The hydrogen evolution reaction (HER) usually has sluggish kinetics in alkaline solution due to the difficulty in forming binding protons. Herein we report an electrocatalyst in which sulfur atoms are doping in the oxygen vacancies (VO ) of inverse spinel NiFe2 O4 (S-NiFe2 O4 ) to create active sites with enhanced electron transfer capability. This electrocatalyst has an ultralow overpotential of 61 mV at the current density of 10 mA cm-2 and long-term stability of 60 h at 1.0 Acm-2 in 1.0 M KOH media. In situ Raman spectroscopy revealed that S sites adsorb hydrogen adatom (H*) and in situ form S-H*, which favor the production of hydrogen and boosts HER in alkaline solution. DFT calculations further verified that S introduction lowered the energy barrier of H2 O dissociation. Both experimental and theoretical investigations confirmed S atoms are active sites of the S-NiFe2 O4 .Mycophenolic acid (MPA) is a fungal natural product and first-line immunosuppressive drug for organ transplantations and autoimmune diseases. In the compartmentalized biosynthesis of MPA, the acyl-coenzyme A (CoA) hydrolase MpaH’ located in peroxisomes catalyzes the highly specific hydrolysis of MPA-CoA to produce the final product MPA. The strict substrate specificity of MpaH’ not only averts undesired hydrolysis of various cellular acyl-CoAs, but also prevents MPA-CoA from further peroxisomal β-oxidation catabolism. To elucidate the structural basis for this important property, in this study, we solve the crystal structures of the substrate-free form of MpaH’ and the MpaH’S139A mutant in complex with the product MPA. The MpaH’ structure reveals a canonical α/β-hydrolase fold with an unusually large cap domain and a rare location of the acidic residue D163 of catalytic triad after strand β6. MpaH’ also forms an atypical dimer with the unique C-terminal helices α13 and α14 arming the cap domain of the other protomer and indirectly participating in the substrate binding. With these characteristics, we propose that MpaH’ and its homologs form a new subfamily of α/β hydrolase fold protein. The crystal structure of MpaH’S139A /MPA complex and the modeled structure of MpaH’/MPA-CoA, together with the structure-guided mutagenesis analysis and isothermal titration calorimetry (ITC) measurements, provide important mechanistic insights into the high substrate specificity of MpaH’.

Treatment strategies in locally recurrent rectal cancer (LRRC) are complex and need to be balanced against previous treatments received for the primary rectal cancer. Radiotherapy is an important component of treatment in LRRC. However, there is little high-quality evidence on the role of reirradiation in this cohort. Therefore, the aim of this trial is to assess the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with LRRC.

GRECCAR 15 is a prospective, multicentre, open-label, outcome assessor-blinded, superiority randomized controlled phase III clinical trial comparing neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone in patients with LRRC previously irradiated for the primary cancer. Adult patients (>18years old) with a histologically proven resectable LRRC, who have previously received pelvic radiotherapy for their primary r this trial will inform definitively the neoadjuvant treatment strategy in previously irradiated patients and assess whether there is any associated benefit of reirradiation in combination with induction chemotherapy in improving R0 resection rates.The first examples of Lewis base adducts of the parent boraphosphaketene (H2 B-PCO) and their cyclodimers are prepared. One of these adducts is shown to undergo mild decarbonylation and phosphinidene insertion into a B-C bond of a borole, forming very rare examples of 1,2-phosphaborinines, B/P isosteres of benzene. The strong donor properties of these 1,2-phosphaborinines are confirmed by the synthesis of their π complexes with the Group 6 metals.Subtype selectivity represents a challenge in many drug discovery campaigns. A typical example is the FK506 binding protein 51 (FKBP51), which has emerged as an attractive drug target. The most advanced FKBP51 ligands of the SAFit class are highly selective vs. AF-353 order FKBP52 but poorly discriminate against the homologs and off-targets FKBP12 and FKBP12.6. During a macrocyclization pilot study, we observed that many of these macrocyclic analogs have unanticipated and unprecedented preference for FKBP51 over FKBP12 and FKBP12.6. Structural studies revealed that these macrocycles bind with a new binding mode featuring a transient conformation, which is disfavored for the small FKBPs. Using a conformation-sensitive assay we show that this binding mode occurs in solution and is characteristic for this new class of compounds. The discovered macrocycles are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51 on IKKα. Our findings provide a new chemical scaffold for improved FKBP51 ligands and the structural basis for enhanced selectivity.Inspired by the nontrivial and controlled movements of molecular machines, we report an azobenzene-based molecular shuttle PR2, which can perform light-gated ion transport across lipid membranes. The amphiphilicity and membrane-spanning molecular length enable PR2 to insert into the bilayer membrane and efficiently transport K+ (EC50 =4.1 μm) through the thermally driven stochastic shuttle motion of the crown ether ring along the axle. The significant difference in shuttling rate between trans-PR2 and cis-PR2 induced by molecular isomerization enables a light-gated ion transport, i.e., ON/OFF in situ regulation of transport activity and single-channel current. This work represents an example of using a photoswitchable molecular machine to realize gated ion transport, which demonstrates the value of molecular machines functioning in biomembranes.The abilities of the long-acting, dual-agonist anti-diabetic peptides [D-Ala2 ]palmitoyl-lamprey GLP-1 and [D-Ser2 ]palmitoyl-paddlefish glucagon to induce α-cell to β-cell transdifferentiation were investigated in GluCreERT2 ;ROSA26-eYFP mice. These animals have been genetically engineered so that yellow fluorescent protein is specifically expressed in glucagon-producing α-cells, thereby allowing cell lineage tracing. Insulin deficiency was produced by treatment of the mice with multiple low doses of streptozotocin. Administration of the peptides (twice daily intraperitoneal injections of 25 nmol/kg body weight over 10 days) to streptozotocin-treated mice produced significant (P  less then  0.05) increases in pancreatic insulin content and plasma insulin concentrations compared with control mice. Immunohistochemical studies demonstrated a significant (P  less then  0.05) increase in the % of cells staining for both insulin and fluorescent protein in islets located in the head region of the pancreas (from 10.