The PhoQ/PhoP signaling system responds to low magnesium and the presence of certain cationic antimicrobial peptides. It regulates genes important for growth under these conditions, as well as ...additional genes important for virulence in many gram-negative pathogens. PhoQ is a sensor kinase that phosphorylates and activates the transcription factor PhoP. Since feedback inhibition is a common theme in stress-response circuits, we hypothesized that some members of the PhoP regulon may play such a role in the PhoQ/PhoP pathway. We therefore screened for PhoP-regulated genes that mediate feedback in this system. We found that deletion of mgrB (yobG), which encodes a 47 amino acid peptide, results in a potent increase in PhoP-regulated transcription. In addition, over-expression of mgrB decreased transcription at both high and low concentrations of magnesium. Localization and bacterial two-hybrid studies suggest that MgrB resides in the inner-membrane and interacts directly with PhoQ. We further show that MgrB homologs from Salmonella typhimurium and Yersinia pestis also repress PhoP-regulated transcription in these organisms. In cell regulatory circuits, feedback has been associated with modulating the induction kinetics and/or the cell-to-cell variability in response to stimulus. Interestingly, we found that elimination of MgrB-mediated feedback did not have a significant effect on the kinetics of reporter protein production and did not decrease the variability in expression among cells. Our results indicate MgrB is a broadly conserved membrane peptide that is a critical mediator of negative feedback in the PhoQ/PhoP circuit. This new regulator may function as a point of control that integrates additional input signals to modulate the activity of this important signaling system.
Abstract
This paper provides an update of our previous scaling relations between galaxy-integrated molecular gas masses, stellar masses, and star formation rates (SFRs), in the framework of the star ...formation main sequence (MS), with the main goal of testing for possible systematic effects. For this purpose our new study combines three independent methods of determining molecular gas masses from CO line fluxes, far-infrared dust spectral energy distributions, and ∼1 mm dust photometry, in a large sample of 1444 star-forming galaxies between
z
= 0 and 4. The sample covers the stellar mass range log(
M
*
/
M
⊙
) = 9.0–11.8, and SFRs relative to that on the MS,
δ
MS = SFR/SFR(MS), from 10
−1.3
to 10
2.2
. Our most important finding is that all data sets, despite the different techniques and analysis methods used, follow the same scaling trends, once method-to-method zero-point offsets are minimized and uncertainties are properly taken into account. The molecular gas depletion time
t
depl
, defined as the ratio of molecular gas mass to SFR, scales as (1 +
z
)
−0.6
× (
δ
MS)
−0.44
and is only weakly dependent on stellar mass. The ratio of molecular to stellar mass
μ
gas
depends on (
1
+
z
)
2.5
×
(
δ
MS
)
0.52
×
(
M
*
)
−
0.36
, which tracks the evolution of the specific SFR. The redshift dependence of
μ
gas
requires a curvature term, as may the mass dependences of
t
depl
and
μ
gas
. We find no or only weak correlations of
t
depl
and
μ
gas
with optical size
R
or surface density once one removes the above scalings, but we caution that optical sizes may not be appropriate for the high gas and dust columns at high
z
.
To determine whether neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) measured in serum relate to traumatic brain injury (TBI) ...diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) measures of traumatic axonal injury (TAI) in patients with TBI.
Patients with TBI (n = 162) and controls (n = 68) were prospectively enrolled between 2011 and 2019. Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days, and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury.
At enrollment, patients with TBI had increased serum NfL compared to controls (
0.0001). Serum NfL decreased over the course of 5 years but remained significantly elevated compared to controls. Serum NfL at 30 days distinguished patients with mild, moderate, and severe TBI from controls with an area under the receiver-operating characteristic curve (AUROC) of 0.84, 0.92, and 0.92, respectively. At enrollment, serum GFAP was elevated in patients with TBI compared to controls (
0.001). GFAP showed a biphasic release in serum, with levels decreasing during the first 6 months of injury but increasing over the subsequent study visits. The highest AUROC for GFAP was measured at 30 days, distinguishing patients with moderate and severe TBI from controls (both 0.89). Serum tau and UCH-L1 showed weak associations with TBI severity and neuroimaging measures. Longitudinally, serum NfL was the only biomarker that was associated with the likely rate of MRI brain atrophy and DTI measures of progression of TAI.
Serum NfL shows greater diagnostic and prognostic utility than GFAP, tau, and UCH-L1 for subacute and chronic TBI.
This study provides Class III evidence that serum NfL distinguishes patients with mild TBI from healthy controls.
Sub-concussive injuries have emerged as an important factor in the long-term brain health of athletes and military personnel. The objective of this study was to explore the relationship between ...service member and veterans (SMVs) lifetime blast exposure and recovery from a traumatic brain injury (TBI). A total of 558 SMVs with a history of TBI were examined. Lifetime blast exposure (LBE) was based on self-report (M = 79.4, standard deviation = 392.6; range = 0-7500) categorized into three groups: Blast Naive (
= 121), Low LBE (
= 223; LBE range 1-9), and High LBE (
= 214; LBE >10). Dependent variables were the Neurobehavioral Symptom Inventory (NSI) and Post-traumatic Stress Disorder Checklist-Civilian (PCL-C) and the Traumatic Brain Injury Quality of Life (TBI-QOL). Analyses controlled for demographic factors (age, gender, and race) as well as TBI factors (months since index TBI, index TBI severity, and total number lifetime TBIs). The Blast Naive group had significantly lower NSI and PCL-C scores compared with the Low LBE group and High LBE group, with small to medium effect sizes. On the TBI-QOL, the Blast Naïve group had better quality life on 10 of the 14 scales examined. The Low LBE did not differ from the High LBE group on the PCL-C, NSI, or TBI-QOL. Blast exposure over an SMV's career was associated with increased neurobehavioral and post-traumatic stress symptoms following a TBI. The influence of psychological trauma associated with blasts may be an important factor influencing symptoms as well as the accuracy of self-reported estimates of LBE.
Purpose
This study examined the clinical utility of post-traumatic stress disorder (PTSD), low resilience, poor sleep, and lifetime blast exposure as risk factors for predicting future ...neurobehavioral outcome following traumatic brain injury (TBI).
Methods
Participants were 591 U.S. military service members and veterans who had sustained a TBI (
n
= 419) or orthopedic injury without TBI (
n
= 172). Participants completed the Neurobehavioral Symptom Inventory, PTSD Checklist, and the TBI-Quality of Life (TBI-QOL) scale at baseline and follow-up.
Results
Using the four risk factors at baseline, 15 risk factor combinations were examined by calculating odds ratios to predict poor neurobehavioral outcome at follow-up (i.e., number of abnormal scores across five TBI-QOL scales e.g., Fatigue, Depression). The vast majority of risk factor combinations resulted in odds ratios that were considered to be clinically meaningful (i.e., ≥ 2.5) for predicting poor outcome. The risk factor combinations with the highest odds ratios included PTSD singularly, or in combination with poor sleep and/or low resilience (odds ratios = 4.3–72.4). However, poor sleep and low resilience were also strong predictors in the absence of PTSD (odds ratios = 3.1–29.8).
Conclusion
PTSD, poor sleep, and low resilience, singularly or in combination, may be valuable risk factors that can be used clinically for targeted early interventions.
We report the detection of continuous positional and polarization changes of the compact source SgrA* in high states (“flares”) of its variable near-infrared emission with the near-infrared ...GRAVITY-Very Large Telescope Interferometer (VLTI) beam-combining instrument. In three prominent bright flares, the position centroids exhibit clockwise looped motion on the sky, on scales of typically 150 μas over a few tens of minutes, corresponding to about 30% the speed of light. At the same time, the flares exhibit continuous rotation of the polarization angle, with about the same 45(±15) min period as that of the centroid motions. Modelling with relativistic ray tracing shows that these findings are all consistent with a near face-on, circular orbit of a compact polarized “hot spot” of infrared synchrotron emission at approximately six to ten times the gravitational radius of a black hole of 4 million solar masses. This corresponds to the region just outside the innermost, stable, prograde circular orbit (ISCO) of a Schwarzschild–Kerr black hole, or near the retrograde ISCO of a highly spun-up Kerr hole. The polarization signature is consistent with orbital motion in a strong poloidal magnetic field.
Objective: Over the past two decades, there has been much research on measures of response bias and myriad measures have been validated in a variety of clinical and research samples. This critical ...review aims to guide clinicians through the use of performance validity tests (PVTs) from test selection and administration through test interpretation and feedback. Method/results: Recommended cutoffs and relevant test operating characteristics are presented. Other important issues to consider during test selection, administration, interpretation, and feedback are discussed including order effects, coaching, impact on test data, and methods to combine measures and improve predictive power. When interpreting performance validity measures, neuropsychologists must use particular caution in cases of dementia, low intelligence, English as a second language/minority cultures, or low education. Conclusions: PVTs provide valuable information regarding response bias and, under the right circumstances, can provide excellent evidence of response bias. Only after consideration of the entire clinical picture, including validity test performance, can concrete determinations regarding the validity of test data be made.
The PhoQ/PhoP two-component system is repressed by divalent cations, such as Mg2+ and Ca2+, in the growth medium and stimulated by low pH and certain cationic antimicrobial peptides. In Escherichia ...coli, it was recently shown that the histidine kinase PhoQ is also modulated by at least two additional factors, the small membrane proteins SafA and MgrB. This raises the possibility that the PhoQ/PhoP circuit has additional regulatory components and integrates additional input signals. We screened E. coli transposon insertion mutants to look for proteins that modulate the activity of the PhoQ/PhoP system, and we uncovered a role for DsbA, a periplasmic oxidant that facilitates the formation of disulfide bonds. Deletion of dsbA or dsbB, which maintains a pool of oxidized DsbA, leads to increased transcription of at least two PhoP-regulated genes. Addition of the reducing agent dithiothreitol to wild-type cells had a similar effect, and treatment of a dsbA null strain with the oxidant Cu2+ rescued the reporter gene expression phenotype. We also demonstrated that expression of an MgrB mutant that lacked cysteines blocked the effect of a dsbA null mutation on PhoQ/PhoP activity, suggesting that MgrB acts downstream of DsbA in this pathway. Taken together, these results demonstrate that a decrease in the oxidizing activity of the periplasm stimulates PhoQ/PhoP and may reveal a new input stimulus for this important two-component system.
The present study aimed to examine the impact of lifetime blast exposure (LBE) on neuropsychological functioning in service members and veterans (SMVs).
Participants were 282 SMVs, with and without ...history of traumatic brain injury (TBI), who were prospectively enrolled in a Defense and Veterans Brain Injury Center (DVBIC)-Traumatic Brain Injury Center of Excellence (TBICoE) Longitudinal TBI Study. A cross-sectional analysis of baseline data was conducted. LBE was based on two factors: Military Occupational Speciality (MOS) and SMV self-report. Participants were divided into three groups based on LBE: Blast Naive (
= 61), Blast + Low Risk MOS (
= 96), Blast + High Risk MOS (
= 125). Multivariate analysis of variance (MANOVA) was used to examine group differences on neurocognitive domains and the Minnesota Multiphasic Personality Inventory-2 Restructured Form.
There were no statistically significant differences in attention/working memory, processing speed, executive functioning, and memory (
< 1.75, ps > .1, η
s < .032) or in General Cognition (
0.95, ps > .3, η
s < .008). Prior to correction for covariates, lifetime blast exposure was related to Restructured Clinical (
(18,542)
1.77,
= .026, η
= .055), Somatic/Cognitive (
(10,550)
1.99,
= .033, η
= .035), and Externalizing Scales (
(8,552)
2.17,
= .028, η
= .030); however, these relationships did not remain significant after correction for covariates (
1.53, ps > .145, η
s < .032).
We did not find evidence of a relationship between LBE and neurocognitive performance or psychiatric symptoms. This stands in contrast to prior studies demonstrating an association between lifetime blast exposure and highly sensitive blood biomarkers and/or neuroimaging. Overall, findings suggest the neuropsychological impact of lifetime blast exposure is minimal in individuals remaining in or recently retired from military service.
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