Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeted mutagenesis on PDGFRα-Fc identifies amino acid modifications that allow efficient inhibition of HCMV infection while abolishing PDGF sequestration

Platelet-derived growth factor receptor alpha (PDGFRα) serves as an entry receptor for the human cytomegalovirus (HCMV), and soluble PDGFRα-Fc can neutralize HCMV at a half-maximal effective concentration (EC50) of about 10 ng/ml. While this indicates a potential for usage as an HCMV entry inhibitor PDGFRα-Fc can also bind the physiological ligands of PDGFRα (PDGFs), which likely interferes with the respective signaling pathways and represents a potential source of side effects. Therefore, we tested the hypothesis that interference with PDGF signaling can be prevented by mutations in PDGFRα-Fc or combinations thereof, without losing the inhibitory potential for HCMV. To this aim, a targeted mutagenesis approach was chosen. The mutations were quantitatively tested in biological assays for interference with PDGF-dependent signaling as well as inhibition of HCMV infection and biochemically for reduced affinity to PDGF-BB, facilitating quantification of PDGFRα-Fc selectivity for HCMV inhibition. Mutation of Ile 139 to Glu and Tyr 206 to Ser strongly reduced the affinity for PDGF-BB and hence interference with PDGF-dependent signaling. Inhibition of HCMV infection was less affected, thus increasing the selectivity by factor 4 and 8, respectively. Surprisingly, the combination of these mutations had an additive effect on binding of PDGF-BB but not on inhibition of HCMV, resulting in a synergistic 260fold increase of selectivity. In addition, a recently reported mutation, Val 242 to Lys, was included in the analysis. PDGFRα-Fc with this mutation was fully effective at blocking HCMV entry and had a drastically reduced affinity for PDGF-BB. Combining Val 242 to Lys with Ile 139 to Glu and/or Tyr 206 to Ser further reduced PDGF ligand binding beyond detection. In conclusion, this targeted mutagenesis approach identified combinations of mutations in PDGFRα-Fc that prevent interference with PDGF-BB but maintain inhibition of HCMV, which qualifies such mutants as candidates for the development of HCMV entry inhibitors.
Consecutive Esotropia with and without Abduction Limitation – Risk Factors and Surgical Outcomes of Lateral Rectus Advancement

ABSTRACT Purpose: To identify risk factors for abduction limitation in consecutive esotropia following surgical correction of exotropia. To study outcomes of lateral rectus advancement for consecutive esotropia correction. Methods: Patients with consecutive esotropia (>10PD) operated between 2007 and 2019 with a minimum follow-up of 2 months were reviewed retrospectively. Preoperative and postoperative alignment and ocular motility were recorded. Patients were classified into those with full abduction (group-A) and with abduction limitation (group-B). Success was defined as deviation ≤10 PD of esotropia or exotropia in the primary position. Results: Forty-cases fulfilled the inclusion criteria (group-A = 28 and group-B = 12). Median age at surgery was five years, median consecutive esotropia was 20PD and follow-up was 29.18 months. Abduction limitation (group-B) was associated with constant exotropia (p = .01) and larger bilateral lateral rectus recession (group-A = 13 mm, group-B = 15 mm; p = .04). Nineteen patients underwent lateral rectus advancement (group-A = 12, group-B = 7), one underwent medial-rectus recession and two were excluded due to lack of postoperative follow-up. Five patients had spontaneous resolution with good alignment (group-A = 3, group-B = 2), two refused surgery, three were observed and eight were lost to follow-up. Success following second surgery was similar in both groups (group-A = 86%, group-B = 77%)(p = 1). Conclusion: Constant exotropia and larger lateral rectus recession were associated with abduction limitation in consecutive esotropia. Lateral rectus advancement produced good outcomes irrespective of abduction limitation.
Dietary inflammatory potential, oxidative balance score, and risk of breast cancer: Findings from the Sister Study

Diet, inflammation, and oxidative stress may be important in breast carcinogenesis, but evidence on the role of the inflammatory and prooxidative potential of dietary patterns is limited. Energy adjusted‐Dietary Inflammatory Index (E‐DII™) and dietary oxidative balance score (D‐OBS) were calculated for 43 563 Sister Study cohort participants who completed a Block 1998 food frequency questionnaire at enrollment in 2003–2009 and satisfied eligibility criteria. D‐OBS was validated using measured F2‐isoprostanes and metabolites. High E‐DII score and low D‐OBS represent a more proinflammatory and prooxidant diet, respectively, and associations of quartiles of each index with breast cancer (BC) risk were estimated using multivariable Cox proportional hazards regression. There were 2619 BCs diagnosed at least 1 year after enrollment (mean follow‐up 8.4 years). There was no overall association between E‐DII and BC risk, whereas there was a suggestive inverse association for the highest vs lowest quartile of D‐OBS (HR 0.92 [95% CI, 0.81‐1.03]). The highest quartile of E‐DII was associated with risk of triple‐negative BC (HR 1.53 [95% CI, 0.99‐2.35]). When the two indices were combined, a proinflammatory/prooxidant diet (highest tertile of E‐DII and lowest tertile of D‐OBS) was associated with increased risk for all BC (HR 1.13 [95% CI, 1.00‐1.27]) and for triple‐negative BC (1.72 [95% CI, 1.10‐2.70]), compared to an antiinflammatory/antioxidant diet (lowest tertile of E‐DII and highest tertile of D‐OBS). Diets with increased inflammatory potential and reduced oxidative balance were positively associated with overall and triple‐negative BC.
Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

De novo, heterozygous, loss‐of‐function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole‐exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss‐of‐function variants in POU4F1 are causative of a novel ataxia syndrome.
Mapping temperature-dependent conformational change in the voltage-sensing domain of an engineered heat-activated K+ channel

Significance Our understanding of fundamental biophysical mechanisms that underlie temperature-dependent gating remains limited despite the elucidation of structures of thermosensitive ion channels. According to current thinking, thermosensitive channels are expected to undergo a significant change in solvation upon activation by temperature, but direct evidence of such a change is lacking. Here, we utilize NMR spectroscopy and atomistic simulations to probe the solvation dynamics of an engineered temperature-sensitive variant of Shaker potassium channel at two different temperatures. Our studies reveal that this temperature-sensitive variant undergoes a dramatic shift in hydration at higher temperatures in contrast to the wild-type channels. Our findings illustrate how point mutations can cause dramatic differences in overall solvation dynamics and thereby alter temperature-dependent function. Temperature-dependent regulation of ion channel activity is critical for a variety of physiological processes ranging from immune response to perception of noxious stimuli. Our understanding of the structural mechanisms that underlie temperature sensing remains limited, in part due to the difficulty of combining high-resolution structural analysis with temperature stimulus. Here, we use NMR to compare the temperature-dependent behavior of Shaker potassium channel voltage sensor domain (WT-VSD) to its engineered temperature sensitive (TS-VSD) variant. Further insight into the molecular basis for temperature-dependent behavior is obtained by analyzing the experimental results together with molecular dynamics simulations. Our studies reveal that the overall secondary structure of the engineered TS-VSD is identical to the wild-type channels except for local changes in backbone torsion angles near the site of substitution (V369S and F370S). Remarkably however, these structural differences result in increased hydration of the voltage-sensing arginines and the S4–S5 linker helix in the TS-VSD at higher temperatures, in contrast to the WT-VSD. These findings highlight how subtle differences in the primary structure can result in large-scale changes in solvation and thereby confer increased temperature-dependent activity beyond that predicted by linear summation of solvation energies of individual substituents.
Early Acute Kidney Injury in Preterm and Term Neonates: Incidence, Outcome, and Associated Clinical Features

Background: Critically ill neonates are at high risk of kidney injury, mainly in the first days of life. Acute kidney injury (AKI) may be underdiagnosed due to lack of a uniform definition. In addition, long-term renal follow-up is limited. Objective: To describe incidence, etiology, and outcome of neonates developing AKI within the first week after birth in a cohort of NICU-admitted neonates between 2008 and 2018. Renal function at discharge in infants with early AKI was assessed. Methods and Subjects: AKI was defined as an absolute serum Cr (sCr) value above 1.5 mg/dL (132 μmol/L) after the first 24 h or as stage 2–3 of the NIDDK neonatal definition. Clinical data and outcomes were collected from medical records and retrospectively analyzed. Results: From January 2008 to December 2018, a total of 9,376 infants were admitted to the NICU of Wilhelmina Children’s Hospital/UMC Utrecht, of whom 139 were diagnosed with AKI during the first week after birth. In 72 term infants, the most common etiology was perinatal asphyxia (72.2%), followed by congenital kidney and urinary tract malformations (CAKUT) (8.3%), congenital heart disease (6.9%), and sepsis (2.8%). Associated conditions in 67 preterm infants were medical treatment of a hemodynamic significant PDA (27.2%), CAKUT (21%), and birth asphyxia (19.4%). Among preterm neonates and neonates with perinatal asphyxia, AKI was mainly diagnosed by the sCr >1.5 mg/dL criterion. Renal function at discharge improved in 76 neonates with AKI associated with acquired conditions. Neonates with stage 3 AKI showed increased sCr values at discharge. Half of these were caused by congenital kidney malformations and evolved into chronic kidney disease (CKD) later in life. Neurodevelopmental outcome (NDO) at 2 years was favorable in 93% of surviving neonates with detailed follow-up. Conclusion: During the first week after birth, AKI was seen in 1.5% of infants admitted to a level III NICU. Renal function at discharge had improved in most neonates with acquired AKI but not in infants diagnosed with stage 3 AKI. Long-term renal function needs further exploration, whereas NDO appears to be good.
Does proximal migration of the first metacarpal correlate with remaining pain after trapeziectomy?

Abstract Proximal migration of the thumb metacarpal has been suggested as a possible cause of remaining pain after trapeziectomy for trapeziometacarpal joint osteoarthritis. The aim of this study was to investigate if proximal migration after trapeziectomy is associated with a poorer long-term outcome in terms of pain and objective physical variables. We retrospectively examined 91 thumbs in 65 patients after a mean of 10 years following trapeziectomy with or without ligament reconstruction and tendon interposition. Proximal migration of the thumb metacarpal was measured on plain lateral radiographs of the thumb and correlated to visual analogue pain scale (VAS), thumb range of motion and strength. Most thumbs had a severe proximal migration of the first metacarpal, the mean scaphoid metacarpal distance was 2.7 mm. Most patients reported no or little pain, median VAS was 0 at rest and 1 after load. There were no differences in reported VAS pain at rest or after load between patients with severe (<2 mm scaphoid metacarpal joint space) or less severe (≥2 mm metacarpal joint space) proximal migration. Patients that reported more pain (VAS >2) did not exhibit more migration than patients reporting less or no pain. Thumbs with severe migration had weaker key pinch (3.4 vs. 4.6 kg, p = 0.008) and grip strength (15 vs. 21 kg p = 0.002). We conclude that proximal migration most likely does not cause residual or recurrent pain after trapeziectomy.
Current density dependence of peroxide formation in the Li–O2 battery and its effect on charge

We report a significant difference in the growth mechanism of Li2O2 in Li–O2 batteries for toroidal and thin-film morphologies which is dependent on the current rate that governs the electrochemical pathway. Evidence from diffraction, electrochemical, FESEM and STEM measurements shows that slower current densities favor aggregation of lithium peroxide nanocrystallites nucleated via solution dismutase on the surface of the electrode; whereas fast rates deposit quasi-amorphous thin films. The latter provide a lower overpotential on charge due to their nature and close contact with the conductive electrode surface, albeit at the expense of lower discharge capacity.
Can we delineate brain injury in full-term neonates using serum biomarkers?

ABSTRACT OBJECTIVE: Early identification of neonates at risk of neurological impairment is particularly important for the bedside clinician. Clinical value of S100b and neuron-specific enolase in neonates has not been yet established. We investigated their kinetics and possible early clinical utility in neonatal encephalopathy (NE). STUDY DESIGN: 36 full-term neonates (13 with moderate/severe encephalopathy, 11 with mild encephalopathy, 12 controls) were enrolled and studied prospectively. Serum S100b and neuron-specific enolase (NSE) were measured serially on days(d) 1, 3, 9 and 18 of life. Brain MRI and long-term neurodevelopmental outcome were also assessed. RESULT: Neonates with moderate/severe encephalopathy had significantly increased S100b (d1) and NSE levels (d1, d3, d9) compared to controls. Neuron-specific enolase significantly correlated with the degree of encephalopathy, and a cutoff of 38.8 μg/l (d1) accurately predicted moderate/severe encephalopathy. S100b (d1) cutoff points of 1.6 μg/l and 11.4 μg/l prognosticated severe encephalopathy and death/cerebral palsy, respectively. Both biomarkers correlated well with neuroimaging and Bayley-III scores. CONCLUSION: Combined clinical, laboratory, imaging and neurodevelopmental data indicate that serum S100b and NSE can be useful biomarkers for the diagnosis and prognosis of neonatal brain injury, providing useful information to the bedside clinician.
Substrate discrimination and quality control require each catalytic activity of TRAMP and the nuclear RNA exosome

Significance Defects in RNA quality control pathways manifest as disease because they function to selectively remove aberrant or defective species to ensure cellular homeostasis. The RNA exosome and TRAMP complexes encompass key components of the RNA surveillance machinery. Here we show that exoribonuclease activities of Rrp6-associated RNA exosomes protect stable RNA species from TRAMP-mediated polyadenylation and degradation, and that each catalytic activity of the RNA exosome-TRAMP complex contributes to substrate discrimination and degradation of less stable RNA species. Our results highlight a previously unappreciated role for Rrp6 in protecting stable RNA species from degradation and suggest additional mechanistic analogies between RNA and protein quality control pathways with respect to proofreading mechanisms that protect stable species while targeting unstable species for destruction. Quality control requires discrimination between functional and aberrant species to selectively target aberrant substrates for destruction. Nuclear RNA quality control in Saccharomyces cerevisiae includes the TRAMP complex that marks RNA for decay via polyadenylation followed by helicase-dependent 3′ to 5′ degradation by the RNA exosome. Using reconstitution biochemistry, we show that polyadenylation and helicase activities of TRAMP cooperate with processive and distributive exoribonuclease activities of the nuclear RNA exosome to protect stable RNA from degradation while selectively targeting and degrading less stable RNA. Substrate discrimination is lost when the distributive exoribonuclease activity of Rrp6 is inactivated, leading to degradation of stable and unstable RNA species. These data support a proofreading mechanism in which deadenylation by Rrp6 competes with Mtr4-dependent degradation to protect stable RNA while selectively targeting and degrading unstable RNA.
Health Care Expenditures and Financial Burden: A Comparison of Adults in Same-Sex Couples and Different-Sex Couples

We used data from the 2014-2017 Medical Expenditure Panel Survey to compare health care expenditures and financial burden between adults in same-sex couples (n = 514) and adults in different-sex couples (n = 41,043). Compared with men in different-sex couples ($3,994), men in same-sex couples ($6,896) were more likely to spend more on health care, especially on prescription medications ($2,745 vs. $1,050), which was primarily driven by antiviral medications ($1,061 vs. $35). Women in same-sex couples ($5,886) reported similar health care expenditures compared with women in different-sex couples ($5,619). However, women in same-sex couples were significantly more likely to experience financial burden compared with women in different-sex couples (25.7% vs. 11.3%). We speculate that the disparities reported here are due to a variety of issues, including elevated health needs requiring prescriptions for lesbian, gay, bisexual, and transgender (LGBT) men and lower incomes for LGBT women. More research is needed to understand health services utilization and expenditure patterns among LGBT populations.
The diversity of stomatal development regulation in Callitriche is related to the intrageneric diversity in lifestyles

Significance Plant stomata are produced through divisions and differentiation of stem cells, termed meristemoids. During stomatal development, we see diverse patterns of meristemoid behavior among land plant lineages. However, both the ecological significance and the diversification processes of this diversity remain mostly unknown. Here we report that the ecologically diverse genus Callitriche shows unprecedented intrageneric diversity in meristemoid behavior. While meristemoids in terrestrial species of Callitriche undergo a series of asymmetric divisions before differentiation, those in amphibious species skip the divisions and directly differentiate into stomata. The simple shift in the expression times of two key transcription factors underlies these different patterns. This study provides important insights into the evolution and ecological significance of stomatal patterning. Stomata, the gas exchange structures of plants, are formed by the division and differentiation of stem cells, or meristemoids. Although diverse patterns of meristemoid behavior have been observed among different lineages of land plants, the ecological significance and diversification processes of these different patterns are not well understood. Here we describe an intrageneric diversity in the patterns of meristemoid division within the ecologically diverse genus Callitriche (Plantaginaceae). Meristemoids underwent a series of divisions before differentiating into stomata in the terrestrial species of Callitriche, but these divisions did not occur in amphibious species, which can grow in both air and water, in which meristemoids differentiated directly into stomata. These findings imply the adaptive significance of diversity in meristemoid division. Molecular genetic analyses showed that the different expression times of the stomatal key transcription factors SPEECHLESS and MUTE, which maintain and terminate the meristemoid division, respectively, underlie the different division patterns of meristemoids. Unlike terrestrial species, amphibious species prematurely expressed MUTE immediately after expressing SPEECHLESS, which corresponded to their early termination of stomatal division. By linking morphological, ecological, and genetic elements of stomatal development, this study provides significant insight that should aid ecological evolutionary developmental biology investigations of stomata.
Shift Work Adaptation Among Police Officers: The BCOPS Study

ABSTRACT Few studies have examined shiftwork adaptation among police officers or potential differences in disease biomarkers among adapted and maladapted shiftworkers. This study characterized shiftwork adaptation among 430 police officers from the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) study. Police officers working fixed night shifts with symptoms characteristic of adaptation and maladaptation were identified using latent class analysis (n = 242). Two approaches were applied, one with police-specific symptoms and another using more general symptoms as shiftwork adaptation indicators. Biomarkers of inflammation, heart rate variability, and cardiometabolic risk were then compared between shiftwork adaptation groups, and with officers working day shifts, after adjusting for confounding. When analyses included police-specific symptoms, maladapted shiftworkers (n = 73) had more self-reported stress, sleep disturbances, fatigue, and less social support than adapted shiftworkers (n = 169). Using more general symptoms, maladapted officers (n = 56) reported more stress and depression, and less social support than adapted officers (n = 186). In police-specific models, adjusted (least-squares) means (± standard error) of circulating interleukin-6 (IL-6) concentrations in maladapted officers (0.8 ± 0.1 ln[pg/ml]) were modestly elevated relative to adapted shiftworkers (0.7 ± 0.1 ln[pg/ml], p = .09) and relative to permanent day workers (0.5 ± 0.1 ln[pg/ml], p ≤ 0.01), and leptin levels in maladapted officers (9.6 ± 0.1 ln[pg/ml]) exceeded those in the adapted (9.4 ± 0.1 ln[pg/ml], p ≤ 0.01) and day shift groups (9.4 ± 0.1 ln[pg/ml], p = .03). In the general model, adjusted mean tumor necrosis factor-alpha (TNF-α) concentrations among maladapted officers (5.6 ± 0.23 pg/ml) exceeded the adapted (4.8 ± 0.2 pg/ml, p ≤ 0.01) and day workers (5.0 ± 0.2 pg/ml, p = .04), and insulin among maladapted officers was higher (2.4 ± 0.1 ln[uu/ml]) than the adapted group (1.8 ± 0.1 ln[uu/ml], p = .03). No differences were observed for the other biomarkers. The results suggest that maladaptation among police officers working fixed night shifts may lead to increases in leptin, insulin, IL-6, and TNF-α; however, the cross-sectional design and possible residual confounding preclude interpretation of cause and effect. Prospective studies are planned to further characterize the relationship between shiftwork maladaptation and biomarkers of chronic disease risk in this police officer cohort.