A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A.

Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in aging and metabolism regulation. Targeted sequencing of SIRT6 locus in a population of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ individuals without a family history of exceptional longevity identified enrichment of a SIRT6 allele containing two linked substitutions (N308K/A313S) in centenarians compared with AJ control individuals. Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double-strand break repair, and more robustly kill cancer cells compared with wild-type SIRT6. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which was correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

Ultrafine mapping of chromosome conformation at hundred basepair resolution reveals regulatory genome architecture.

The resolution limit of chromatin conformation capture methodologies (3Cs) has restrained their application in detection of fine-level chromatin structure mediated by cis-regulatory elements (CREs). Here, we report two 3C-derived methods, Tri-4C and Tri-HiC, which utilize multirestriction enzyme digestions for ultrafine mapping of targeted and genome-wide chromatin interaction, respectively, at up to one hundred basepair resolution. Tri-4C identified CRE loop interaction networks and quantitatively revealed their alterations underlying dynamic gene control. Tri-HiC uncovered global fine-gauge regulatory interaction networks, identifying >20-fold more enhancer:promoter (E:P) loops than in situ Hi-C. In addition to vastly improved identification of subkilobase-sized E:P loops, Tri-HiC also uncovered interaction stripes and contact domain insulation from promoters and enhancers, revealing their loop extrusion behaviors resembling the topologically associating domain boundaries. Tri-4C and Tri-HiC provide robust approaches to achieve the high-resolution interactome maps required for characterizing fine-gauge regulatory chromatin interactions in analysis of development, homeostasis, and disease.

Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives.

Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1-2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15-20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10-40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.

High Configuration Entropy Promises Electrochemical Stability of Chloride Electrolytes for High-Energy, Long-Life All-Solid-State Batteries.

Solid-state electrolytes (SSEs) with high ionic conductivity, stability, and interface compatibility are indispensable for high-energy-density and long-life all-solid-state batteries (ASSBs), yet there are scarce SSEs with sufficient ionic conductivity and electrochemical stability. In this study, with a high-entropy SSE (HE-SSE, Li2.9In0.75Zr0.1Sc0.05Er0.05Y0.05Cl6), we show the high configuration entropy has a thermodynamically positive relationship with the high-voltage stability. As a result, the ASSBs with HE-SSE and high-voltage cathode materials exhibit superior high-voltage and long-cycle stability, achieving 250 cycles with 81.4% capacity retention when charged to 4.8 V (vs. Li+/Li), and even 5000 cycles if charged to 4.6 V (vs. Li+/Li).  Experimental characterizations and density functional theory calculations confirm that the HE-SSE greatly suppresses the high-voltage degradation of SSE at the interface, promoting the high-voltage stability coordinately through high entropy and interface stability. The high entropy design offers a general strategy to simultaneously improve the high-voltage stability and ionic conductivity of SSEs, creating an avenue to building high-energy and long-life ASSBs.

The promoting effects of pyriproxyfen on autophagy and apoptosis in silk glands of non-target insect silkworm, Bombyx mori.

Pyriproxyfen is a juvenile hormone analogue. The physiological effects of its low-concentration drift during the process of controlling agricultural and forestry pests on non-target organisms in the ecological environment are unpredictable, especially the effects on organs that play a key role in biological function are worthy of attention. The silk gland is an important organ for silk-secreting insects. Herein, we studied the effects of trace pyriproxyfen on autophagy and apoptosis of the silk gland in the lepidopteran model insect, Bombyx mori (silkworm). After treating fifth instar silkworm larvae with pyriproxyfen for 24 h, we found significant shrinkage, vacuolization, and fragmentation in the posterior silk gland (PSG). In addition, the results of autophagy-related genes of ATG8 and TUNEL assay also demonstrated that autophagy and apoptosis in the PSG of the silkworm was induced by pyriproxyfen. RNA-Seq results showed that pyriproxyfen treatment resulted in the activation of juvenile hormone signaling pathway genes and inhibition of 20-hydroxyecdysone (20E) signaling pathway genes. Among the 1808 significantly differentially expressed genes, 796 were upregulated and 1012 were downregulated. Among them, 30 genes were identified for autophagy-related signaling pathways, such as NOD-like receptor signaling pathway and mTOR signaling pathway, and 30 genes were identified for apoptosis-related signaling pathways, such as P53 signaling pathway and TNF signaling pathway. Further qRT-PCR and in vitro gland culture studies showed that the autophagy-related genes Atg5, Atg6, Atg12, Atg16 and the apoptosis-related genes Aif, Dronc, Dredd, and Caspase1 were responsive to the treatment of pyriproxyfen, with transcription levels up-regulated from 24 to 72 h. In addition, ATG5, ATG6, and Dronc genes had a more direct response to pyriproxyfen treatment. These results suggested that pyriproxyfen treatment could disrupt the hormone regulation in silkworms, promoting autophagy and apoptosis in the PSG. This study provides more evidence for the research on the damage of juvenile hormone analogues to non-target organisms or organs in the environment, and provides reference information for the scientific and rational use of juvenile hormone pesticides.

Porous Ga2 O3 Nanotubes Derived from Urease-Mediated Interfacially-Grown NH4 Ga(OH)2 CO3 for High-Efficient Hydrogen Evolution.

The authors proposed a novel template-free strategy, urease-mediated interfacial growth of NH4 Ga(OH)2 CO3 nanotubes at 20-50 °C, to fabricate the porous Ga2 O3 nanotubes. The subtlety of the proposed strategy is all the products from urea enzymolysis are utilized in formation of NH4 Ga(OH)2 CO3 precipitates, and the key for interfacial growth of NH4 Ga(OH)2 CO3 nanotubes is the dynamic match between the rate of CO2 bubble fusion and NH4 Ga(OH)2 CO3 precipitation. The proposed strategy works well for the doped porous Ga2 O3 nanotubes. As a proof-of-concept, the porous ß-Ga2 O3 and ß-Ga2 O3 :Cr0.001 nanotubes are used as photocatalysts or co-catalysts with Pt, for H2 evolution from water splitting. The H2 evolution rate of porous ß-Ga2 O3 nanotubes reach 39.3 mmol g-1 h-1 with solar-to-hydrogen (STH) conversion efficiency of 2.11% (Hg lamp) or 498 µmol g-1 h-1 with STH of 0.03% (Xe lamp) respectively, both about 3 times of ß-Ga2 O3 nanoparticles synthesized at pH 9.0 without urease. The Cr-doping enhances the in-the-dark H2 evolution rate pre-lighted by Hg lamp, and Pt co-catalysis further elevates the H2 evolution rate, for instance, the H2 evolution rate of Pt-loaded ß-Ga2 O3 :Cr0.001 nanotubes reaches 54.7 mmol g-1 h-1 with STH of 2.94% under continuous lighting of Hg lamp and 1062 µmol g-1 h-1 in-the-dark.

Materials Design Principles for Air-Stable Lithium/Sodium Solid Electrolytes.

Sulfide solid electrolytes are promising inorganic solid electrolytes for all-solid-state batteries. Despite their high ionic conductivity and desirable mechanical properties, many known sulfide solid electrolytes exhibit poor air stability. The spontaneous hydrolysis reactions of sulfides with moisture in air lead to the release of toxic hydrogen sulfide and materials degradation, hindering large-scale manufacturing and applications of sulfide-based solid-state batteries. In this work, we systematically investigate the hydrolysis and reduction reactions in Li- and Na-containing sulfides and chlorides by applying thermodynamic analyses based on a first principles computation database. We reveal the stability trends among different chemistries and identify the effect of cations, anions, and Li/Na content on moisture stability. Our results identify promising materials systems to simultaneously achieve desirable moisture stability and electrochemical stability, and provide the design principles for the development of air-stable solid electrolytes.

mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases.

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.

Comparison of 3 Treatment Methods for Distal Tibial Fractures: A Network Meta-Analysis.

BACKGROUND The choice of optimal internal fixation device for distal tibial fractures remains controversial. The purpose of our study was to evaluate the effectiveness and safety of open reduction and internal fixation, minimally invasive percutaneous osteosynthesis, and intramedullary nailing of distal tibial fractures in adults using network meta-analysis of data from clinical trials. MATERIAL AND METHODS The studies were abstracted from MEDLINE, EMBASE, CNKI, and the Cochrane Central Register of Controlled Trials. Randomized controlled trials meeting inclusion and exclusion criteria were selected. Statistical analyses were conducted using Stata software, version 13.0 (Stata Corporation, College Station, Texas, USA). RESULTS Eleven randomized controlled trials were included. The total number of participants was 710 and the studies were published between 2005 and 2017. There were no significant differences in rates of delayed union, nonunion, or malunion among the various treatments (all p>0.05). The intramedullary nailing group had a lower incidence of wound complications than did the open reduction and internal fixation group and minimally invasive percutaneous osteosynthesis technique group. The SUCRA probabilities were 28.6% for ORIF, 98.4% for IMN, and 22.9% for MIPPO. CONCLUSIONS Given the superior results for intramedullary nailing in terms of wound complications, we recommend this procedure for treatment of distal tibial fractures. More RCTs focused on distal tibial fractures are needed to support the current evidence.

Transition from Superlithiophobicity to Superlithiophilicity of Garnet Solid-State Electrolyte.

All-solid-state Li-batteries using solid-state electrolytes (SSEs) offer enhanced safety over conventional Li-ion batteries with organic liquid electrolytes due to the nonflammable nature of SSEs. The superior mechanical strength of SSEs can also protect against Li dendrite penetration, which enables the use of the highest specific capacity (3861 mAh/g) and lowest redox potential (-3.04 V vs standard hydrogen electrode) anode: Li metal. However, contact between the Li metal and SSEs presents a major challenge, where a large polarization occurs at the Li metal/SSE interface. Here, the chemical properties of a promising oxide-based SSE (garnet) changed from "super-lithiophobicity" to "super-lithiophilicity" through an ultrathin coating of amorphous Si deposited by plasma-enhanced chemical vapor deposition (PECVD). The wettability transition is due to the reaction between Li and Si and the in situ formation of lithiated Si. As a result, symmetric cells composed of a Si-coated garnet-structured SSE and Li metal electrodes exhibited much smaller impedance and excellent stability upon plating/stripping cycles compared to cells using bare garnet SSE. Specifically, the interfacial resistance between Li and garnet dramatically decreased from 925 to 127 Ω cm(2) when lithiated Si was formed on the garnet. Our discovery of switchable lithiophobic-lithiophilic surfaces to improve the Li metal/SSE interface opens opportunities for improving many other SSEs.

Sodiation Kinetics of Metal Oxide Conversion Electrodes: A Comparative Study with Lithiation.

The development of sodium ion batteries (NIBs) can provide an alternative to lithium ion batteries (LIBs) for sustainable, low-cost energy storage. However, due to the larger size and higher m/e ratio of the sodium ion compared to lithium, sodiation reactions of candidate electrodes are expected to differ in significant ways from the corresponding lithium ones. In this work, we investigated the sodiation mechanism of a typical transition metal-oxide, NiO, through a set of correlated techniques, including electrochemical and synchrotron studies, real-time electron microscopy observation, and ab initio molecular dynamics (MD) simulations. We found that a crystalline Na2O reaction layer that was formed at the beginning of sodiation plays an important role in blocking the further transport of sodium ions. In addition, sodiation in NiO exhibits a "shrinking-core" mode that results from a layer-by-layer reaction, as identified by ab initio MD simulations. For lithiation, however, the formation of Li antisite defects significantly distorts the local NiO lattice that facilitates Li insertion, thus enhancing the overall reaction rate. These observations delineate the mechanistic difference between sodiation and lithiation in metal-oxide conversion materials. More importantly, our findings identify the importance of understanding the role of reaction layers on the functioning of electrodes and thus provide critical insights into further optimizing NIB materials through surface engineering.

Synthesis of directly fused porphyrin dimers through Fe(OTf)3-mediated oxidative coupling.

An efficient and general Fe(OTf)3-mediated oxidative coupling method was developed for the synthesis of doubly or triply linked porphyrin dimers. Besides the central metal and peripheral substituent, regioselectivity of the oxidative coupling was found to be closely relevant to the onset oxidation potential of the porphyrin substrate, and the reactant with higher E(onset(ox)) tends to generate meso-ß doubly fused porphyrin dimer.

Werner complex deficiency in cells disrupts the Nuclear Pore Complex and the distribution of lamin B1.

From the surrounding shell to the inner machinery, nuclear proteins provide the functional plasticity of the nucleus. This study highlights the nuclear association of Pore membrane (POM) protein NDC1 and Werner protein (WRN), a RecQ helicase responsible for the DNA instability progeria disorder, Werner Syndrome. In our previous publication, we connected the DNA damage sensor Werner's Helicase Interacting Protein (WHIP), a binding partner of WRN, to the NPC. Here, we confirm the association of the WRN/WHIP complex and NDC1. In established WRN/WHIP knockout cell lines, we further demonstrate the interdependence of WRN/WHIP and Nucleoporins (Nups). These changes do not completely abrogate the barrier of the Nuclear Envelope (NE) but do affect the distribution of FG Nups and the RAN gradient, which are necessary for nuclear transport. Evidence from WRN/WHIP knockout cell lines demonstrates changes in the processing and nucleolar localization of lamin B1. The appearance of "RAN holes" void of RAN corresponds to regions within the nucleolus filled with condensed pools of lamin B1. From WRN/WHIP knockout cell line extracts, we found three forms of lamin B1 that correspond to mature holoprotein and two potential post-translationally modified forms of the protein. Upon treatment with topoisomerase inhibitors lamin B1 cleavage occurs only in WRN/WHIP knockout cells. Our data suggest the link of the NDC1 and WRN as one facet of the network between the nuclear periphery and genome stability. Loss of WRN complex leads to multiple alterations at the NPC and the nucleolus.

Clawlike tripodal porphyrin trimer: ion-controlled on­off fullerene binding.

A practical method for the preparation of novel tripodal tris(porphyrinato-urea) TP3 1 was readily achieved. Because of its appreciable preorganized triangular cone-shaped cavity resulting from the intramolecular hydrogen bonds of the tripodal tris-urea backbone, this porphyrin trimer host was found to have a high affinity toward fullerenes to form stable inclusion complexes in solution. A 120-fold binding selectivity toward C70 (Kassoc = 1.81 × 10(7) M(­1)) over C60 (Kassoc = 1.51 × 10(5) M(­1)) was further achieved in toluene. Moreover, the dissociation of such inclusion complexes can be easily realized by introducing H2PO4(­), and recapturing of the fullerene can be achieved after withdrawing H2PO4(­) by Ca(2+). A recyclable process for the inclusion and release of fullerene was therefore built by alternately feeding H2PO4(­) and Ca(2+). Benefiting from this approach, TP3 1 was sequentially applied to isolate C70 from the C60-enriched fullerene mixture successfully.

Metal-free iodine(III)-promoted synthesis of isoquinolones.

A metal-free oxidative cycloaddition reaction of substituted benzamides and alkynes has been developed for the synthesis of isoquinolones by using bis(trifluoracetoxy)iodobenzene (PIFA) and trifluoroacetic acid (TFA). Under mild conditions, a wide variety of isoquinolones were conveniently prepared via oxidative annulation of simple N-methoxybenzamide and diarylacetylene or aryl/alkyl acetylene derivatives in yields up to 87%.

Switchable regioselectivity in the PIFA-BF3·Et2O mediated oxidative coupling of meso-brominated Ni(II) porphyrin.

A simple and efficient method has been developed for the switchable synthesis of directly linked meso-brominated Ni(II) porphyrin dimers through PIFA-BF3·Et2O mediated oxidative coupling. The respective syntheses of meso-meso or meso-ß singly, doubly, and triply linked porphyrin dimers can be easily realized with the same reagent system.

FecBB mutation enhances follicle stimulating hormone sensitivity of granulosa cells by up-regulating the SMAD1/5-USF1-FSHR signaling pathway.

The FecBB mutation, a single-point mutation (c.A746G; p.Q249R) in bone morphogenetic protein receptor type 1 B (BMPR1B), is associated with increased ovulation quotas and litter size in sheep. However, the regulatory mechanism of the FecBB mutation in increased fecundity remains to be elucidated. Therefore, creating an immortal cell model harboring the FecBB mutation would elucidate the regulatory mechanism of this mutation. Here, we report the creation of a human granulosa cell, COV434, model containing a homozygous FecBB mutation through homology-directed repair (HDR) induced by clustered, regularly-interspaced, short palindromic repeats-CRISPR-associated protein 9 along with a single-stranded oligodeoxynucleotide (ssODN) template. We found that the FecBB mutation enhanced the basal SMAD1/5 signaling activity in COV434 cells, leading to increased expression of FSHR, probably through increased formation of the SMAD1/5-SMAD4 complex to bind to the SBE element, which in turn promotes the binding of USF1 to the regulatory element E-box in the promoter of FSHR. Furthermore, the FecBB mutation substantially enhanced estradiol (E2) synthesis in granulosa cells under follicle stimulating hormone (FSH) stimulation, indicating an enhanced sensitivity to FSH, which may promote the growth of more small follicles into mature follicles, leading to increased fecundity. Our study provides novel insights into the possible regulatory mechanisms of FecBB mutations in increased fecundity.

High-Voltage Long-Cycling All-Solid-State Lithium Batteries with High-Valent-Element-Doped Halide Electrolytes.

All-solid-state batteries (ASSBs) have garnered considerable attention as promising candidates for next-generation energy storage systems due to their potentially simultaneously enhanced safety capacities and improved energy densities. However, the solid future still calls for materials with high ionic conductivity, electrochemical stability, and favorable interfacial compatibility. In this study, we present a series of halide solid-state electrolytes (SSEs) utilizing a doping strategy with highly valent elements, demonstrating an outstanding combination of enhanced ionic conductivity and oxidation stability. Among these, Li2.6In0.8Ta0.2Cl6 emerges as the standout performer, displaying a superionic conductivity of up to 4.47 mS cm-1 at 30 °C, along with a low activation energy barrier of 0.321 eV for Li+ migration. Additionally, it showcases an extensive oxidation onset of up to 5.13 V (vs Li+/Li), enabling high-voltage ASSBs with promising cycling performance. Particularly noteworthy are the ASSBs employing LiCoO2 cathode materials, which exhibit an extended cyclability of over 1400 cycles, with 70% capacity retention under 4.6 V (vs Li+/Li), and a capacity of up to 135 mA h g-1 at a 4 C rate, with the loading of active materials at 7.52 mg cm-2. This study demonstrates a feasible approach to designing desirable SSEs for energy-dense, highly stable ASSBs.

Stabilizing Interlayer Repulsion in Layered Sodium-Ion Oxide Cathodes via Hierarchical Layer Modification.

Layered sodium-ion oxides hold considerable promise in achieving high-performance sodium-ion batteries. However, the notorious phase transformation during charging, attributed to increased O2-─O2- repulsion, results in substantial performance decay. Here, a hierarchical layer modification strategy is proposed to stabilize interlayer repulsion. During desodiation, migrated Li+ from the transition metal layer and anchored Ca2+ in sodium sites maintain the cationic content within the sodium layer. Meanwhile, partial oxygen substitution by fluorine and the involvement of oxygen in redox reactions increase the average valence of the oxygen layer. This sustained cation presence and elevated anion valence collectively mitigate increasing O2-─O2- repulsion during sodium extraction, enabling the Na0.61Ca0.05[Li0.1Ni0.23Mn0.67]O1.95F0.05 (NCLNMOF) cathode to retain a pure P2-type structure across a wide voltage range. Unexpected insights reveal the interplay between different doping elements: the robust Li─F bonds and Ca2+ steric effects suppressing Li+ loss. The NCLNMOF electrode exhibits 82.5% capacity retention after 1000 cycles and a high-rate capability of 94 mAh g-1 at 1600 mA g-1, demonstrating the efficacy of hierarchical layer modification for high-performance layered oxide cathodes.