Activity

Mechanically, our results indicate that an inhibitory effect of MTHFD2 knockdown may be mediated by the downregulation of cyclin B1/Cdc2 complex and the inhibitory effect on its activity. Additionally, MTHFD2 could regulate cell growth and aggressiveness via activation of STAT3 and the STAT3-induced epithelial-mesenchymal transition (EMT) signaling pathway. These findings indicate that MTHFD2 is overexpressed in ovarian cancer and regulates cell proliferation and metastasis, presenting an attractive therapeutic target.

Animal models have demonstrated an interactive relationship between the epithelial anion exchanger SLC26A6 and transporter NaDC-1 that regulates citrate and oxalate homeostasis. This relationship is a potential mechanism to protect against kidney stones as higher urine oxalate is accompanied by higher urine citrate but it has not been explored in humans.

We examined 24-h urine data on 13,155kidney stone forming patients (SF) from separate datasets at the University of Chicago and Litholink, a national laboratory, and 143 non-kidney stone forming participants (NSF) to examine this relationship in humans. We used multivariate linear regression models to examine the association between oxalate and citrate in all study participants and separately in SF and NSF.

Higher urinary oxalate was associated with higher urinary citrate in both SF and NSF. In NSF, the multivariate adjusted urine citrate excretion was 3.0 (1.5-4.6) (mmol)/creatinine (mmol) per oxalate (mmol)/creatinine (mmol). In SF, the multivariate adjusted urine citrate excretion was 0.3 (0.2-0.4) (mmol)/creatinine (mmol) per oxalate (mmol)/creatinine (mmol).

Higher urinary oxalate excretion was associated with higher urinary citrate excretion and this effect was larger in non-kidney stone forming participants compared with those who form kidney stones.

Higher urinary oxalate excretion was associated with higher urinary citrate excretion and this effect was larger in non-kidney stone forming participants compared with those who form kidney stones.Early oligomerization of human islet amyloid polypeptide (hIAPP), which is accountable for β-cell death, has been implicated in the progression of type 2 diabetes mellitus. Some researches have shown the connection between hIAPP and Alzheimer’s disease as well. However, the mechanism of peptide accumulation and associated cytotoxicity remains unclear. Due to the unique properties and significant role of histidine in protein sequences, here for the first time, the tautomeric effect of histidine at the early stages of amylin misfolding was investigated via molecular dynamics simulations. Considering Tau and Pi tautomeric forms of histidine (Tau and Pi tautomers are denoted as ϵ and δ, respectively), simulations were performed on two possible isomers of amylin. Our analysis revealed a higher probability of transient α-helix generation in the δ isomer in monomeric form. check details In dimeric forms, the δδ and δϵ conformations showed an elevated amount of α-helix and lower coil in comparison to the ϵϵ dimer. Due to the significant role of α-helix in membrane disruption and transition to β-sheet structure, these results may imply a noticeable contribution of the δ isomer and the δδ and δϵ dimers rather than ϵ and ϵϵ conformations in the early stages of diabetes initiation. Our results may aid in elucidating the hIAPP self-association process in the etiology of amyloidosis.The goal of this paper is to investigate the validity of a hybrid embedded/homogenized in-silico approach for modeling perfusion through solid tumors. The rationale behind this novel idea is that only the larger blood vessels have to be explicitly resolved while the smaller scales of the vasculature are homogenized. As opposed to typical discrete or fully resolved 1D-3D models, the required data can be obtained with in-vivo imaging techniques since the morphology of the smaller vessels is not necessary. By contrast, the larger vessels, whose topology and structure is attainable noninvasively, are resolved and embedded as one-dimensional inclusions into the three-dimensional tissue domain which is modeled as a porous medium. A sound mortar-type formulation is employed to couple the two representations of the vasculature. We validate the hybrid model and optimize its parameters by comparing its results to a corresponding fully resolved model based on several well-defined metrics. These tests are performed on a complex data set of three different tumor types with heterogeneous vascular architectures. The correspondence of the hybrid model in terms of mean representative elementary volume blood and interstitial fluid pressures is excellent with relative errors of less than 4%. Larger, but less important and explicable errors are present in terms of blood flow in the smaller, homogenized vessels. We finally discuss and demonstrate how the hybrid model can be further improved to apply it for studies on tumor perfusion and the efficacy of drug delivery.

Acute colonic pseudo-obstruction (ACPO) is a severe form of colonic dysmotility and is associated with considerable morbidity. The pathophysiology of ACPO is considered to be multifactorial but has not been clarified. Although colonic motility is commonly assumed to be hypoactive, there is little direct pathophysiological evidence to support this claim.

A 56-year-old woman who developed ACPO following spinal surgery underwent 24h of continuous high-resolution colonic manometry (1cm resolution over 36cm) following endoscopic decompression. Manometry data were analyzed and correlated with a three-dimensional colonic model developed from computed tomography (CT) imaging.

The distal colon was found to be profoundly hyperactive, showing near-continuous non-propagating motor activity. Dominant frequencies at 2-6 and 8-12 cycles per minute were observed. The activity was often dissociated and out-of-phase across adjacent regions. The mean amplitude of motor activity was higher than that reported from pre- and post-prandial healthy controls. Correlation with CT imaging suggested that these disordered hyperactive motility sequences might act as a functional pseudo-obstruction in the distal colon resulting in secondary proximal dilatation.

This is the first detailed description of motility patterns in ACPO and suggests a novel underlying disease mechanism, warranting further investigation and identification of potential therapeutic targets.

This is the first detailed description of motility patterns in ACPO and suggests a novel underlying disease mechanism, warranting further investigation and identification of potential therapeutic targets.