Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition,Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice

Treatments with sodium–glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin–angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.     

Functional Delineation of a Protein–Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8

Antibody engagement with the membrane-proximal external region (MPER) of the envelope glycoprotein (Env) of HIV-1 constitutes a distinctive molecular recognition phenomenon, the full appreciation of which is crucial for understanding the mechanisms that underlie the broad neutralization of the virus. Recognition of the HIV-1 Env antigen seems to depend on two specific features developed by antibodies with MPER specificity: (i) a large cavity at the antigen-binding site that holds the epitope amphipathic helix; and (ii) a membrane-accommodating Fab surface that engages with viral phospholipids. Thus, besides the main Fab–peptide interaction, molecular recognition of MPER depends on semi-specific (electrostatic and hydrophobic) interactions with membranes and, reportedly, on specific binding to the phospholipid head groups. Here, based on available cryo-EM structures of Fab–Env complexes of the anti-MPER antibody 10E8, we sought to delineate the functional antibody–membrane interface using as the defining criterion the neutralization potency and binding affinity improvements induced by Arg substitutions. This rational, Arg-based mutagenesis strategy revealed the position-dependent contribution of electrostatic interactions upon inclusion of Arg-s at the CDR1, CDR2 or FR3 of the Fab light chain. Moreover, the contribution of the most effective Arg-s increased the potency enhancement induced by inclusion of a hydrophobic-at-interface Phe at position 100c of the heavy chain CDR3. In combination, the potency and affinity improvements by Arg residues delineated a protein–membrane interaction site, whose surface and position support a possible mechanism of action for 10E8-induced neutralization. Functional delineation of membrane-interacting patches could open new lines of research to optimize antibodies of therapeutic interest that target integral membrane epitopes.     

Topdressing nitrogen recommendation in wheat after applying organic manures: the use of field diagnostic tools

Nitrogen is the largest input used by farmers, but they often apply excessive quantities of N fertilizer, causing nitrogen losses. In recent years, the management of large quantities of manure and slurry compounds has become a challenge. The aim of this study was to assess the usefulness of the proxy tools Yara N-tester? and RapidScan CS-45 for diagnosing the N nutritional status of wheat crops when farmyard manures were applied. Our second objective was to start designing a N fertilization strategy based on these measurements. To achieve these objectives, two field trials were established with three factors: growing season, three kinds of initial fertilizers [dairy slurry (40 t ha^?1), sheep manure (40 t ha^?1) and conventional (no organic fertilizer on basal dressing and 40 kg N ha^?1 at tillering)] and five N mineral fertilization dose applied at stem elongation. The proxy tools for diagnosing the N nutritional status were used at stem elongation before applying the mineral N. Proxy tool readings as indicators of the nitrogen nutritional status of the field were as good as soil mineral nitrogen (N_min) or Nitrogen Nutrition Index (NNI). When the readings were approximately 65% (as compared to an overfertilized control), the optimal N rate applied at stem elongation was slightly higher (10–20 kg N ha^?1) than the readings at 88%. The first N topdressing at the beginning of tillering could be avoided when manure was applied before sowing, unfolding new possibilities for a later application that might improve the protein content with lower likely fertilization costs.     

Targeting Myotonic Dystrophy Type 1 with Metformin

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 patients. Metformin is a biguanide antidiabetic drug, with potential to delay aging at cellular and organismal levels. In DM1, different studies revealed that metformin rescues multiple phenotypes of the disease. This review provides an overview of recent findings describing metformin as a novel therapy to combat DM1 and their link with aging.     

乳酸菌在肉制品中的生物防腐作用

<正> 肉制品是人们喜爱的食物,并具备丰富的营养。它不但能补充人体所需,促进人体健康,亦是各种自然细菌滋长的良好基质,能提供理想的细菌繁殖和生长条件,导致产品易腐败,甚至使人生病。所以,肉制品的质量在很大程度上受细菌群落的种类影响;至于肉制品中细菌群落的种类,则取决于原料肉的质量、加工过程中原料肉的处理方法,以及运输和贮存时的温度。 在中国,目前经加工处理后出售的肉制品,只占肉类总产量的5～10％。     

Latex allergy in patients with spinal dysraphism: the role of multiple surgery

OBJECTIVE: To investigate whether multiple surgery is responsible for the high prevalence of latex hypersensitivity in patients with spinal dysraphism by comparing the results of a skin-prick test in three groups of patients with different surgical histories. PATIENTS AND METHODS: An in vivo diagnostic kit was used to determine the sensitivity to latex using a skin-prick test in three groups of patients, 23 with spinal dysraphism who had undergone surgery, 20 patients who had undergone non-urological surgery and urological patients who had not undergone surgery (control). There was no history of latex allergy in any individual from the three groups. RESULTS: The skin-test was positive in six patients with spinal dysraphism, in one who had undergone previous non-urological surgery and in none of the control patients. The prevalence of latex hypersensitivity was significantly higher in patients with spinal dysraphism than in the other groups (non-urological surgery P < 0.05 and control P < 0.01). This difference occurred despite the patients in each surgical group having undergone a mean of less than two operations. There was no significant difference in latex sensitivity between control patients and those undergoing non-urological surgery. CONCLUSION: Despite having no history of latex hypersensitivity, about a quarter of patients with spinal dysraphism were sensitive to latex. Repeated surgery alone cannot be responsible for the greater incidence of latex hypersensitivity in these patients. Despite multiple surgery being accepted as playing a major role in the development of latex hypersensitivity, relatively fewer surgical episodes than reported previously seem to be sufficient to elicit latex allergy.     

Silk Fibroin as Sustainable Advanced Material: Material Properties and Characteristics,Processing, and Applications

Biobased resources are proposed as next-generation materials for advanced application. Among them, silk fibroin, a protein-based material generally obtained from Bombyx mori cocoons, is considered to play an increasing role in the development of a more sustainable generation of devices. In this review, the silk fibroin molecular structure and its original properties are presented, together with a wide overview of the available modifications and processing methods to reach custom structural and functional variations.     

Stable Graphene Membranes for Selective Ion Transport and Emerging Contaminants Removal in Water

Carbon-based materials, such as graphene oxide and reduced graphene oxide membranes have been recently used to fabricate ultrathin, high-flux, and energy-efficient membranes for ionic and molecular sieving in aqueous solution. However, these membranes appeared rather unstable during long-term operation in water with a tendency to swell over time. Membranes produced from pristine, stable, layered graphene materials may overcome these limitations while providing high-level performance. In this paper, an efficient and “green” strategy is proposed to fabricate µm-thick, graphene-based laminates by liquid phase exfoliation in Cyrene and vacuum filtration on a PVDF support. The membranes appear structurally robust and mechanically stable, even after 90 days of operation in water. In ion transport studies, the membranes show size selection (>3.3 Å) and anion-selectivity via the positively charged nanochannels forming the graphene laminate. In antibiotic (tetracycline) diffusion studies under dynamic conditions, the membrane achieve rejection rates higher than 95%. Sizable antibacterial properties are demonstrated in contact method tests with Staphylococcus aureus and Escherichia coli bacteria. Overall, these “green” graphene-based membranes represent a viable option for future water management applications.