Glucose-sensitive insulin with attenuation of hypoglycaemia.

The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes. Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fluctuating glucose levels is difficult because even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence, which can be anything from uncomfortable to life-threatening. It has therefore been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia.

Could the contraceptive counselling improve contraceptive choice after abortion? A multicentric study to evaluate patients' perception.

Introduction: 24 % of abortion in Italy are repeated procedure. The cause of repeated abortion can be traced back to the inadequacy of the contraceptive counseling during the previous admission or to the adoption of an ineffective contraception method. This study aims to evaluate the Italian situation on the perceived quality of contraceptive counselling by patients undergoing abortion.

Identification and engineering of potent cyclic peptides with selective or promiscuous binding through biochemical profiling and bioinformatic data analysis.

As our understanding of biological systems grows, so does the need to selectively target individual or multiple members of specific protein families in order to probe their function. Many targets of current biological and pharmaceutical interest are part of a large family of closely related proteins and achieving ligand selectivity often remains either an elusive or time-consuming endeavour. Cyclic peptides (CPs) occupy a key niche in ligand space, able to achieve high affinity and selectivity while retaining synthetic accessibility.

Predictive Maintenance of Pins in the ECD Equipment for Cu Deposition in the Semiconductor Industry.

Nowadays, Predictive Maintenance is a mandatory tool to reduce the cost of production in the semiconductor industry. This paper considers as a case study a critical part of the electrochemical deposition system, namely, the four Pins that hold a wafer inside a chamber. The aim of the study is to replace the schedule of replacement of Pins presently based on fixed timing (Preventive Maintenance) with a Hardware/Software system that monitors the conditions of the Pins and signals possible conditions of failure (Predictive Maintenance).

A Case Manager-Led Pneumonia Care Bundle in a Subacute Rehabilitation Facility.

Purpose Of The Study: To evaluate the relationship between a case manager-led pneumonia care bundle at skilled nursing facilities (SNFs) and 30-day hospital readmissions for pneumonia.

Primary Practice Settings: The primary practice settings included patients hospitalized with pneumonia at 2 community hospitals between October 2018 and June 2019 and who were subsequently transferred to an SNF.

Methodology And Sample: A retrospective cohort study was completed comparing patients in the preintervention cohort who received pneumonia standard of care versus patients in the postintervention cohort who received a case manager-led evidence-based pneumonia care bundle at an SNF.

Conserved conformational dynamics determine enzyme activity.

Homologous enzymes often exhibit different catalytic rates despite a fully conserved active site. The canonical view is that an enzyme sequence defines its structure and function and, more recently, that intrinsic protein dynamics at different time scales enable and/or promote catalytic activity. Here, we show that, using the protein tyrosine phosphatase PTP1B, residues surrounding the PTP1B active site promote dynamically coordinated chemistry necessary for PTP1B function.

Sequence and structural conservation reveal fingerprint residues in TRP channels.

Transient receptor potential (TRP) proteins are a large family of cation-selective channels, surpassed in variety only by voltage-gated potassium channels. Detailed molecular mechanisms governing how membrane voltage, ligand binding, or temperature can induce conformational changes promoting the open state in TRP channels are still a matter of debate. Aiming to unveil distinctive structural features common to the transmembrane domains within the TRP family, we performed phylogenetic reconstruction, sequence statistics, and structural analysis over a large set of TRP channel genes.

An integrated platform approach enables discovery of potent, selective and ligand-competitive cyclic peptides targeting the GIP receptor.

In any drug discovery effort, the identification of hits for further optimisation is of crucial importance. For peptide therapeutics, display technologies such as mRNA display have emerged as powerful methodologies to identify these desired hit ligands against targets of interest. The diverse peptide libraries are genetically encoded in these technologies, allowing for next-generation sequencing to be used to efficiently identify the binding ligands.

Third-trimester ultrasound for antenatal diagnosis of placenta accreta spectrum in women with placenta previa: results from the ADoPAD study.

Objective: To evaluate the performance of third-trimester ultrasound for the diagnosis of clinically significant placenta accreta spectrum disorder (PAS) in women with low-lying placenta or placenta previa.

Methods: This was a prospective multicenter study of pregnant women aged ≥ 18 years who were diagnosed with low-lying placenta (< 20 mm from the internal cervical os) or placenta previa (covering the internal cervical os) on ultrasound at ≥ 26 + 0 weeks' gestation, between October 2014 and January 2019. Ultrasound suspicion of PAS was raised in the presence of at least one of these signs on grayscale ultrasound: (1) obliteration of the hypoechogenic space between the uterus and the placenta; (2) interruption of the hyperechogenic interface between the uterine serosa and the bladder wall; (3) abnormal placental lacunae.

Synergistic stabilization of a double mutant in chymotrypsin inhibitor 2 from a library screen in E. coli.

Most single point mutations destabilize folded proteins. Mutations that stabilize a protein typically only have a small effect and multiple mutations are often needed to substantially increase the stability. Multiple point mutations may act synergistically on the stability, and it is often not straightforward to predict their combined effect from the individual contributions.

Polyamine blockade and binding energetics in the MthK potassium channel.

Polyamines such as spermidine and spermine are found in nearly all cells, at concentrations ranging up to 0.5 mM. These cations are endogenous regulators of cellular K+ efflux, binding tightly in the pores of inwardly rectifying K+ (Kir) channels in a voltage-dependent manner.

Analysis of the Destabilization of Bacterial Membranes by Quaternary Ammonium Compounds: A Combined Experimental and Computational Study.

The mechanism of action of quaternary ammonium compound (QAC) antiseptics has long been assumed to be straightforward membrane disruption, although the process of approaching and entering the membrane has little modeling precedent. Furthermore, questions have more recently arisen regarding bacterial resistance mechanisms, and why select classes of QACs (specifically, multicationic QACs) are less prone to resistance. In order to better understand such subtleties, a series of molecular dynamics simulations were utilized to help identify these molecular determinants, directly comparing mono-, bis-, and triscationic QACs in simulated membrane intercalation models.

Evolutionarily Conserved Interactions within the Pore Domain of Acid-Sensing Ion Channels.

Despite the sequence homology between acid-sensing ion channels (ASICs) and epithelial sodium channel (ENaCs), these channel families display very different functional characteristics. Whereas ASICs are gated by protons and show a relatively low degree of selectivity for sodium over potassium, ENaCs are constitutively active and display a remarkably high degree of sodium selectivity. To decipher if some of the functional diversity originates from differences within the transmembrane helices (M1 and M2) of both channel families, we turned to a combination of computational and functional interrogations, using statistical coupling analysis and mutational studies on mouse ASIC1a.

Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments.

Mutations in the tumor suppressor SPOP (speckle-type POZ protein) cause prostate, breast, and other solid tumors. SPOP is a substrate adaptor of the cullin3-RING ubiquitin ligase and localizes to nuclear speckles. Although cancer-associated mutations in SPOP interfere with substrate recruitment to the ligase, mechanisms underlying assembly of SPOP with its substrates in liquid nuclear bodies and effects of SPOP mutations on assembly are poorly understood.

Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites.

Voltage-gated sodium (Na) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic Na channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac.

Propofol inhibits prokaryotic voltage-gated Na channels by promoting activation-coupled inactivation.

Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block.

Dynamic activation and regulation of the mitogen-activated protein kinase p38.

Mitogen-activated protein kinases, which include p38, are essential for cell differentiation and autophagy. The current model for p38 activation involves activation-loop phosphorylation with subsequent substrate binding leading to substrate phosphorylation. Despite extensive efforts, the molecular mechanism of activation remains unclear.

Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel.

Voltage-gated, sodium ion-selective channels (Na) generate electrical signals contributing to the upstroke of the action potential in animals. Nas are also found in bacteria and are members of a larger family of tetrameric voltage-gated channels that includes Cas, Ks, and Nas. Prokaryotic Nas likely emerged from a homotetrameric Ca-selective voltage-gated progenerator, and later developed Na selectivity independently.

Patterns of coevolving amino acids unveil structural and dynamical domains.

Patterns of interacting amino acids are so preserved within protein families that the sole analysis of evolutionary comutations can identify pairs of contacting residues. It is also known that evolution conserves functional dynamics, i.e.

Electron-band theory inspired design of magnesium-precious metal bulk metallic glasses with high thermal stability and extended ductility.

Magnesium-based bulk metallic glasses (BMGs) exhibit high specific strengths and excellent glass-forming ability compared to other metallic systems, making them suitable candidates for next-generation materials. However, current Mg-based BMGs tend to exhibit low thermal stability and are prone to structural relaxation and brittle failure. This study presents a range of new magnesium-precious metal-based BMGs from the ternary Mg-Ag-Ca, Mg-Ag-Yb, Mg-Pd-Ca and Mg-Pd-Yb alloy systems with Mg content greater than 67 at.

Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac.

Voltage-gated sodium channels (Na) play an important role in general anesthesia. Electrophysiology measurements suggest that volatile anesthetics such as isoflurane inhibit Na by stabilizing the inactivated state or altering the inactivation kinetics. Recent computational studies suggested the existence of multiple isoflurane binding sites in Na, but experimental binding data are lacking.