Dynamics of Structural Elements of GB1 β-Hairpin Revealed by Tryptophan-Cysteine Contact Formation Experiments

Quenching of the triplet state of tryptophan by close contact with cysteine provides a tool for measuring the rate of intramolecular contact formation, one of the most elementary events in the folding process, in peptides and proteins using only natural probes. Here we present a study performed on a stabilized mutant of the second \u3b2-hairpin of the GB1 domain, where we combine steady-state fluorescence, laser-induced temperature-jump, and contact formation measurements to unveil the role of elementary structural components on hairpin dynamics and overall stability. In particular, our methodology provides access to the conformational dynamics of both the folded and unfolded state of the hairpin under native conditions, revealing the presence of extremely slow dynamics on the microsecond time scale in the unfolded state and coexistence of structures with partial pairing of the tails in the folded state. Comparing model peptides that mimic the turn sequence, we found that both ion pairing and hydrogen bonding due to the threonine side chain contribute to the propensity of turn formation but not to the much slower dynamics of the hydrophobic core formation. Interestingly, the dynamics of the turn region in isolation are significantly faster than the dynamics measured for the unfolded state of the complete hairpin, suggesting that non-native hydrophobic contacts slow down the reconfiguration dynamics of the unfolded state. Overall, the information extracted from these experiments provides kinetic limits on interconversions among conformational populations, hence enabling a simplified multistate free-energy landscape for the GB1 hairpin to be drawn

Origin of Life Scenarios: between Fantastic Luck and Marvelous Fine-Tuning

The unequivocal sign of creativity in science is the emergence of previously unrecognized links between facts, concepts, strategies and goals. Observations and speculations become real discoveries as they partake in a network of conceptual implications, thus becoming significant to knowledge. The anticipation of acquiring new beneficial knowledge has always motivated the work of scientists and spurred unconventional thinking, often leading to scientific discoveries that have affected our perception of reality, nature and life. The desire of new revolutionary, paradigm-breaking understanding pushes science toward topics relevant for our metaphysical or even religious perspective on reality: the boundaries of the cosmos, consciousness, the constituents of matter, the destiny of the universe and so on. In this article we offer a short description of the state of the art in the origin of life research and describe examples of creative thinking in this field. We will also discuss the far reaching implications of the direction underlying the most recent research efforts and visions. The occasion for this discussion is given by the recent finding involving the authors, of a new mechanism of molecular self-association: namely, the self-assembly of extremely short fragments of DNA or RNA into large scale ordered structures which could help explaining the prebiotic formation of polymers

Linking Adult Reproduction and Larval Density of Invasive Carp in a Large River

Eeotogists increasingly recognize the need to understand how landscapes ami food webs interact. Reservoir ecosystems are heavily subsidized by nutrients and detritus from surrounding watersheds, and ofren contain abundant populations of gizzard shad, an omnivorous ftsh that consumes plankton and detritus. Gizzard shad link terrestrial landscapes ami pelagic reservoir food webs by consuming detritus, translocating nutrients from sedimctn detritus to the water column, and consuming zooplaukton. The abundance of gizzard shad increases with watershed agricuhuralization, most likely through n variety oj mechanisms npeniting on ttuvat and adult life stages. Gizzard shad have myriad effects on reservoirs, including impacts on nutrients, phytoplankton, zooplankton, and fish, and many of their effects vary with ecosystem productivity (i.e., watershed land use). Interactive feedbacks among watersheds, gizzard shad populations, and reservoir food webs operate to maintain dominance of gizzard shad in highly productive systems. Thus, effective stewardship of reservoir ecosystems must incorporate both watershed and food-web perspective

Risk Factors for Recurrent Acute Kidney Injury in Children Who Undergo Multiple Cardiac Surgeries: A Retrospective Analysis

Objectives: Determine the risk factors for repeated episodes of acute kidney injury in children who undergo multiple cardiac surgical procedures. Design: Single-center retrospective chart review. Setting: Cardiac ICU at a quaternary pediatric care center. Patients: Birth to 18 years who underwent at least two cardiac surgical procedures with cardiopulmonary bypass. Interventions: None. Measurements and main results: One-hundred eighty patients underwent two cardiac surgical procedures and 89 underwent three. Acute kidney injury was defined by the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Acute kidney injury frequency was 26% (n = 46) after surgery 1, 20% (n = 36) after surgery 2, and 24% (n = 21) after surgery 3, with most acute kidney injury occurring on postoperative days 1 and 2. The proportion of patients with severe acute kidney injury increased from surgery 1 to surgery 3. Patients with acute kidney injury had a significantly longer duration of ventilation and length of stay after each surgery. The odds of acute kidney injury after surgery 3 was 2.40 times greater if acute kidney injury was present after surgery 1 or 2 (95% CI, 1.26-4.56; p = 0.008) after adjusting for confounders. The time between surgeries was not significantly associated with acute kidney injury (p = 0.85). Conclusions: In a heterogeneous population of pediatric patients with congenital heart disease undergoing multiple cardiopulmonary bypass surgeries, odds of acute kidney injury after a third surgery was increased by the presence of acute kidney injury after prior procedures. Time between surgery did not play a role in increasing odds of acute kidney injury. Further studies in a larger multicenter investigation are necessary to confirm these findings

Trends in the representation of women in the American Society of Pediatric Nephrology program at the Pediatric Academic Society annual meetings 2012–2021

IntroductionWomen are under-represented in virtually all fields of academic medicine. Even in pediatrics, a field that historically attracts a workforce with a majority of women physicians, substantial gender disparities persist in leadership positions. However, previous studies of gender representation in various academic settings are limited to small studies or aggregate pediatric subspecialties, thereby omitting important granularity within each subspecialty. No prior studies have investigated potential gender disparities in pediatric nephrology. The aim of this study is to determine the representation of women physicians in leadership and speaking roles in the annual American Society of Pediatric Nephrology (ASPN) meeting.MethodsData were analyzed from the 2012–2022 ASPN annual scientific meetings at the Pediatric Academic Society (PAS). Data were abstracted regarding gender and roles: speaker, chair/moderator, and lifetime achievement awardee. We performed a time series analysis using linear regression, with the year as the independent variable and the proportion of women as the dependent variable.ResultsOverall, there were statistically significant increases in the proportion of women speakers per year and percentage of women chairs or moderators. There were no specific trends noted for lifetime achievement awards and no statistically significant changes in the number of lifetime achievement awards.DiscussionWe found proportionate representations of gender representation with regards to speakers and chairs or moderators, although our data was limited by comparison to the American Board of Pediatrics (ABP) workforce cumulative “ever certified” data. The ABP data include a disproportionate representation of faculty who are men from earlier certification periods who may no longer be actively practicing pediatric nephrology

Risk factors for acute kidney injury in neonates with congenital diaphragmatic hernia

This article is made available for unrestricted research re-use and secondary analysis in any form or be any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Objective: To examine incidence of acute kidney injury (AKI), antenatal and postnatal predictors, and impact of AKI on outcomes in infants with congenital diaphragmatic hernia (CDH). Study design: Single center retrospective study of 90 CDH infants from 2009-2017. Baseline characteristics, CDH severity, possible AKI predictors, and clinical outcomes were compared between infants with and without AKI. Result: In total, 38% of infants developed AKI, 44% stage 1, 29% stage 2, 27% stage 3. Lower antenatal lung volumes and liver herniation were associated with AKI. Extracorporeal life support (ECLS), diuretics, abdominal closure surgery, hypotension, and elevated plasma free hemoglobin were associated with AKI. Overall survival was 79%, 47% with AKI, and 35% with AKI on ECLS. AKI is associated with increased mechanical ventilation duration and length of stay. Conclusion: AKI is common among CDH infants and associated with adverse outcomes. Standardized care bundles addressing AKI risk factors may reduce AKI incidence and severity

Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms

The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer\u27s disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically detailed model of monomeric ApoE4 and probe the effect of lipid association. Importantly, our approach overcomes previous limitations by allowing us to work at picomolar concentrations where only the monomer is present. Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids. Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble. Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein

Multiscale Drivers of Water Chemistry of Boreal Lakes and Streams

The variability in surface water chemistry within and between aquatic ecosystems is regulated by many factors operating at several spatial and temporal scales. The importance of geographic, regional-, and local-scale factors as drivers of the natural variability of three water chemistry variables representing buffering capacity and the importance of weathering (acid neutralizing capacity, ANC), nutrient concentration (total phosphorus, TP), and importance of allochthonous inputs (total organic carbon, TOC) were studied in boreal streams and lakes using a method of variance decomposition. Partial redundancy analysis (pRDA) of ANC, TP, and TOC and 38 environmental variables in 361 lakes and 390 streams showed the importance of the interaction between geographic position and regional-scale variables. Geographic position and regional-scale factors combined explained 15.3% (streams) and 10.6% (lakes) of the variation in ANC, TP, and TOC. The unique variance explained by geographic, regional, and local-scale variables alone was <10%. The largest amount of variance was explained by the pure effect of regional-scale variables (9.9% for streams and 7.8% for lakes), followed by local-scale variables (2.9% and 5.8%) and geographic position (1.8% and 3.7%). The combined effect of geographic position, regional-, and local-scale variables accounted for between 30.3% (lakes) and 39.9% (streams) of the variance in surface water chemistry. These findings lend support to the conjecture that lakes and streams are intimately linked to their catchments and have important implications regarding conservation and restoration (management) endeavors