DNA polymerases make up a family of enzymes responsible for regulating DNA replication and repair, which in turn maintains the integrity of the genome. However, despite intensive kinetic, crystallographic, and computational studies, elucidation of the detailed enzymatic mechanism still presents a significant challenge. We recently developed an alternative strategy for exploring the fidelity and me

Phosphate monoester and anhydride hydrolysis is ubiquitous in biology, being involved in, amongst other things, signal transduction, energy production, and the regulation of protein function. Therefore, this reaction has understandably been the focus of intensive research. Nevertheless, the precise mechanism by which phosphate monoester hydrolysis proceeds remains controversial. Traditionally, it

Many phosphatases make use of metal ions to aid catalysis of phosphate ester hydrolysis. Here, we investigate the impact of metal ions on the potential energy surface (PES), and hence the preferred reaction mechanism, for a simple model for hydrolysis of phosphate ester monoanions. We show that, while both associative (A(N) + D(N)) and dissociative (D(N) + A(N)) mechanisms are represented on the p

The hydrolysis of phosphate esters is crucially important to biological systems, being involved in, among other things, signaling, energy transduction, biosynthesis, and the regulation of protein function. Despite this, there are many questions that remain unanswered in this important field, particularly with regard to the preferred mechanism of hydrolysis of phosphate esters, which can proceed th

Hybrid quantum mechanical/molecular mechanical (QM/MM) approaches have been used to provide a general scheme for chemical reactions in proteins. However, such approaches still present a major challenge to computational chemists, not only because of the need for very large computer time in order to evaluate the QM energy but also because of the need for proper computational sampling. This review fo

Phosphate ester hydrolysis is ubiquitous in biology, playing a central role in energy production, signaling, biosynthesis, and the regulation of protein function among other things. Although the mechanism of action of the enzymes regulating this reaction has been the focus of intensive research in the past few decades, the correct description of this apparently simple reaction remains controversia

Protein tyrosine phosphatase 1B (PTP1B) is an important drug target for the treatment of type II diabetes and obesity. There are strong indications that a novel class of allosteric inhibitors act by preventing the closure of the WPD-loop [C. Wiesmann, K.J. Barr, J. Kung, J. Zhu, D.A. Erlanson, W. Shen, B.J. Fahr, M. Zhong, L. Taylor, M. Randall, R.S. McDowell, S.K. Hansen, Allosteric inhibition of

Targeted molecular dynamics was used to examine the mechanism of WPD loop closure in PTP1B, which is essential for the activity of the enzyme. Two important regions are identified: the R-loop (residues 113-118), which assists in substrate binding, and the S-loop (residues 198-209), which undergoes a conformational change that appears to be vital for the movement of the WPD loop. The S-loop is adja

Non-islet cell tumor hypoglycemia (NICTH) is one of the paraneoplastic syndromes manifesting severe hypoglycemia caused by aberrant production of high-molecular-weight insulin-like growth factor 2 (big-IGF2). Two surgical cases of extremely large thoracic solitary fibrous tumors (SFT) with unusual history of NICTH are presented. One case manifested severe hypoglycemia after four years of the first

BACKGROUND: Tumor-produced high molecular weight insulin-like growth factor-II (big insulin-like growth factor-II) is considered to cause non-islet cell tumor hypoglycemia. This paper presents a case of surgically resected retroperitoneal liposarcoma that produced big insulin-like growth factor-II.CASE PRESENTATION: Here, we report the case of a 62-year-old woman who presented with an abdominal ma

BACKGROUND: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a tumor-producing high molecular weight form of insulin-like growth factor 2 (IGF2) known as big IGF2. The only curative treatment for this condition is surgical resection of the responsible tumors. However, this may not be feasible in cases with multiple metastases at diagnosis of NICTH, and no stand

BACKGROUND: SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the lipid metabolism between the two types of antidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin and sitagliptin on serum lipid and apolipoprotein profiles and other c

BACKGROUND AND AIM: This study aimed to clarify the efficacy and safety of 48-week pemafibrate treatment in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) complicated by dyslipidemia.METHODS: A total of 110 patients diagnosed with MASLD complicated by dyslipidemia received pemafibrate at a dose of 0.1 mg twice daily for 48 weeks.RESULTS: The participants were 54 mal

OBJECTIVE: Widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to an increase in the number of reported cases of immunotherapy-related endocrinopathies. This study aimed to analyze and compare human leukocyte antigen (HLA) signatures associated with ICI-induced type 1 diabetes (ICI-T1D) and isolated adrenocorticotropic hormone deficiency (ICI-IAD) in patients with bot

AIMS: To evaluate the efficacy and safety of oral semaglutide for type 2 diabetes mellitus (T2DM) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).MATERIALS AND METHODS: This was a single-arm, multicentre, prospective study. Among 80 consecutive patients with MASLD and T2DM who newly received oral semaglutide, 70 completed 48-week oral semaglutide treatment as sche

Background: Middle Eastern (ME) immigrants to Europe have a heavy burden of metabolic disorders including a higher prevalence of insulin resistance, T2D and obesity as compared to native-born Europeans. Vitamin D insufficiency and deficiency are prevalent conditions in people originating from the ME. Aims: To study the differences in the levels of 25(OH)D and parathyroid hormone (PTH) across ME an

Seasonal water level fluctuations in rivers significantly influenced the cross-media migration, transformation, and risk diffusion of antibiotics from the vadose zone into groundwater. This study developed a coupled model integrating machine learning (ML) with HYDRUS-3D and GMS to accurately predict sulfamethazine migration under dynamic water levels. The predictive accuracy (E≥0.98) of this ML-HY

Om att kung Frederik X tagit bort de tre kronorna från det kungliga danska vapnet.

Background: Middle Eastern (ME) immigrants to Europe have a higher prevalence of type 2 diabetes (T2D) as compared to Europeans. Previous findings from the MEDIM population-based cohort (Impact of ethnicity and migration on diabetes in Malmö) have shown that ME immigrants are more insulin resistant before developing T2D as compared to native Swedes. However, knowledge is still lacking if there are

Coating synthetic nanoparticles (NPs) with lipid membranes is a promising approach to enhance the performance of nanomaterials in various biological applications, including therapeutic delivery to target organs. Current methods for achieving this coating often rely on bulk approaches which can result in low efficiency and poor reproducibility. Continuous processes coupled with quality control repr