A comparative calorimetric study of the effects of cholesterol and the plant sterols campesterol and brassicasterol on the thermotropic phase behavior of dipalmitoylphosphatidylcholine bilayer membranes

AbstractWe present a comparative differential scanning calorimetric study of the effects of the animal sterol cholesterol (Chol) and the plant sterols campesterol (Camp) and brassicasterol (Bras) on the thermotropic phase behavior of dipalmitoylphosphatidylcholine (DPPC) bilayers. Camp and Bras differ from Chol in having a C24 methyl group and, additionally for Bras, a C22 trans-double bond. Camp and especially Bras decrease the temperature, cooperativity and enthalpy of the DPPC pretransition more than Chol, although these effects are attenuated at higher sterol levels. This indicates that they destabilize gel-state DPPC bilayers to a greater extent, but are less soluble, than Chol. Not surprisingly, all three sterols have similar effects on the sterol-poor sharp component of the DPPC main phase transition. However, Camp and especially Bras less effectively increase the temperature and decrease the cooperativity and enthalpy of the broad component of the main transition than Chol. This indicates that at higher sterol concentrations, Camp and Bras are less miscible and less effective than Chol at ordering the hydrocarbon chains of the sterol-enriched fluid DPPC bilayers. Overall, these alkyl side chain modifications generally reduce the ability of Chol to produce its characteristic effects on DPPC bilayer physical properties. These differences are likely due to the less extended and more bent conformations of the alkyl side chains of Camp and Bras, producing sterols with a greater effective cross-sectional area and reduced length than Chol. Hence, the structure of Chol is likely optimized for maximum solubility in, as opposed to maximum ordering of, phospholipid bilayers

Epidemiology of Signet Ring Cell Adenocarcinomas

Signet ring cell adenocarcinomas (SRCCs) are a rare histological subtype of adenocarcinomas with a poor prognosis, typically due to advanced disease at diagnosis. A signet ring cell, mimicking its moniker, contains abundant intracytoplasmic mucin that pushes the nucleus to the periphery. In these cancers, this cell feature comprises more than 50% of the tumor. Despite predilection for the gastrointestinal tract, and in particular the stomach, primary SRCCs are also described in other sites, typically in case reports. This literature, however, lacks a standardized overview of the SRCC disease entity. Using a retrospective cohort approach, we summarize the clinicodemographic and mortality outcomes of SRCCs in thirteen primary sites, comprising 95% of all SRCCs in the Surveillance, Epidemiology, and End Results Program (SEER), a population-level cancer database covering nearly one-third of the United States population. SRCCs general trends compared to matching nonvariant adenocarcinomas are earlier age of onset, with initial presentation favoring higher rates of regional or distant disease presentation and poor tumor differentiation. After multivariable analysis, SRCCs typically have worse overall survivals, but substantial variances exist depending on tumor location. Identifying SRCCs at earlier disease stages is likely the single most important intervention to improving outcomes for these patients

Resisting death by metal:metabolism and Cu/Zn homeostasis in bacteria

Metal ions such as zinc and copper play important roles in host-microbe interactions and their availability can drastically affect the survival of pathogenic bacteria in a host niche. Mechanisms of metal homeostasis protect bacteria from starvation, or intoxication, defined as when metals are limiting, or in excess, respectively. In this mini-review, we summarise current knowledge on the mechanisms of resistance to metal stress in bacteria, focussing specifically on the homeostasis of cellular copper and zinc. This includes a summary of the factors that subvert metal stress in bacteria, which are independent of metal efflux systems, and commentary on the role of small molecules and metabolic systems as important mediators of metal resistance

CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation

Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data bankin

Population turnover in remote oceania shortly after initial settlement

Ancient DNA from Vanuatu and Tonga dating to about 2,900–2,600 years ago (before present, BP) has revealed that the “First Remote Oceanians” associated with the Lapita archaeological culture were directly descended from the population that, beginning around 5000 BP, spread Austronesian languages from Taiwan to the Philippines, western Melanesia, and eventually Remote Oceania. Thus, ancestors of the First Remote Oceanians must have passed by the Papuan-ancestry populations they encountered in New Guinea, the Bismarck Archipelago, and the Solomon Islands with minimal admixture [1]. However, all present-day populations in Near and Remote Oceania harbor >25% Papuan ancestry, implying that additional eastward migration must have occurred. We generated genome-wide data for 14 ancient individuals from Efate and Epi Islands in Vanuatu from 2900–150 BP, as well as 185 present-day individuals from 18 islands. We find that people of almost entirely Papuan ancestry arrived in Vanuatu by around 2300 BP, most likely reflecting migrations a few hundred years earlier at the end of the Lapita period, when there is also evidence of changes in skeletal morphology and cessation of long-distance trade between Near and Remote Oceania [2, 3]. Papuan ancestry was subsequently diluted through admixture but remains at least 80%–90% in most islands. Through a fine-grained analysis of ancestry profiles, we show that the Papuan ancestry in Vanuatu derives from the Bismarck Archipelago rather than the geographically closer Solomon Islands. However, the Papuan ancestry in Polynesia—the most remote Pacific islands—derives from different sources, documenting a third stream of migration from Near to Remote Oceania

Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease