The mucosal firewalls against commensal intestinal microbes

Mammals coexist with an extremely dense microbiota in the lower intestine. Despite the constant challenge of small numbers of microbes penetrating the intestinal surface epithelium, it is very unusual for these organisms to cause disease. In this review article, we present the different mucosal firewalls that contain and allow mutualism with the intestinal microbiot

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

Several human diseases are thought to evolve due to a combination of host genetic mutations and environmental factors that include alterations in intestinal microbiota composition termed dysbiosis. Although in some cases, host genetics may shape the gut microbiota and enable it to provoke disease, experimentally disentangling cause and consequence in such host-microbe interactions requires strict control over non-genetic confounding factors. Mouse genetic studies previously proposed Nlrp6/ASC inflammasomes as innate immunity regulators of the intestinal ecosystem. In contrast, using littermate-controlled experimental setups, we recently showed that Nlrp6/ASC inflammasomes do not alter the gut microbiota composition. Our analyses indicated that maternal inheritance and long-term separate housing are non-genetic confounders that preclude the use of non-littermate mice when analyzing host genetic effects on intestinal ecology. Here, we summarize and discuss our gut microbiota analyses in inflammasome-deficient mice for illustrating the importance of littermate experimental design in studying host-microbiota interactions

Subcommittee Report on the Establishment of a State Ethics Commission

The establishment of a State Ethics Commission relates directly to ethics reform in the state of New Mexico. Such a commission does not exist in New Mexico, the establishment of which would represent a tangible and concrete manifestation of a state commitment to ethics reform, as well as the top-down expectation that state officials (elected or otherwise) will be held to the highest standard of conduct in the performance of their duties. In addition, while New Mexico does have statutory proscriptions against certain kinds or conduct or requiring other kinds of conduct (i.e., the Government Conduct Act, the Procurement Act, Campaign Practices Act), there is no common set of ethical guidelines that apply uniformly to all executive agencies, elected officials, and employees. Moreover, there is no agency or organization that is charged with receiving reports of ethical misconduct, investigating such reports, and taking action as necessary, including disciplinary action. A state ethics commission could be established to do exactly that. This report reviews the options for establishing a state ethics commission and provides recommendations

Locally performed postoperative circulating tumour DNA testing performed during routine clinical care to predict recurrence of colorectal cancer

Background: Identifying patients at high risk for colorectal cancer recurrence is essential for improving prognosis. In the postoperative period, circulating tumour DNA (ctDNA) has been demonstrated as a significant prognostic indicator of recurrence. These results have been obtained under the strict rigours of clinical trials, but not validated in a real-world setting using in-house testing. We report the outcomes of locally performed postoperative ctDNA testing conducted during routine clinical care and the association with the recurrence of colorectal cancer. Methods: We recruited 36 consecutive patients with newly diagnosed colorectal cancer between 2018 and 2020. Postoperative plasma samples were collected at the first outpatient review following resection. Tumour-informed ctDNA analysis was performed using droplet digital polymerase chain reaction or targeted next-generation sequencing. Results: At the time of surgery, there were 24 patients (66.7%) with localized cancer, nine (25%) with nodal spread, and three (8.3%) with metastatic disease. The median time from surgery to plasma sample donation was 22 days (IQR 20–28 days). At least one somatic mutation was identified in primary tumour tissue for 28 (77.8%) patients. Postoperative ctDNA was detected in five patients (13.9%). The median duration of follow-up was 32.0 months (IQR 27.2–38.1 months). Two patients (5.56%) developed metastatic recurrence. However, neither had detectable postoperative ctDNA. There were no instances of loco-regional recurrence. Conclusion: Analysis of postoperative ctDNA testing can be performed locally, however this study did not reproduce the adverse association between detectable postoperative ctDNA and the development of colorectal cancer recurrence seen in clinical trials

Prospectus, October 31, 1984

PARKAND\u27S TEAMS PLACE HIGH; C.A.A.R. responds to Mohn; Dear Prospectus Staff…; StuGo News; Sharing of problems essential to recovery; President Reagan: Leadership that\u27s working; Sargent actively involved in politics; Women\u27s Workshop teaches acting versus reacting; Halloween brings out the supernatural; Interview with Auntie Miranda; Creative Corner...Especially for you!; Trip to a Graveyard ona Moonless Night; Doom Story-Nathanial Dark\u27s identity is exposed; PC Happenings; Operating room legalities; Workshop on memory disorders; Classifieds; Artist struggles for identity; McLain family to appear at Krannert; American Playhouse season opens; Music madness; Illini make music video; Videos need to be rethought; Clifton, Payne enjoy spiking and dunking in their sport; Henkels, Leggett share similar philosophies; Joni Mullen, Hawkins use instinct to play defense; Cobra harriers end season; Jill Mullen, Douglas portray thinking person\u27s position; Cobra harriers end seasonhttps://spark.parkland.edu/prospectus_1984/1006/thumbnail.jp

Investigation of Heavy Metals in a Large Mortality Event in Caribou of Northern Alaska

We measured element concentrations (As, Cd, Cu, Pb, Zn, Fe) and body condition (gross and histologic endpoints) of animals from a caribou (Rangifer tarandus) mortality event that occurred in Alaska, in the area of Point Hope and Cape Thompson (including the Chariot site), in 1995. These were compared to results from hunter-killed caribou from reference sites (Barrow and Teshekpuk Lake, Alaska) and from the area of a mine (Red Dog Mine) to determine whether heavy metals had played a role in the mortality event or whether any elements were at concentrations of concern for human consumers. Starvation and malnutrition were major factors leading to death or severe weakness, as very little or no fat (very low body condition scores) and serous atrophy of fat (observed as watery contents of the marrow cavity, with no apparent fat, and histologically) were more prevalent in caribou associated with the mortality event than in hunter-killed animals from reference sites. Accumulation of hepatic (liver) hemosiderin in Kupffer cells (macrophages) was noted as an indicator of cachexia. Concentrations of lead in feces and liver, copper in the rumen contents, and arsenic in muscle were higher in caribou harvested near Red Dog Mine, as might be expected in that mineral-rich area, but were not at levels of concern for toxicoses. Kidney concentrations of cadmium, which increased significantly with increasing age, present a potential concern for human consumers, and this is an expected finding. We concluded that caribou had starved and that heavy metals had played no role in the mortality event. Further investigation of regional mineral differences is required to understand the sources and transport mechanisms that explain these findings and to properly address mining activity. Mortality events on the north slope of Alaska are common and likely involve starvation as described here, but in most cases they are not investigated, even though recent industrial activities have heightened concern among some local residents and wildlife managers.On a mesuré la concentration en éléments (As, Cd, Cu, Pb, Zn, Fe) et l'état corporel (points limites bruts et histologiques) de caribous (Rangifer tarandus) prélevés lors d'un épisode de mortalité qui s'est produit en 1995 en Alaska, dans la région de Point Hope et de Cape Thompson (y compris le site Chariot). On a comparé ces résultats à ceux de caribous tués par des chasseurs à des emplacements témoins (Barrow et Teshekpuk Lake, en Alaska) et à proximité d'une mine (Red Dog Mine) pour trouver si les métaux lourds avaient joué un rôle dans l'épisode de mortalité ou si la concentration d'un ou plusieurs éléments pouvait constituer un risque pour la consommation humaine. La famine et la malnutrition étaient des facteurs majeurs ayant causé la mort ou une extrême faiblesse, vu que la présence minime ou l'absence de graisse (très basses notes d'état corporel) et une atrophie séreuse de la graisse (observée sous forme de contenu aqueux de la cavité médullaire, sans graisse visible, et à la suite de l'examen histologique) étaient plus courantes chez le caribou associé à l'épisode de mortalité que chez les animaux des emplacements témoins tués par les chasseurs. On a noté dans le foie une accumulation d'hémosidérine hépatique des cellules de Kupffer (cellules macrophages) témoignant d'une cachexie. La concentration de plomb dans les matières fécales et le foie, de cuivre dans le rumen et d'arsenic dans le tissu musculaire était plus élevée chez le caribou provenant de Red Dog Mine, comme on pouvait s'y attendre dans cette zone riche en minéraux, mais cette concentration n'atteignait pas un niveau pouvant provoquer des toxicoses. La concentration de cadmium dans le rein, qui augmentait de façon significative avec l'âge, pourrait constituer un risque pour la consommation humaine, ce qui n'est pas surprenant. On a conclu que les caribous étaient morts de faim et que les métaux lourds n'avaient joué aucun rôle dans l'épisode de mortalité. Il faudrait effectuer des recherches plus poussées sur les différences régionales en minéraux afin de comprendre les mécanismes d'origine et de transport qui expliquent ces résultats et d'aborder comme il le faut les activités minières. Les épisodes de mortalité sont courants sur le versant Nord de l'Alaska et sont probablement liés à la famine, comme le décrit cet article, mais dans la plupart des cas ils ne font pas l'objet d'une enquête, même si l'activité industrielle récente est un sujet qui préoccupe de plus en plus certains résidents et gestionnaires locaux de la faune

Nonneutralizing antibodies binding to the surface glycoprotein of lymphocytic choriomeningitis virus reduce early virus spread

The biological relevance of nonneutralizing antibodies elicited early after infection with noncytopathic persistence-prone viruses is unclear. We demonstrate that cytotoxic T lymphocyte–deficient TgH(KL25) mice, which are transgenic for the heavy chain of the lymphocytic choriomeningitis virus (LCMV)–neutralizing monoclonal antibody KL25, mount a focused neutralizing antibody response following LCMV infection, and that this results in the emergence of neutralization escape virus variants. Further investigation revealed that some of the escape variants that arose early after infection could still bind to the selecting antibody. In contrast, no antibody binding could be detected for late isolates, indicating that binding, but nonneutralizing, antibodies exerted a selective pressure on the virus. Infection of naive TgH(KL25) mice with distinct escape viruses differing in their antibody-binding properties revealed that nonneutralizing antibodies accelerated clearance of antibody-binding virus variants in a partly complement-dependent manner. Virus variants that did not bind antibodies were not affected. We therefore conclude that nonneutralizing antibodies binding to the same antigenic site as neutralizing antibodies are biologically relevant by limiting early viral spread

Sensitization to gliadin induces moderate enteropathy and insulitis in nonobese diabetic-DQ8 mice

Celiac disease (CD) is frequently diagnosed in patients with type 1 diabetes (T1D), and T1D patients can exhibit Abs against tissue transglutaminase, the auto-antigen in CD. Thus, gliadin, the trigger in CD, has been suggested to have a role in T1D pathogenesis. The objective of this study was to investigate whether gliadin contributes to enteropathy and insulitis in NOD-DQ8 mice, an animal model that does not spontaneously develop T1D. Gliadin-sensitized NOD-DQ8 mice developed moderate enteropathy, intraepithelial lymphocytosis, and barrier dysfunction, but not insulitis. Administration of anti-CD25 mAbs before gliadin-sensitization induced partial depletion of CD25+Foxp3+ T cells and led to severe insulitis, but did not exacerbate mucosal dysfunction. CD4+T cells isolated from pancreatic lymph nodes of mice that developed insulitis showed increased proliferation and proinflammatory cytokines after incubation with gliadin but not with BSA. CD4+ T cells isolated from nonsensitized controls did not response to gliadin or BSA. In conclusion, gliadin sensitization induced moderate enteropathy in NOD-DQ8 mice. However, insulitis development required gliadin-sensitization and partial systemic depletion of CD25+Foxp3+ T cells. This humanized murine model provides a mechanistic link to explain how the mucosal intolerance to a dietary protein can lead to insulitis in the presence of partial regulatory T cell deficiency.Facultad de Ciencias Exacta