Summary
Chemotaxis is important for
H
elicobacter pylori
to colonize the stomach. Like other bacteria,
H
. pylori
uses chemoreceptors and conserved chemotaxis proteins to phosphorylate the flagellar ...rotational response regulator,
C
he
Y
, and modulate the flagellar rotational direction. Phosphorylated
C
he
Y
is returned to its non‐phosphorylated state by phosphatases such as
C
he
Z
. In previously studied cases, chemotaxis phosphatases localize to the cellular poles by interactions with either the
C
he
A
chemotaxis kinase or flagellar motor proteins. We report here that the
H
. pylori
C
he
Z
,
C
he
Z
HP
, localizes to the poles independently of the flagellar motor,
C
he
A
, and all typical chemotaxis proteins. Instead,
C
he
Z
HP
localization depends on the chemotaxis regulatory protein
C
he
P
ep, and reciprocally,
C
he
P
ep requires
C
he
Z
HP
for its polar localization. We furthermore show that these proteins interact directly. Functional domain mapping of
C
he
Z
HP
determined the polar localization motif lies within the central domain of the protein and that the protein has regions outside of the active site that participate in chemotaxis. Our results suggest that
C
he
Z
HP
and
C
he
P
ep form a distinct complex. These results therefore suggest the intriguing idea that some phosphatases localize independently of the other chemotaxis and motility proteins, possibly to confer unique regulation on these proteins' activities.
Chemotaxis is important for Helicobacter pylori to colonize the stomach. Like other bacteria, H. pylori uses chemoreceptors and conserved chemotaxis proteins to phosphorylate the flagellar rotational ...response regulator, CheY, and modulate the flagellar rotational direction. Phosphorylated CheY is returned to its non-phosphorylated state by phosphatases such as CheZ. In previously studied cases, chemotaxis phosphatases localize to the cellular poles by interactions with either the CheA chemotaxis kinase or flagellar motor proteins. We report here that the H. pylori CheZ, CheZ..., localizes to the poles independently of the flagellar motor, CheA, and all typical chemotaxis proteins. Instead, CheZ... localization depends on the chemotaxis regulatory protein ChePep, and reciprocally, ChePep requires CheZ... for its polar localization. We furthermore show that these proteins interact directly. Functional domain mapping of CheZ... determined the polar localization motif lies within the central domain of the protein and that the protein has regions outside of the active site that participate in chemotaxis. Our results suggest that CheZ... and ChePep form a distinct complex. These results therefore suggest the intriguing idea that some phosphatases localize independently of the other chemotaxis and motility proteins, possibly to confer unique regulation on these proteins' activities. (ProQuest: ... denotes formulae/symbols omitted.)
Summary
Chemotaxis is important for Helicobacter pylori to colonize the stomach. Like other bacteria, H. pylori uses chemoreceptors and conserved chemotaxis proteins to phosphorylate the flagellar ...rotational response regulator, CheY, and modulate the flagellar rotational direction. Phosphorylated CheY is returned to its non‐phosphorylated state by phosphatases such as CheZ. In previously studied cases, chemotaxis phosphatases localize to the cellular poles by interactions with either the CheA chemotaxis kinase or flagellar motor proteins. We report here that the H. pylori CheZ, CheZHP, localizes to the poles independently of the flagellar motor, CheA, and all typical chemotaxis proteins. Instead, CheZHP localization depends on the chemotaxis regulatory protein ChePep, and reciprocally, ChePep requires CheZHP for its polar localization. We furthermore show that these proteins interact directly. Functional domain mapping of CheZHP determined the polar localization motif lies within the central domain of the protein and that the protein has regions outside of the active site that participate in chemotaxis. Our results suggest that CheZHP and ChePep form a distinct complex. These results therefore suggest the intriguing idea that some phosphatases localize independently of the other chemotaxis and motility proteins, possibly to confer unique regulation on these proteins' activities.
Chemotaxis phosphatases such as CheZ localize to specific cellular sites to provide optimal chemotaxis performance. We show here that phosphatases exploit unexpected locations beyond the flagellar and chemoreceptor complexes. Specifically, the CheZ phosphatase of Helicobacter pylori localizes independent of the motility and chemoreceptor proteins, and instead relies on interactions with the ChePep chemotaxis protein. Localizing some chemotaxis proteins separate from the canonical motility and chemotaxis complexes may be a mechanism to provide unique regulatory inputs to CheZ and ChePep.
Regulatory T cells (T regs ) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and ...strain-specific molecules that can affect intestinal immune responses, including species that modulate T reg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic T regs . We determined that short-chain fatty acids, gut microbiota—derived bacterial fermentation products, regulate the size and function of the colonic T reg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.
Chemotaxis is important for Helicobacter pylori to colonize the stomach. Like other bacteria, H. pylori uses chemoreceptors and conserved chemotaxis proteins to phosphorylate the flagellar rotational ...response regulator, CheY, and modulate the flagellar rotational direction. Phosphorylated CheY is returned to its non-phosphorylated state by phosphatases such as CheZ. In previously studied cases, chemotaxis phosphatases localize to the cellular poles by interactions with either the CheA chemotaxis kinase or flagellar motor proteins. We report here that the H. pylori CheZ, CheZ(HP), localizes to the poles independently of the flagellar motor, CheA, and all typical chemotaxis proteins. Instead, CheZ(HP) localization depends on the chemotaxis regulatory protein ChePep, and reciprocally, ChePep requires CheZ(HP) for its polar localization. We furthermore show that these proteins interact directly. Functional domain mapping of CheZ(HP) determined the polar localization motif lies within the central domain of the protein and that the protein has regions outside of the active site that participate in chemotaxis. Our results suggest that CheZ(HP) and ChePep form a distinct complex. These results therefore suggest the intriguing idea that some phosphatases localize independently of the other chemotaxis and motility proteins, possibly to confer unique regulation on these proteins' activities.
The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite ...instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status.
To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy.
The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine-endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope.
Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract.
An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories.
Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions LSIL, CIN1) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable ...resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ, but LSILs include SCJ and SCJ subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ and SCJ using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ LSIL in all cases (100%). However, for SCJ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ and SCJ LSILs, 60.2% and 94.9% were p16 positive, 23% and 74.4% showed strong (full-thickness) p16 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions.
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