The developmental and criminal histories of subgroups of sexual murderers engaging, or not engaging, in post mortem sexual interference, compared to rapists

Purpose Identifying factors that may predict sexual aggression in the context of directly sexual murder, indirectly sexual murder, and non-fatal outcomes is necessary for advancing a field lacking a substantiated multifactorial theoretical model. Methods Eighty-nine sexual murderers engaging in post mortem sexual interference were compared to 92 non-post mortem sexual interference sexual murderers and 72 rapists on developmental factors, adult lifestyle, and criminal history. An overall model was built using a series of multinomial logistic regression analyses. Results Unlike rapists, both groups of sexual murderers experienced a lack of success in sexually intimate relationships. Perpetrators of post mortem sexual interference were rarely necrophiles, but having a history of sadistic behaviors or interests uniquely predicted sexual murder involving post mortem sexual interference. Chronic violent and sexual offending was characteristic of rapists. Psychopathy, measured using the screening version of the Psychopathy Checklist (Hart, Cox, & Hare, 1995), was not predictive of any outcome. Conclusion Results support criticism of existing theoretical models; that they do not apply to non-sadistic sexual murder. Findings are discussed in relation to gaps in theoretical understanding of sexual murder, and concerning implications for forensic policies and practice

Subacute ruminal acidosis affects fermentation and endotoxin concentration in the rumen and relative expression of the CD14/TLR4/MD2 genes involved in lipopolysaccharide systemic immune response in dairy cows

The first objective of this study was to investigate the effects of subacute ruminal acidosis (SARA) on fermentation, ruminal free lipopolysaccharides (LPS), and expression of the cluster of differentiation 14 (CD14), toll-like receptor 4 (TLR4), and myeloid differentiation protein 2 (MD2) complex in white blood cells involved in the systemic immune response in dairy cows. The second objective was a study of whether increased expression of the LPS receptor complex led to increases in the concentrations of plasma high-density lipoprotein (HDL) and serum Ca. Three hundred five dairy cows located in 13 Polish high-yielding dairy commercial farms were selected according to their days in milk (40-150 d; average = 75), 305-d milk yield (10,070-12,041 kg; average = 10,940), and number of lactations (primiparous, n = 139 and multiparous, n = 166). Next, the herds were segregated into 3 groups based on the percentages of cows with an assigned value of ruminal fluid pH: SARA-positive, SARA-risk, and SARA-negative herds. Moreover, 305 selected dairy cows were divided according to the classification based on ruminal fluid pH into 3 groups as healthy (pH > 5.81), risk (pH 5.8-5.6) and acidotic cows (pH < 5.6). Rumen fluid samples were collected via rumenocentesis. In the AC group, we recorded higher concentrations of ruminal free LPS [4.57 Log(10) endotoxin units (EU)/mL; 42,206 EU/mL] compared with the healthy group (4.48 Log(10) EU/mL; 34,179 EU/mL). Similarly, the concentration of ruminal free LPS was higher in SARA-positive herds (4.60 Log(10) EU/mL; 43,000 EU/mL) compared with SARA-negative herds (4.47 Log(10) EU/mL; 32,225 EU/mL). The relative mRNA abundance of genes associated with the function of LPS receptors, such as CD14, TLR4, and MD2, in white blood cells differed between all experimental groups on both cow and herd levels. In the acidotic group, we recorded higher concentrations of HDL (78.16 vs. 68.32 mg/dL) and serum amyloid A (10.80 vs. 9.16 mu g/mL) and lower concentrations of Ca (8.26 vs. 10.16 mg/dL) and haptoglobin (470.19 vs. 516.85 ng/mL) compared with the healthy group. Similar results were obtained in the SARA herd status analysis, but the concentration of lipopolysaccharide-binding protein differed statistically. Moreover, the pH of ruminal fluid was negatively correlated with relative mRNA abundance of genes such as CD14, TLR4, MD2, and concentrations of serum HDL and serum amyloid A, although positively correlated with serum Ca. The results indicated that decreases in ruminal fluid pH increased the release of free LPS into the rumen and stimulated the expression of the LPS receptor complex and immune response. Moreover, an increase in the expression of the LPS receptor led to higher concentrations of plasma HDL and lower serum Ca, which may be a protective mechanism against endotoxemia. However, the biological significance of these results needs to be investigated further in larger field trials

Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity

DNA hypomethylation was previously implicated in cancer progression and metastasis. The purpose of this study was to examine whether stilbenoids, resveratrol and pterostilbene thought to exert anticancer effects, target genes with oncogenic function for de novo methylation and silencing, leading to inactivation of related signaling pathways. Following Illumina 450K, genome-wide DNA methylation analysis reveals that stilbenoids alter DNA methylation patterns in breast cancer cells. On average, 75% of differentially methylated genes have increased methylation, and these genes are enriched for oncogenic functions, including NOTCH signaling pathway. MAML2, a coactivator of NOTCH targets, is methylated at the enhancer region and transcriptionally silenced in response to stilbenoids, possibly explaining the downregulation of NOTCH target genes. The increased DNA methylation at MAML2 enhancer coincides with increased occupancy of repressive histone marks and decrease in activating marks. This condensed chromatin structure is associated with binding of DNMT3B and decreased occupancy of OCT1 transcription factor at MAML2 enhancer, suggesting a role of DNMT3B in increasing methylation of MAML2 after stilbenoid treatment. Our results deliver a novel insight into epigenetic regulation of oncogenic signals in cancer and provide support for epigenetic-targeting strategies as an effective anticancer approach

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Structure and function of the Ts2631 endolysin of <i>Thermus scotoductus</i> phage vB_Tsc2631 with unique N-terminal extension used for peptidoglycan binding

Abstract To escape from hosts after completing their life cycle, bacteriophages often use endolysins, which degrade bacterial peptidoglycan. While mesophilic phages have been extensively studied, their thermophilic counterparts are not well characterized. Here, we present a detailed analysis of the structure and function of Ts2631 endolysin from thermophilic phage vB_Tsc2631, which is a zinc-dependent amidase. The active site of Ts2631 consists of His30, Tyr58, His131 and Cys139, which are involved in Zn2+ coordination and catalysis. We found that the active site residues are necessary for lysis yet not crucial for peptidoglycan binding. To elucidate residues involved in the enzyme interaction with peptidoglycan, we tested single-residue substitution variants and identified Tyr60 and Lys70 as essential residues. Moreover, substitution of Cys80, abrogating disulfide bridge formation, inactivates Ts2631, as do substitutions of His31, Thr32 and Asn85 residues. The endolysin contains a positively charged N-terminal extension of 20 residues that can protrude from the remainder of the enzyme and is crucial for peptidoglycan binding. We show that the deletion of 20 residues from the N-terminus abolished the bacteriolytic activity of the enzyme. Because Ts2631 exhibits intrinsic antibacterial activity and unusual thermal stability, it is perfectly suited as a scaffold for the development of antimicrobial agents

Brief Review Renal Aging. Causes and consequences

Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis—age–associated histologic changes in the kidneys. Recent studies have shown that the aged kidney undergoes a range of structural changes and has altered transcriptomic, hemodynamic, and physiologic behavior at rest and in response to renal insults. These changes impair the ability of the kidney to withstand and recover from injury, contributing to the high susceptibility of the aged population to AKI and their increased propensity to develop subsequent progressive CKD. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging in both experimental animal models and humans. We also discuss the potential for additional study to increase understanding of the aged kidney and lead to novel therapeutic strategies

Two-year imaging outcomes from a phase 3 randomized trial of secukinumab in patients with non-radiographic axial spondyloarthritis

Background: Radiographic progression and course of inflammation over 2 years in patients with non-radiographic axial spondyloarthritis (nr-axSpA) from the phase 3, randomized, PREVENT study are reported here. Methods: In the PREVENT study, adult patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for nr-axSpA with elevated CRP and/or MRI inflammation received secukinumab 150 mg or placebo. All patients received open-label secukinumab from week 52 onward. Sacroiliac (SI) joint and spinal radiographs were scored using the modified New York (mNY) grading (total sacroiliitis score; range, 0-8) and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS; range, 0-72), respectively. SI joint bone marrow edema (BME) was assessed using the Berlin Active Inflammatory Lesions Scoring (0-24) and spinal MRI using the Berlin modification of the AS spine MRI (ASspiMRI) scoring (0-69). Results: Overall, 78.9% (438/555) of patients completed week 104 of the study. Over 2 years, minimal changes were observed in total radiographic SI joint scores (mean [SD] change, - 0.04 [0.49] and 0.04 [0.36]) and mSASSS scores (0.04 [0.47] and 0.07 [0.36]) in the secukinumab and placebo-secukinumab groups. Most of the patients showed no structural progression (increase = 1 new syndesmophyte over 2 years. Reduction in SI joint BME observed at week 16 with secukinumab (mean [SD], - 1.23 [2.81] vs - 0.37 [1.90] with placebo) was sustained through week 104 (- 1.73 [3.49]). Spinal inflammation on MRI was low at baseline (mean score, 0.82 and 1.07 in the secukinumab and placebo groups, respectively) and remained low (mean score, 0.56 at week 104). Conclusion: Structural damage was low at baseline and most patients showed no radiographic progression in SI joints and spine over 2 years in the secukinumab and placebo-secukinumab groups. Secukinumab reduced SI joint inflammation, which was sustained over 2 years.Pathophysiology and treatment of rheumatic disease

IL-6 Mediated Degeneration of Forebrain GABAergic Interneurons and Cognitive Impairment in Aged Mice through Activation of Neuronal NADPH Oxidase

BACKGROUND:Multiple studies have shown that plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) are elevated in patients with important and prevalent adverse health conditions, including atherosclerosis, diabetes, obesity, obstructive sleep apnea, hypertension, and frailty. Higher plasma levels of IL-6, in turn, increase the risk of many conditions associated with aging including age-related cognitive decline. However, the mechanisms underlying this association between IL-6 and cognitive vulnerability remain unclear. METHODS AND FINDINGS:We investigated the role of IL-6 in brain aging in young (4 mo) and aged (24 mo) wild-type C57BL6 and genetically-matched IL-6(-/-) mice, and determined that IL-6 was necessary and sufficient for increased neuronal expression of the superoxide-producing immune enzyme, NADPH-oxidase, and this was mediated by non-canonical NFkappaB signaling. Furthermore, superoxide production by NADPH-oxidase was directly responsible for age-related loss of parvalbumin (PV)-expressing GABAergic interneurons, neurons essential for normal information processing, encoding, and retrieval in hippocampus and cortex. Targeted deletion of IL-6 or elimination of superoxide by chronic treatment with a superoxide-dismutase mimetic prevented age-related loss of PV-interneurons and reversed age-related cognitive deficits on three standard tests of spatial learning and recall. CONCLUSIONS:Present results indicate that IL-6 mediates age-related loss of critical PV-expressing GABAergic interneurons through increased neuronal NADPH-oxidase-derived superoxide production, and that rescue of these interneurons preserves cognitive performance in aging mice, suggesting that elevated peripheral IL-6 levels may be directly and mechanistically linked to long-lasting cognitive deficits in even normal older individuals. Further, because PV-interneurons are also selectively affected by commonly used anesthetic agents and drugs, our findings imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically