Disulfide bonds between cysteine residues are important post-translational modifications in proteins that have critical roles for protein structure and stability, as redox-active catalytic groups in ...enzymes or allosteric redox switches that govern protein function
. In addition to forming disulfide bridges, cysteine residues are susceptible to oxidation by reactive oxygen species, and are thus central not only to the scavenging of these but also to cellular signalling and communication in biological as well as pathological contexts
. Oxidized cysteine species are highly reactive and may form covalent conjugates with, for example, tyrosines in the active sites of some redox enzymes
. However, to our knowledge, regulatory switches with covalent crosslinks other than disulfides have not previously been demonstrated. Here we report the discovery of a covalent crosslink between a cysteine and a lysine residue with a NOS bridge that serves as an allosteric redox switch in the transaldolase enzyme of Neisseria gonorrhoeae, the pathogen that causes gonorrhoea. X-ray structure analysis of the protein in the oxidized and reduced state reveals a loaded-spring mechanism that involves a structural relaxation upon redox activation, which is propagated from the allosteric redox switch at the protein surface to the active site in the protein interior. This relaxation leads to a reconfiguration of key catalytic residues and elicits an increase in enzymatic activity of several orders of magnitude. The redox switch is highly conserved in related transaldolases from other members of the Neisseriaceae; for example, it is present in the transaldolase of Neisseria meningitides (a pathogen that is the primary cause of meningitis and septicaemia in children). We surveyed the Protein Data Bank and found that the NOS bridge exists in diverse protein families across all domains of life (including Homo sapiens) and that it is often located at catalytic or regulatory hotspots. Our findings will inform strategies for the design of proteins and peptides, as well as the development of new classes of drugs and antibodies that target the lysine-cysteine redox switch
.
The increasing use of smartphones by providers and patients alike demonstrates that digital health utilizing mobile applications has the potential to transform perioperative care and education in ...anesthesia.
This literature review describes the current scope of the use of mobile applications in anesthesiology.
Literature was searched using PubMed, Scopus, and clinicaltrials.gov for articles published from January 1, 2010, through April 1, 2020. Only English language studies were included. Articles were included if they examined the use of a mobile health application in the setting of anesthesia or the perioperative (immediate preoperative, intraoperative, and postoperative) period. Studies were excluded if they explored video interventions or did not examine the feasibility or efficacy of the mobile app.
We included 29 articles, and three areas of clinical functionality were identified: patient-centered care (preoperative, intraoperative, and postoperative), systems-based improvement, and medical education. Several studies demonstrate the feasibility and reliability of mobile apps in these areas, but many are only tested for efficacy in simulated environments or with small patient samples.
Mobile health applications show promise in improving communication between anesthesiologists, improving workflow efficiency, enhancing medical education, and reducing hospital costs. However, there is a need for validation and improvement before full implementation by the provider, patients, and hospital systems. Future studies are needed to demonstrate meaningful health outcomes to create guidelines and recommendations specific to the application of mobile technology to health care.
Reaction‐based sensing: A fluorescent probe for the detection of hydrogen sulfide was prepared and evaluated on the basis of H2S‐mediated benzodithiolone formation. The probe showed good selectivity ...and sensitivity for hydrogen sulfide.
Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, ...using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.
Artificial intelligence and machine learning (AI/ML) is becoming increasingly more accessible to biomedical researchers with significant potential to transform biomedicine through optimization of ...highly-accurate predictive models and enabling better understanding of disease biology. Automated machine learning (AutoML) in particular is positioned to democratize artificial intelligence (AI) by reducing the amount of human input and ML expertise needed. However, successful translation of AI/ML in biomedicine requires moving beyond optimizing only for prediction accuracy and towards establishing reproducible clinical and biological inferences. This is especially challenging for clinical studies on rare disorders where the smaller patient cohorts and corresponding sample size is an obstacle for reproducible modeling results. Here, we present a model-agnostic framework to reinforce AutoML using strategies and tools of explainable and reproducible AI, including novel metrics to assess model reproducibility. The framework enables clinicians to interpret AutoML-generated models for clinical and biological verifiability and consequently integrate domain expertise during model development. We applied the framework towards spinal cord injury prognostication to optimize the intraoperative hemodynamic range during injury-related surgery and additionally identified a strong detrimental relationship between intraoperative hypertension and patient outcome. Furthermore, our analysis captured how evolving clinical practices such as faster time-to-surgery and blood pressure management affect clinical model development. Altogether, we illustrate how expert-augmented AutoML improves inferential reproducibility for biomedical discovery and can ultimately build trust in AI processes towards effective clinical integration.
Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that potently degrades angiotensin II to angiotensin 1-7. Previous studies showed that injection of the enzymatic ectodomain of ...recombinant ACE2 (rACE2) markedly increases circulatory levels of ACE2 activity, and effectively lowered blood pressure in angiotensin II-induced hypertension. However, due to the short plasma half-life of rACE2, its therapeutic potential for chronic use is limited. To circumvent this, we generated a chimeric fusion of rACE2 and the immunoglobulin fragment Fc segment to increase its plasma stability. This rACE2-Fc fusion protein retained full peptidase activity and exhibited greatly extended plasma half-life in mice, from less than two hours of the original rACE2, to over a week. A single 2.5 mg/kg injection of rACE2-Fc increased the overall angiotensin II-conversion activities in blood by up to 100-fold and enhanced blood pressure recovery from acute angiotensin II induced hypertension seven days after administration. To assess rACE2-Fc given weekly on cardiac protection, we performed studies in mice continuously infused with angiotensin II for 28 days and in a Renin transgenic mouse model of hypertension. The angiotensin II infused mice achieved sustained blood pressure control and reduced cardiac hypertrophy and fibrosis. In chronic hypertensive transgenic mice, weekly injections of rACE2-Fc effectively lowered plasma angiotensin II and blood pressure. Additionally, rACE2-Fc ameliorated albuminuria, and reduced kidney and cardiac fibrosis. Thus, our chimeric fusion strategy for rACE2-Fc is suitable for future development of new renin angiotensin system-based inhibition therapies.
Data on the safety of COVID-19 vaccines in early pregnancy are limited. We conducted a national, population-based, matched cohort study assessing associations between COVID-19 vaccination and ...miscarriage prior to 20 weeks gestation and, separately, ectopic pregnancy. We identified women in Scotland vaccinated between 6 weeks preconception and 19 weeks 6 days gestation (for miscarriage; n = 18,780) or 2 weeks 6 days gestation (for ectopic; n = 10,570). Matched, unvaccinated women from the pre-pandemic and, separately, pandemic periods were used as controls. Here we show no association between vaccination and miscarriage (adjusted Odds Ratio aOR, pre-pandemic controls = 1.02, 95% Confidence Interval CI = 0.96-1.09) or ectopic pregnancy (aOR = 1.13, 95% CI = 0.92-1.38). We undertook additional analyses examining confirmed SARS-CoV-2 infection as the exposure and similarly found no association with miscarriage or ectopic pregnancy. Our findings support current recommendations that vaccination remains the safest way for pregnant women to protect themselves and their babies from COVID-19.
The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRAB
(GPCR-activation-based ACh) sensor to ...achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor. Using this sensor, we revealed compartmental ACh signals in the olfactory center of transgenic flies in response to external stimuli including odor and body shock. Using fiber photometry recording and two-photon imaging, our ACh sensor also enabled sensitive detection of single-trial ACh dynamics in multiple brain regions in mice performing a variety of behaviors.
Abstract
We present constraints on cosmological parameters from the Pantheon+ analysis of 1701 light curves of 1550 distinct Type Ia supernovae (SNe Ia) ranging in redshift from
z
= 0.001 to 2.26. ...This work features an increased sample size from the addition of multiple cross-calibrated photometric systems of SNe covering an increased redshift span, and improved treatments of systematic uncertainties in comparison to the original Pantheon analysis, which together result in a factor of 2 improvement in cosmological constraining power. For a flat ΛCDM model, we find Ω
M
= 0.334 ± 0.018 from SNe Ia alone. For a flat
w
0
CDM model, we measure
w
0
= −0.90 ± 0.14 from SNe Ia alone,
H
0
= 73.5 ± 1.1 km s
−1
Mpc
−1
when including the Cepheid host distances and covariance (SH0ES), and
w
0
=
−
0.978
−
0.031
+
0.024
when combining the SN likelihood with Planck constraints from the cosmic microwave background (CMB) and baryon acoustic oscillations (BAO); both
w
0
values are consistent with a cosmological constant. We also present the most precise measurements to date on the evolution of dark energy in a flat
w
0
w
a
CDM universe, and measure
w
a
=
−
0.1
−
2.0
+
0.9
from Pantheon+ SNe Ia alone,
H
0
= 73.3 ± 1.1 km s
−1
Mpc
−1
when including SH0ES Cepheid distances, and
w
a
=
−
0.65
−
0.32
+
0.28
when combining Pantheon+ SNe Ia with CMB and BAO data. Finally, we find that systematic uncertainties in the use of SNe Ia along the distance ladder comprise less than one-third of the total uncertainty in the measurement of
H
0
and cannot explain the present “Hubble tension” between local measurements and early universe predictions from the cosmological model.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, involving neuroinflammation and T cell infiltration in the central nervous system. However, the contribution of T cell ...responses to the pathology of the disease is not fully understood. Here we show, by flow cytometric analysis of blood and cerebrospinal fluid (CSF) samples of a cohort of 89 newly diagnosed ALS patients in Stockholm, Sweden, that T cell phenotypes at the time of diagnosis are good predictors of disease outcome. High frequency of CD4
FOXP3
effector T cells in blood and CSF is associated with poor survival, whereas high frequency of activated regulatory T (Treg) cells and high ratio between activated and resting Treg cells in blood are associated with better survival. Besides survival, phenotypic profiling of T cells could also predict disease progression rate. Single cell transcriptomics analysis of CSF samples shows clonally expanded CD4
and CD8
T cells in CSF, with characteristic gene expression patterns. In summary, T cell responses associate with and likely contribute to disease progression in ALS, supporting modulation of adaptive immunity as a viable therapeutic option.
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