Kayhealy5763

eded.

To present and evaluate a method to objectively quantify the functional regions of joint lumped passive stiffness.

Joint passive stiffness has an important clinical role in constraining the degrees of freedom at a given joint. Links between passive stiffness and injury, pathology and function may be better understood if joint passive stiffness can be accurately quantified. Thus, a technique was developed to objectively partition passive stiffness curves into 3 linear regions (low, transition and high stiffness).

The passive stiffness of the lumbar spine is presented as an example. Simulated data was used to determine the sensitivity of the method to Gaussian white noise in force measurements. An experimentally determined lumbar passive flexion curve was used to demonstrate the technique on human data. Breakpoint analysis was employed on the resulting moment-angle cures to partition the curve into low, transition and high stiffness zones.

The proposed method was successful at discriminating between the three stiffness zones and quantifying the passive stiffness within each zone. The algorithm had difficulty determining parameters in the low-stiffness zone in the presence of noise.

The proposed method can be used as an objective method to investigate passive stiffness. Breakpoint Analysis can identify the three functional linear zones of passive stiffness. The slopes of these linear regions are then used as a measure of passive stiffness, which have applications in clinical populations and research studies, to assess time varying responses, or changes in stiffness following an intervention.

The proposed method can be used as an objective method to investigate passive stiffness. Breakpoint Analysis can identify the three functional linear zones of passive stiffness. The slopes of these linear regions are then used as a measure of passive stiffness, which have applications in clinical populations and research studies, to assess time varying responses, or changes in stiffness following an intervention.Epstein-Barr Virus (EBV) exposure and illness is common in undergraduate university students and may affect academic achievement, social life, and quality of life. We designed a study to measure EBV exposure (EBV-IgG, either Epstein-Barr nuclear antigen 1 (EBNA-1)-IgG or viral capsid antigen (VCA)-IgG) and current viral shedding (EBV-DNA) using self-collected oral swabs among university undergraduate students. Of 184 students enrolled, 129 (70.1%) tested positive for EBV-IgG. Salivopositivity was associated with being in a current relationship, but not with enrollment year. Forty (21.7%) of the participants tested positive for EBV-DNA, which was associated with all symptom scores, including history of sore throat, fever, swollen glands, muscle weakness, and fatigue in the previous 6 months. Our findings suggest that noninvasive, self-collected oral flocked swabs are feasible and potentially valuable for measuring EBV IgG antibodies and DNA.

Fulminant hepatitis (FH) is a clinical syndrome characterized by sudden and severe liver dysfunction. Dot1L, a histone methyltransferase, is implicated in various physiologic and pathologic processes, including transcription regulation and leukemia. However, the role of Dot1L in regulating inflammatory responses during FH remains elusive.

Propionibacterium acnes (P.acnes)-primed, lipopolysaccharides (LPS)-induced FH was established in C57BL/6 mice and was treated with the Dot1L inhibitor EPZ-5676. Myeloid derived suppressor cells (MDSCs) were depleted by anti-Gr-1 antibody to evaluate their therapeutic roles in Dot1L treatment of FH. Moreover, peripheral blood of patients suffered with FH and healthy controls was collected to determine the expression profile of Dot1L-SOCS1-iNOS axis in their MDSCs.

Here we identified that EPZ-5676, pharmacological inhibitor of Dot1L, attenuated the liver injury of mice subjected to FH. Dot1L inhibition led to decreased T helper 1 cell response and expansion of regulatory T cells (Tregs) during FH. Interestingly, Dot1L inhibition didn't directly target T cells, but dramatically enhanced the immunosuppressive function of MDSCs. Mechanistically, Dot1L inhibition epigenetically suppressed SOCS1 expression, thus inducing inducible nitric oxide synthase (iNOS) expression in a STAT1-dependent manner. Moreover, in human samples, the levels of Dot1L and SOCS1 expression were upregulated in MDSCs, accompanied by decreased expression of iNOS in patients with FH, compared with healthy controls.

Altogether, our findings established Dot1L as a critical regulator of MDSC immunosuppressive function for the first time, and highlighted the therapeutic potential of Dot1L inhibitor for FH treatment.

Altogether, our findings established Dot1L as a critical regulator of MDSC immunosuppressive function for the first time, and highlighted the therapeutic potential of Dot1L inhibitor for FH treatment.

Defining the genetic heterogeneity of intrahepatic biliary epithelial cells (BECs) is challenging, and tools for identifying BEC subpopulations are limited. Here, we characterize the expression of a Sox9

transgene in the liver and demonstrate that green fluorescent protein (GFP) expression levels are associated with distinct cell types.

Sox9

BAC transgenic mice were assayed by immunofluorescence, flow cytometry, and gene expression profiling to characterize invivo characteristics of GFP populations. Single BECs from distinct GFP populations were isolated by fluorescence-activated cell sorting, and functional analysis was conducted in organoid forming assays. Intrahepatic ductal epithelium was grown as organoids and treated with a Yes-associated protein (Yap) inhibitor or bile acids to determine upstream regulation of Sox9 in BECs. Sox9

mice were subjected to bile duct ligation, and GFP expression was assessed by immunofluorescence.

BECs express low or high levels of GFP, whereas periportal hepatocytes express sublow GFP. Sox9

BECs are differentially distributed by duct size and demonstrate distinct gene expression signatures, with enrichment of Cyr61 and Hes1 in GFP

BECs. Single Sox9

cells form organoids that exhibit heterogeneous survival, growth, and HNF4A activation dependent on culture conditions, suggesting that exogenous signaling impacts BEC heterogeneity. Yap is required to maintain Sox9 expression in biliary organoids, but bile acids are insufficient to induce BEC Yap activity or Sox9 invivo and invitro. Sox9

remains restricted to BECs and periportal hepatocytes after bile duct ligation.

Our data demonstrate that Sox9

levels provide readout of Yap activity and delineate BEC heterogeneity, providing a tool for assaying subpopulation-specific cellular function in the liver.

Our data demonstrate that Sox9EGFP levels provide readout of Yap activity and delineate BEC heterogeneity, providing a tool for assaying subpopulation-specific cellular function in the liver.

The purpose of the current study was to compare levels of anxiety sensitivity (AS) across a treatment-seeking sample of individuals primarily using opioids, stimulants, or cannabis. Consistent with the idea that individuals high in AS may be motivated to use substances with real or perceived anxiolytic properties, it was hypothesized that individuals primarily using opioids or cannabis would evidence higher levels of AS compared to individuals primarily using stimulants.

The sample consisted of 110 veterans (including 29 individuals primarily using opioids, 42 primarily using cannabis, and 39 primarily using stimulants) presenting for psychological services to a Posttraumatic Stress Disorder (PTSD) and Substance Use Disorder (SUD) specialty clinic at a large southeastern Veteran Affairs (VA) hospital.

AS levels varied by group with individuals primarily using stimulants evidencing the highest levels followed by those primarily using opioids and then those primarily using cannabis. Individuals primarily using stimulants had statistically significantly higher levels of AS physical concerns compared to individuals primarily using cannabis but not those primarily using opioids. Further, individuals who primarily use opioids did not differ from those primarily using cannabis.

Taken together, these findings call into question the notion that AS may be negatively related to the use of substances that have anxiogenic properties.

Taken together, these findings call into question the notion that AS may be negatively related to the use of substances that have anxiogenic properties.

Apolipoprotein (apo) C1 is a 6.6kDa protein associated with HDL and VLDL. ApoC1 alters triglyceride clearance, and it also favors cholesterol accumulation in HDL, especially by inhibiting CETP in human plasma. Apart from studies in mice, which lack CETP, the impact of apoC1 on atherosclerosis in animal models expressing CETP, like in humans, is not known. This study aimed at determining the net effect of human apoC1 on atherosclerosis in rabbits, a species with naturally high CETP activity but with endogenous apoC1 without CETP inhibitory potential.

Rabbits expressing a human apoC1 transgene (HuApoC1Tg) were generated and displayed significant amounts of human apoC1 in plasma.

After cholesterol feeding, atherosclerosis lesions were significantly less extensive (-22%, p<0.05) and HDL displayed a reduced ability to serve as CETP substrates (-25%, p<0.05) in HuApoC1Tg rabbits than in WT littermates. It was associated with rises in plasma HDL cholesterol level and PON-1 activity, and a decrease in the plasma level of the lipid oxidation markers 12(S)-HODE and 8(S)HETE. In chow-fed animals, the level of HDL-cholesterol was also significantly higher in HuApoC1Tg than in WT animals (0.83±0.11 versus 0.73±0.11mmol/L, respectively, p<0.05), and it was associated with significantly lower CETP activity (cholesteryl ester transfer rate, -10%, p<0.05; specific CETP activity, -14%, p<0.05).

Constitutive expression of fully functional human apoC1 in transgenic rabbit attenuates atherosclerosis. AZD1390 It was found to relate, at least in part, to the inhibition of plasma CETP activity and to alterations in plasma HDL.

Constitutive expression of fully functional human apoC1 in transgenic rabbit attenuates atherosclerosis. It was found to relate, at least in part, to the inhibition of plasma CETP activity and to alterations in plasma HDL.

Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9mmol/L with or without an FH phenotype.

The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and≥4.9mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype.

2267 and 2164 participants had LDL-C <4.9 and≥4.9mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.