-actin in the PS mesenchyme to regulate palatal reorientation. MATERIALS AND METHODS: (1) Firstly, Ctnnb1ex3f (ß-catenin) mice were conditionally overexpressed in the palatal mesenchyme by crossing with the Sox9-creERT2 mice (induced by Tamoxifen injections); (2) Subsequently, histology and immunohistochemistry were used to characterize the variations of PS morphology and expression of key molecules associated with developmental process; (3) Finally, experiments in vivo and ex vivo were employed to identify the critical mechanisms in ß-catenin silenced and overexpressed models. RESULTS: We found that the Sox9CreER; Ctnnb1ex3f mice exhibited failed palatal elevation and visible cleft palate, and overexpression of ß-catenin disturbed the F-actin responsible for cytoskeletal remodeling in palatal mesenchymal cells. qRT-PCR results showed mRNA levels of α-actinin4, a gene involved in F-actin cross-linking, were associated with knockdown or overexpression of ß-catenin in ex vivo, respectively. Experiments in vivo revealed that mesenchymal specific inactivation or overexpression of ß-catenin exhibited decreased or increased α-actinin-4 expression. CONCLUSIONS: Mesenchymal ß-catenin/F-actin plays an essential role in PS reorientation, which mediate α-actinin-4 to regulate F-actin cytoskeleton reorganization.

A fourth dose of Omicron RBD vaccine enhances broad neutralization against SARS-CoV-2 variants including BA.1 and BA.2 in vaccinated mice.

The SARS-CoV-2 vaccines have been widely used to build an immunologic barrier in the population against the COVID-19 pandemic. However, a newly emerging Omicron variant, including BA.1, BA.1.1, BA.2, and BA.3 sublineages, largely escaped the neutralization of existing neutralizing antibodies (nAbs), even those elicited by three doses of vaccines. Here, we used the Omicron BA.1 RBD as a fourth dose of vaccine to induce potent Omicron-specific nAbs and evaluated the broadly neutralizing activities against SARS-CoV-2 variants. The BA.1-based vaccine was indeed prone to induce a strain-specific antibody response substantially cross-reactive with BA.2 sublineage, and yet triggered broad neutralization against SARS-CoV-2 variants when it was used in the sequential immunization with WT and other variant vaccines. These results demonstrated that the booster of Omicron RBD vaccine could be a rational strategy to enhance the broadly nAb response.

Sequential immunization with SARS-CoV-2 RBD vaccine induces potent and broad neutralization against variants in mice.

The current COVID-19 pandemic caused by constantly emerging SARS-CoV-2 variants still poses a threat to public health worldwide. Effective next-generation vaccines and optimized booster vaccination strategies are urgently needed. Here, we sequentially immunized mice with a SARS-CoV-2 wild-type inactivated vaccine and a heterologous mutant RBD vaccine, and then evaluated their neutralizing antibody responses against variants including Beta, Delta, Alpha, Iota, Kappa, and A.23.1. These data showed that a third booster dose of heterologous RBD vaccine especially after two doses of inactivated vaccines significantly enhanced the GMTs of nAbs against all SARS-CoV-2 variants we tested. In addition, the WT and variants all displayed good cross-immunogenicity and might be applied in the design of booster vaccines to induce broadly neutralizing antibodies.

New Strategies in the Efficient Total Syntheses of Polycyclic Natural Products.

Polycyclic natural products are an inexhaustible source of medicinal agents, and their complex molecular architecture renders challenging synthetic targets where innovative and effective approaches for their rapid construction are urgently required. The total synthesis of polycyclic natural products has witnessed exponential progression along with the emergence of new synthetic strategies and concepts, such as sequential C-H functionalizations, radical-based transformations, and functional group pairing strategies. Our group exerts continued interest in the construction of bioactive and structurally complex natural products as well as evaluation of the mode of action of these molecules. In this Account, we will showcase how these new synthetic strategies are employed and guide our total synthesis endeavors.During the last two decades, a series of remarkable advances in C-H functionalization have led to the emergence of many new approaches to directly functionalize C-H bonds into useful functional groups. These selective transformations have provided a great opportunity for the step- and atom-economical construction of key fragments in complex molecule synthesis. We recently furnished the total syntheses for polycyclic natural products: incarviatone A, chrysomycin A, polycarcin V, and gilvocarcin V by employing a multiple C-H bond functionalization strategy. The polysubstituted benzene or naphthalene skeleton was constructed through sequential and site-selective C-H functionalizations from readily available simple starting materials, which reduced the number of steps and streamlined synthesis.Recently, we have also completed the total syntheses for a number of skeletally diverse tetracyclic Isodon diterpenoids inspired by their biogenesis and radical-based retrosynthetic disconnections. Radical transformations are strategically and tactically utilized in our syntheses, and radical-based reactions, including organo-SOMO catalysis, Birch reduction, regioselective 1,6-dienyne reductive cyclization, visible-light-mediated Schenck ene reaction, and photoradical-mediated late-stage skeletal rearrangement, play significant roles in our synthetic endeavors. Protecting-group-free and scalable syntheses are also built into our work to achieve the "ideal" synthesis. Furthermore, our synthetic work reveals that late-stage skeletal rearrangement through a photo radical process is possible in a biological setting in complement with nature's carbocation chemistry in complex natural product biosynthesis.Lycopodium alkaloids are a large family of structurally unique polycyclic natural products with impressive biological activities. Owing to their fascinating polycyclic architectures and diverse biological activities, these alkaloids have continued to serve as targets as well as inspirations for the synthetic community for decades. To access these bioactive natural products or natural product-like molecules for biological exploration and drug discovery, we applied a novel functional group pairing strategy to furnish the total syntheses for several Lycopodium alkaloids and obtained numerous skeletally diverse compounds with structural complexity comparable to natural products.

Comprehensive genomic variation profiling of cervical intraepithelial neoplasia and cervical cancer identifies potential targets for cervical cancer early warning.

BACKGROUND: To better understand the pathogenesis of cervical cancer (CC), we systematically analysed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC. METHODS: We performed whole-genome sequencing or whole-exome sequencing of 102 tumour-normal pairs and human papillomavirus probe capture sequencing of 45 CCs, 44 CIN samples and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis. RESULTS: Mutational analysis identified eight significantly mutated genes in CC including four genes (FAT1, MLL3, MLL2 and FADD), which have not previously been reported in CC. Targetable alterations were identified in 55.9% of patients. In addition, HPV integration breakpoints occurred in 97.8% of the CC samples, 70.5% of the CIN samples and 42.8% of the normal cervical samples with HPV infection. Integrations of high-risk HPV strains in CCs, including HPV16, 18, 33 and 58, also occurred in the CIN samples. Moreover, gene mutations were detected in 52% of the CIN specimens, and 54.8% of these mutations occurred in genes that also mutated in CCs. CONCLUSION: Our results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC.

No Need to Routinely Remove Titanium Implants for Maxillofacial Fractures.

PURPOSE: Titanium implants are typically used to fix maxillofacial fractures and their routine removal is a controversial topic in maxillofacial surgery. This study aimed to estimate the removal rate and risk factors associated with removal. MATERIALS AND METHODS: The authors designed and implemented a retrospective study. Adult patients who underwent open reduction and internal fixation with titanium implants for maxillofacial fractures were included and those who returned for implant removal were identified from January 2007 to December 2016. The predictor variables were gender, age, preoperative infection, injury time, trauma cause, and fracture site. The primary outcome variable was removal of titanium implants. Descriptive and bivariate statistics were computed. Kaplan-Meier survival methods were used to estimate rate of removal. Univariate and multivariate Cox proportional hazards models were used to identify risk factors associated with removal. RESULTS: Of 2,325 patients (1,890 men and 435 women; average age, ∼35.49 yr) registered in this study, 163 (7.01%) had their titanium implants removed and 1-, 2-, and 10-year removal rates were 3, 7, and 8%, respectively. The risk factors most closely associated with removal were preoperative infection, injury by a blow from an object, obsolete fracture, and female gender. CONCLUSIONS: Routinely removing titanium implants in patients with maxillofacial fracture is not necessary. When the risk factors listed earlier are present in these patients, follow-up should be scheduled more frequently.

ent-Jungermannenone C Triggers Reactive Oxygen Species-Dependent Cell Differentiation in Leukemia Cells.

Acute myeloid leukemia (AML) is a hematologic malignancy that is characterized by clonal proliferation of myeloid blasts. Despite the progress that has been made in the treatment of various malignant hematopoietic diseases, the effective treatment of AML remains very challenging. Differentiation therapy has emerged as a promising approach for leukemia treatment, and new and effective chemical agents to trigger the differentiation of AML cells, especially drug-resistant cells, are urgently required. Herein, the natural product jungermannenone C, a tetracyclic diterpenoid isolated from liverworts, is reported to induce cell differentiation in AML cells. Interestingly, the unnatural enantiomer of jungermannenone C (1) was found to be more potent than jungermannenone C in inducing cell differentiation. Furthermore, compound 1 targets peroxiredoxins I and II by selectively binding to the conserved cysteine residues and leads to cellular reactive oxygen species accumulation. Accordingly, ent-jungermannenone C (1) shows potential for further investigation as an effective differentiation therapy against AML.

Effects of different methionine sources on production and reproduction performance, egg quality and serum biochemical indices of broiler breeders.

OBJECTIVE: The study was conducted to evaluate the effects of different methionine (Met) sources on production performance, reproduction performance, egg quality and serum biochemical indices in broiler breeders. METHODS: After receiving a basal diet (containing 0.25% Met) for a 2-wk pretreatment period, a total of 360 39-wk-old Lingnan yellow broiler breeders were randomly allocated to four treatments with six replicates each (15 birds per replicate). Breeders were fed with basal diets (control) or diets supplemented with DL-methionine (DLM), DL-2-hydroxy-4-methylthio butytric calcium (MHA-Ca) and coated DL-Met (CME) respectively. RESULTS: The results showed that CME supplementation promoted laying rate and decreased feed-to-egg ratio (F/E) (p<0.05), DLM and MHA-Ca supplementation decreased F/E (p<0.05) when compared with control group. The rate of fertility, hatchability and birthrate were higher (p<0.05) in DLM, MHA-Ca, and CME groups than control group. Compared with control group, CME increased the eggshell thickness (p<0.05); MHA-Ca improved the eggshell thickness, shell ratio and eggshell strength (p<0.05). Results also showed that CME elevated the concentration of total protein in serum (p<0.05); MHA-Ca improved the concentration of calcium in serum (p<0.05). The concentration of serum uric acid in DLM, MHA-Ca, and CME groups was lower than that in control group (p<0.05). Besides, CME had higher concentrations of serum taurine, cysteine and cystanthionine (p<0.05) while MHA-Ca and DLM promoted the serum taurine concentration (p<0.05) compared with control group. CONCLUSION: Based on the results, it was concluded that Met supplementation could enhance the production and reproduction performance as well as the antioxidant status and egg quality of broiler breeders. In terms of improving the production performance, reproduction performance and antioxidant performance, CME was superior to DLM and MHA-Ca; but in regard to the enhancement of eggshell quality and serum Ca concentration, MHA-Ca was superior to DLM and CME.

A Modified Preauricular Approach for Treating Intracapsular Condylar Fractures to Prevent Facial Nerve Injury: The Supratemporalis Approach.

PURPOSE: The facial nerve remains at risk of injury with the preauricular approach; thus, preservation of the functional integrity of the facial nerve is considered an important factor in the success of temporomandibular joint surgery. The aim of this study was to prevent facial nerve injury using the supratemporalis approach in the treatment of intracapsular condylar fractures. MATERIALS AND METHODS: In this prospective cohort study, the population consisted of patients diagnosed with intracapsular condylar fractures who received surgical treatment from July 2005 to May 2014. Patients in the experimental group were treated with the supratemporalis approach, and patients in the control group were treated with the traditional preauricular surgical technique. The primary outcome variable was facial never injury. The continuity correction χ(2) and test Student t test were used. RESULTS: Eighty-four patients (112 sides) with intracapsular condylar fractures were treated surgically (56 men, 28 women; mean age, 29.85 yr; range, 4 to 70 yr); 44 patients (64 sides) were treated with the supratemporalis approach and 40 patients (48 sides) were treated with the traditional preauricular approach. Facial contours and functions recovered well postoperatively in all 84 patients. Seven cases of facial nerve injury, 2 of which were permanent, were observed in the group treated with the traditional preauricular approach, and no facial nerve injuries were observed in the group treated with the supratemporalis approach. None of the patients sustained auriculotemporal syndrome or wound infection complications. CONCLUSIONS: The supratemporalis approach prevented facial nerve injury and did not increase the frequency of other complications.

Scalable Total Synthesis of rac-Jungermannenones†B and C.

Reported is the first scalable synthesis of rac-jungermannenones B and C starting from the commercially available and inexpensive geraniol in 10 and 9 steps, respectively. The unique jungermannenone framework is rapidly assembled by an unprecedented regioselective 1,6-dienyne reductive cyclization reaction which proceeds through a vinyl radical cyclization/allylic radical isomerization mechanism. DFT calculations explain the high regioselectivity observed in the 1,6-dienyne reductive radical cyclization.

Site-selective and metal-free aliphatic C-H oxidation enabled synthesis of [5,24,25-D3]-(25S)-Δ(7)-dafachronic acid.

Steroid hormones play significant roles in both worms and mammalians. (25S)-Δ(7)-Dafachronic acid (Δ(7)-DA, 1) is a member of the dafachronic acid hormonal series that regulates both development and lifespan of C. elegans. Despite its importance, effective tools for the illumination of its mode of action are lacking. Herein, we report an efficient synthesis of trideuterated Δ(7)-DA, [5,24,25-D3]-(25S)-Δ(7)-dafachronic acid ([D3]-Δ(7)-DA, 2), as a useful chemical tool for subsequent biological studies. Key steps for this bioinspired synthesis approach include site-selective aliphatic C-H oxidation mediated by methyl(trifluoromethyl)dioxirane (TFDO), and the iridium/phosphine-oxazoline-catalyzed late-stage asymmetric deuterium reduction.

Emission Lifetimes of a Fluorescent Dye under Shock Compression.

The emission lifetimes of rhodamine 6G (R6G) were measured under shock compression to 9.1 GPa, with the dual intents of better understanding molecular photophysics in extreme environments and assessing the usefulness of fluorescence lifetime microscopy to measure spatially dependent pressure distributions in shocked microstructured media. R6G was studied as free dye dissolved in poly(methyl methacrylate) (PMMA), or dye encapsulated in silica microparticles suspended in PMMA. Thin layers of these materials in impedance-matched geometries were subjected to planar single-stage shocks created by laser-driven flyer plates. A synchronized femtosecond laser excited the dye at selected times relative to flyer plate arrival and the emission lifetimes were measured with a streak camera. Lifetimes decreased when shocks arrived. The lifetime decrease was attributed to a shock-induced enhancement of R6G nonradiative relaxation. At least part of the relaxation involved shock-enhanced intersystem crossing. For free dye in PMMA, the lifetime decrease during the shock was shown to be a linear function of shock pressure from 0 to 9 GPa, with a slope of -0.22 ns·GPa(-1). The linear relationship makes it simple to convert lifetimes into pressures. Lifetime measurements in shocked microenvironments may be better than emission intensity measurements, because lifetimes are sensitive to the surrounding environment, but insensitive to intensity variations associated with the motion and optical properties of a dynamically changing structure.

Bridging the sanitation gap between disaster relief and development.

By interpreting disasters as opportunities to initiate the fulfilment of development needs, realise the vulnerability of the affected community and environment, and extend the legacy of relief funds and effort, this paper builds upon the concept linking relief, rehabilitation and development (LRRD) in the sanitation sector. It aims to use a composite of case studies to devise a framework for a semi-hypothetical scenario to identify critical components and generic processes for a LRRD action plan. The scenario is based on a latrine wetland sanitation system in a Muslim community. Several sub-frameworks are developed: (i) latrine design; (ii) assessment of human waste treatment; (iii) connective sanitation promotion strategy; and (iv) ecological systems and environmental services for sanitation and development. This scenario illustrates the complex issues involved in LRRD in sanitation work and provides technical notes and references for a legacy plan for disaster relief and development.

A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice.

The incidence of Clostridium difficile infection (CDI) and associated mortality have increased rapidly worldwide in recent years. Therefore, it is critical to develop new therapies for CDI. In this study, we generated a novel, potently neutralizing, tetravalent, and bispecific antibody composed of 2 heavy-chain-only VH (VHH) binding domains against both TcdA and TcdB (designated "ABA") that reverses fulminant CDI in mice infected with an epidemic 027 strain after a single injection of the antibody. We demonstrated that ABA bound to both toxins simultaneously and displayed a significantly enhanced neutralizing activity both in vitro and in vivo. Additionally, ABA was able to broadly neutralize toxins from clinical C. difficile isolates that express both TcdA and TcdB but failed to neutralize the toxin from TcdA(-)TcdB(+) C. difficile strains. This study thus provides a rationale for the development of multivalent VHHs that target both toxins and are broadly neutralizing for treating severe CDI.

Synergistic dual built-in electric fields in 1T-MoS2/Ni3S2/LDH for efficient electrocatalytic overall water splitting reactions.

Designing cost-effective electrocatalysts for water decomposition is crucial for achieving environmental-friendly hydrogen production. A transition metal sulfide/hydroxide electrocatalyst (1T-MoS2/Ni3S2/LDH) with double heterogeneous interfaces was developed through a two-step hydrothermal assisted electrodeposition method. The presence of the two built-in electric fields not only accelerated the charge transfer at the interface, but also enhanced the adsorption of the reactants and intermediate groups, and therefore improved the reaction rate and overall catalytic performance. The results suggest that the 1T-MoS2/Ni3S2/LDH catalysts display exceptional electrocatalytic reactivity. Under alkaline conditions, the overpotential of the electrocatalyst was 187 (η50) mV for OER and 104 (η10) mV for HER. Furthermore, the two-electrode system assembled by the electrocatalyst needs only a voltage of 1.55 V to deliver a current density of 10 mA cm-2. Our result provides a simple and effective methodical approach to the design of dual heterogeneous interfacial electrocatalysts.

Swing Origami-Structure-Based Triboelectric Nanogenerator for Harvesting Blue Energy toward Marine Environmental Applications.

The appearance of triboelectric nanogenerators (TENG) provides a promising energy technology for harvesting abundant water wave energy. Here, the design and fabrication of a swinging origami-structured TENG (SO-TENG) tailored specifically for water wave energy harvesting are presented. The design incorporates an oscillating structure weighted at the bottom, inducing reciprocating motion propelled by the inertia of passing water waves. This reciprocating motion efficiently converts mechanical into electrical energy through the origami structure. By employing origami as the monomer structure, the surface contact area between friction layers is enhanced, thereby optimizing output performance. the swinging structure, combined with the placement of heavy objects, enhances the folding and contact of the origami, allowing it to operate effectively in low-frequency water wave environments. This configuration exhibits robust power generation capabilities, making it suitable for powering small electronic devices in water wave environments. Furthermore, when applied to metal corrosion protection, the SO-TENG demonstrates notable efficacy. Compared to exposed Q235 carbon steel, Q235 carbon steel protected by SO-TENG exhibits a significant reduction in open-circuit potential drop, approximately 155 mV, indicative of superior anti-corrosion properties. It lays a solid foundation for water wave energy collection and self-powered metal corrosion protection in marine environments.