bluuebunny/crossref_metadata_2025 huggingface dataset:
Secondary displacement in distal forearm fractures in children: adequate positioning of the wrist in the cast is more important than cast index
Authors: Kralj Rok , Pešorda Domagoj , Keretić Dorotea , Ivelj Renato , Bumči Bruno , Bumči Igor , Višnjić Stjepan , Žic Rado
Published: April 2022

The objective of this study was to assess whether the positioning of the wrist joint in the cast in such a manner that it counteracts the direction of angulation of fragments is more important than the cast index in the prevention of secondary displacements in distal forearm fractures. A retrospective review of all pediatric patients (0–16 years of age) who were hospitalized in our institution with displaced fractures of the distal forearm (either isolated fractures of the distal radius or both bone fractures) who underwent subsequent closed reduction and splinting in the period from August 2018 to October 2020. Patients with physeal fractures and open fractures, and skeletally mature patients were excluded from the study. Patients were divided into two categories – the first one in which the cast index was below 0.9 and the second in which it was above 0.9. In each category, we have identified two groups of patients – the first one in whom the wrist joint was positioned in such a manner that it counteracts the direction of angulation of fracture fragments and the second one in whom the wrist joint was in a neutral position. The two groups in each category have been compared according to age, sex, initial angulation, fracture type (isolated radius or both bone fractures), displacement type (angulation or complete dislocation) and the rate of secondary displacement. In both categories, the two groups were comparable according to age, sex, initial angulation, fracture and displacement type. In both categories (cast index below 0.9 and cast index above 0.9), a statistically significant higher portion of patients with secondary displacement was identified in the group of patients who had the wrist joint in a neutral position (Z = −2.1997; P = 0.0278 – for cast index <0.9 and Z = −2.1672; P = 0.030216 for cast index >0.9). Our research supports the notion that positioning of the wrist joint in the position that counteracts the force that leads to angulation of fracture fragments is more important than the cast index in the prevention of secondary displacements in pediatric distal forearm fractures.
Outcomes following adolescent athlete proximal hamstring apophyseal avulsion bone fragment excision and direct tendon-ischial tuberosity reattachment
Authors: Kaila Rajiv , French Sofie R. , Wood David G.
Published: April 2022

Apophyseal proximal hamstring bone avulsion is uncommon, occurring in adolescents following sudden forceful contraction of the musculotendinous unit. It can be severely disabling, preventing return to sport. This study assessed outcome following avulsed bone excision and direct hamstring tendon-ischial tuberosity reattachment using bone anchors. Validated hamstring-specific Sydney hamstring orthopaedic research evaluation PROMs were prospectively collected from consecutively treated athletes (7 elite and 11 recreational) by a single surgeon over 13 years. Outcomes at 1-year and final follow-up for primary acute surgery at less than 3 months after injury (group 1), primary chronic surgery at more than 3 months after established nonunion (group 2) and revision following failed screw fixation (group 3) were analyzed with sport participation and level at 1 year. Sixteen primary and two revision procedures were analyzed. Mean injury age was 14.6 years (SD, 1.8). Combined primary mean injury scores improved from 11.89 (SD, 7.32) to 33.31 (SD, 2.30) and showed mean 1 year and final follow-up scores within 0.3–6.1% of preinjury values. Pronounced improvement occurred from injured scores for groups 1 versus 2, respectively at 1 year by 247.7% versus 59.0% and at final follow-up by 251.0% versus 64.1%, for groups 1 versus 2, respectively. Final outcome scores of group 3 were high. All cases returned to preinjury sport level by 1 year and indicated satisfaction to repeat treatment. No significant complications occurred. As the largest series to assess outcomes following this surgical technique, success is highlighted by high score improvements close to preinjury values and return to preinjury sport level.
Early Neuromuscular Electrical Stimulation in Addition to Early Mobilization Improves Functional Status and Decreases Hospitalization Days of Critically Ill Patients
Authors: Campos Débora R. , Bueno Thatiana B. C. , Anjos Jackeline S. G. G. , Zoppi Daniel , Dantas Bruno G. , Gosselink Rik , Guirro Rinaldo R. J. , Borges Marcos C.
Published: April 2022

Objectives:

To evaluate the impact of the additional use of early neuromuscular electrical stimulation (NMES) on an early mobilization (EM) protocol.

Design:

Randomized controlled trial.

Setting:

ICU of the Clinical Hospital of Ribeirão Preto, University of São Paulo, Brazil.

Patients:

One hundred and thirty-nine consecutive mechanically ventilated patients were included in the first 48 hours of ICU admission.

Interventions:

The patients were divided into two groups: EM and EM+NMES. Both groups received EM daily. In the EM+NMES group, patients additionally received NMES 5 days a week, for 60 minutes, starting in the first 48 hours of ICU admission until ICU discharge.

Measurements and Main Results:

Functional status, muscle strength, ICU and hospital length of stay (LOS), frequency of delirium, days on mechanical ventilation, mortality, and quality of life were assessed. Patients in the EM+NMES group presented a significant higher score of functional status measured by the Functional Status Score for the ICU scale when compared with the EM group in the first day awake: 22 (15–26) versus 12 (8–22) (p = 0.019); at ICU discharge: 28 (21–33) versus 18 (11–26) (p = 0.004); and hospital discharge: 33 (27–35) versus 25 (17–33) (p = 0.014), respectively. They also had better functional status measured by the Physical Function Test in the ICU scale, took less days to stand up during the ICU stay, and had a significant shorter hospital LOS, lower frequency of ICU-acquired weakness, and better global muscle strength.

Conclusions:

The additional application of early NMES promoted better functional status outcomes on the first day awake and at ICU and hospital discharge. The patients in the EM+NMES group also took fewer days to stand up and had shorter hospital LOS, lower frequency of ICU-acquired weakness, and better muscle strength. Future studies are still necessary to clarify the effects of therapies associated with EM, especially to assess long-term outcomes.
Nurse practitioner experiences providing nutrition counseling to adult patients in primary care
Authors: Eaton Maggie , Duffy Lisa , Pozzar Rachel , Board Rhonda
Published: April 2022

Background:

Poor nutrition is one of the leading risk factors for preventable chronic diseases in the United States. Nutrition counseling has been shown to improve clinical outcomes in the adult primary care setting. Nurse practitioners (NPs) can help fill the critical need for nutrition counseling, yet little is known about their role providing nutrition counseling.

Purpose:

To describe the primary care NP's experience in providing nutrition counseling to adult patients in primary care practice.

Methods:

Qualitative descriptive study design. Data were collected through virtual semi-structured interviews with 18 board-certified primary care NPs. Interviews were audio-recorded, de-identified, transcribed verbatim, and analyzed. Data collection and analysis took place concurrently and continued until data saturation was achieved.

Results:

Five themes emerged from NPs' descriptions of their experiences in providing nutrition counseling to adult patients in primary care practice: (1) role of nutrition counseling in NP primary care practice; (2) developing NP self-efficacy in nutrition counseling; (3) nutrition counseling is more than the provision of information; (4) emotional aspect of nutrition; and (5) barriers to behavior change.

Conclusions:

Findings suggest that although NPs understand the importance of nutrition counseling in primary care practice and provide it in some capacity, its continuance is limited by multiple barriers. Future research should evaluate ways to enhance NPs' preparedness to provide nutrition counseling, assess specific resources and tools to aid in nutrition counseling, and determine best practices for communication when delivering nutrition counseling.

Implications for practice:

Future interventions have the potential to positively affect patients' dietary practices and improve clinical outcomes.
Interoceptive Awareness and Anorexia Nervosa
Authors: Wollast Robin , Fossion Pierre , Kotsou Ilios , Rebrassé Audrey , Leys Christophe
Published: April 2022

Anorexia nervosa (AN) is related to difficulties in emotion regulation, including a deficit in interoceptive awareness. The lack of interoceptive awareness is considered a vulnerability involved in the development and maintenance of anorexic symptoms. Surprisingly, no study has been conducted that focuses on these associations in an emotional context. This study measures the interoceptive awareness—using heartbeat self-counting and a sphygmomanometer—of 25 subjects suffering from AN and 25 control subjects, first at rest and then in an emotional situation. The results show that a deficit in interoceptive awareness was observed for the subjects suffering from AN at rest as well as when an emotional context was induced. This study encourages future investigations to focus on the impact of interoceptive deficit in AN to develop as efficient a care regimen as possible for these subjects.
The Effect of the Addition of Electrolyte Solutions on the Ferning Patterns of Tears Collected from Normal Eye Subjects
Authors: Alanazi Mana A. , El-Hiti Gamal A. , Alshehri Jaber A. , Alhadyan Ahmed S. , Fagehi Raied , Masmali Ali M. , Almubrad Turki
Published: April 2022

SIGNIFICANCE

The current study is the first report to describe the improvement of ferning patterns of human tears using electrolyte solutions. The results can help in the production of new artificial tears to improve the quality of tears.

PURPOSE

This study aimed to investigate the effect of the addition of different volumes of various electrolyte solutions on ferning patterns of human tears.

METHODS

Tear samples (20 μL) were collected from the right eye of 13 subjects (5 men and 5 women) aged 19 to 36 years (27.1 ± 5.1 years) with normal eyes. Then, 1 μL of each tear sample was dried on a microscopic glass slide, and obtained ferns were observed using light microscopy and graded using the 5-point tear ferning (TF) grading scale. Homogenous mixtures of each tear sample (0.5 μL) and different volumes (0.5 to 5 μL) of each electrolyte were prepared. A sample (1 μL) of each mixture was dried, and the ferns obtained were graded and compared with those of the corresponding tears collected from subjects before the addition of electrolyte solutions.

RESULTS

After the addition of electrolyte solutions, the TF grades of tears collected from healthy humans were generally improved. Significant (Wilcoxon test) improvements have been seen in the TF grades of the tear samples after the addition of a solution of potassium chloride (P = .03), calcium chloride (P = .01), magnesium chloride hexahydrate (P = .002), and sodium dihydrogen phosphate (P = .002). No significant improvements in the TF grades were seen after the addition of sodium chloride solution (P = .33).

CONCLUSIONS

Ferning grades of human tears improved with most of the electrolytes used.
Case Report: Novel Patient Training Technique for the Application and Removal of Scleral Lenses
Authors: Kwok Alan , Derby Stephanie , Zeldin Dina , Brocks Daniel C.
Published: April 2022

SIGNIFICANCE

This report shares a technique that can be used to assist training patients to properly and safely apply and remove prosthetic replacement of the ocular surface ecosystem devices (PD) or scleral lenses to reduce patient training nervousness, limit adverse events from training, and limit training failures.

PURPOSE

This study aimed to introduce a novel scleral lens application and removal training method.

CASE REPORT

A 28-year-old woman with limbal stem cell deficiency secondary to contact lens overwear in the left eye greater than the right eye presented for prosthetic replacement of the ocular surface ecosystem treatment. Her ocular history included herpes simplex keratitis, fungal keratitis, and acanthamoeba keratitis in the left eye, which ultimately resulted in corneal perforation requiring repair with cyanoacrylate adhesive. The patient was initially fitted with a PD in 2015 in the left eye but had difficulty with application of the device on the eye, which resulted in discontinuation of use. She returned to the clinic in 2021 for a reevaluation and PD refitting. To address her past difficulties surrounding application and removal of the device, a novel piggyback technique (applying a second scleral lens on top of the primary customized scleral lens that is already on the eye) was used to successfully train the patient.

CONCLUSIONS

A novel piggyback training technique can be used to overcome obstacles during the scleral lens application and removal training process.
Association Between Loss of SATB2 Expression in Inflammatory Bowel Disease Indefinite for Dysplasia and a Diagnosis of Definitive Dysplasia on Follow-up
Authors: Cretara Anthony , Knee Alexander , Mueller James , Jawale Rahul
Published: April 2022

Special AT-rich sequence-binding protein 2 (SATB2) is a sensitive and specific biomarker for sporadic colonic adenocarcinomas. Previous studies have found that SATB2 is lost in some adenocarcinomas and dysplasias associated with inflammatory bowel disease (IBD). In establishing these findings, the prior studies did not examine cases of IBD interpreted as indefinite for dysplasia. We examined SATB2 expression in this diagnostic category to determine if any potential loss is associated with a diagnosis of definitive dysplasia on follow-up. To investigate this possibility, we collected 87 biopsies of IBD indefinite for dysplasia from 62 patients and stained them with SATB2. Among patients’ indefinite for dysplasia, we found SATB2 loss in 6/62 (9.7%). Among those with follow-up (n=51), we observed 5/6 (83%) with a future dysplasia in those with SATB2 loss compared with 10/45 (22%) in those with SATB2 retention, absolute difference 61.1% (95% confidence interval=28.9%-93.3%). We conclude that loss of SATB2 on biopsies otherwise interpreted as IBD indefinite for dysplasia may mark a population at high risk for showing definitive dysplasia on future biopsies.
Mucinous Tumor Coexisting With Mesonephric-like Proliferation/Tumor in the Ovary
Authors: Nilforoushan Neshat , Liu Lian , Cheang Gloria , Sui Amy C. , Andersen John , Finkelman Brian S. , Liu Ying , Nasseri-Nik Niloofar , Vang Russell , Ronnett Brigitte M. , Song Wei , Xing Deyin
Published: April 2022

The literature indicates that mesonephric carcinoma (MC) and mesonephric-like adenocarcinoma (MLA) typically lack mucinous and squamous features/differentiation. We report 4 cases of ovarian mucinous tumors (1 mucinous cystadenofibroma and 3 mucinous borderline tumors/atypical proliferative mucinous tumors [MBT/APMT]) co-existing with mesonephric-like lesions which were highlighted by Gata3 and Pax8 expression. All cases contained benign mesonephric-like proliferations (MLP) which focally displayed gastrointestinal-type mucinous metaplasia/differentiation and some were intimately admixed with mucinous glands associated with the mucinous tumor. Metaplastic mucinous epithelium retained expression of Gata3 and Pax8 in some areas while 1 mucinous cystadenofibroma and 1 MBT/APMT were focally positive for Pax8. Along with these mesonephric components, case 1 exhibited features of mesonephric hyperplasia and in 2 cases, 3 and 4, MLA was identified. In case 4, a KRAS c.35G>T (p.Gly12Val) somatic mutation was detected in both the MBT/APMT and the MLA, indicating a clonal origin. This same mutation was also detected in the benign MLP, indicating that it was likely an early genetic event. A CTNNB1 c.98C>T (p.Ser33Phe) somatic mutation, FGFR2 amplification, and CDKN2A/p16 deletion were only detected in the MLA but not in the MBT/APMT. Our result provides evidence to demonstrate the clonal relationship between these morphologically distinct components. Although speculative, we postulate that benign MLPs may give rise to lineage-specific mucinous and mesonephric-like lesions and propose that the MLPs are a new possible origin of some ovarian mucinous tumors. Whether these MLPs arise through transdifferentiation of Müllerian tissue or represent true mesonephric remnants, however, remains largely unknown.
Understanding Bilateral Skull Fractures in Infancy
Authors: O'Hara Mandy A. , Valvano Thomas J. , Kashyap Marisha , Daly Jennie C. , Bachim Angela N. , Care Marguerite M. , Egge Melissa K. , Kondis Jamie S. , Lenane Ann M. , Maddocks Alexis B.R. , Metz James B. , Nielsen Anne K. , Reeder Kristen N. , Ruda Michelle T. , Segal Rachel , Sugarman Jacqueline M. , Weeks Kerri , Oral Resmiye
Published: April 2022

Background

Bilateral skull fractures in infancy often raise suspicion for abuse. Nevertheless, literature suggests that they may occur accidentally. However, empiric data are lacking.

Objective

This multicenter retrospective review aimed to characterize bilateral skull fractures in a large sample.

Participants and Setting

Medical records for infants younger than 24 months with bilateral skull fractures involving hospital consultation with a child abuse pediatrician (CAP) were reviewed from 2005 to 2020 at 13 nationally represented institutions.

Methods

Standardized data collection across institutions included historical features, fracture characteristics, and additional injuries, as well as the CAP's determination of accident versus abuse. Pooled data were analyzed for descriptive and bivariate analyses.

Results

For 235 cases, 141 were accidental, and 94 abuse. The majority occurred in young infants, and a history of a fall was common in 70% of cases. More than 80% involved both parietal bones. Bilateral simple linear fractures were more common in accidental cases, 79% versus 35%, whereas a complex fracture was more frequent in abuse cases, 55% versus 21% (P < 0.001). Almost two thirds of accidental cases showed approximation of the fractures at the sagittal suture, compared with one third of abuse cases (P < 0.001). Whereas focal intracranial hemorrhage was seen in 43% of all cases, diffuse intracranial hemorrhage was seen more in abuse cases (45%) than accidents (11%). Skin trauma was more common in abusive than accidental injury (67% vs 17%, P < 0.001), as were additional fractures on skeletal survey (49% vs 3%, P < 0.001).

Conclusions

A fall history was common in bilateral skull fractures deemed accidental by a CAP. Most accidental cases involved young infants with biparietal simple linear fractures, without skin trauma or additional fractures. A skeletal survey may aid in the determination of accidental or abusive injury for unwitnessed events resulting in bilateral skull fractures in infants.
A Longitudinal Study of Age-Based Change in Blood Pressure Reactivity and Negative Affect Reactivity to Natural Stressors
Authors: Koffer Rachel E. , Kamarck Thomas W.
Published: April 2022

Objective

Aging is theoretically accompanied by emotional gains, but physiological self-regulatory losses. Emotional and physiological regulation can be operationalized as the extent of an increase in negative affect and blood pressure upon experiencing a stressor (i.e., reactivity). The direction of age-based changes in negative affect reactivity to stressors is uncertain. In addition, evidence for age-based increases in blood pressure reactivity to stressors is based largely on age-based differences observed in cross-sectional and laboratory-based studies. The present study is the first to examine long-term longitudinal changes in stress-related reactivity for both blood pressure and negative affect in the natural environment.

Methods

A total of 375 healthy adults aged 50 to 70 years completed 6 days of hourly ambulatory blood pressure assessment and electronic diary reports of social conflict and task demand and control. Two hundred fifty-five participants repeated 3 days of assessment in a 6-year follow-up. With reactivity operationalized as the change in an outcome in association with momentary social conflict, task strain, or task demand (i.e., a model-derived slope parameter), multilevel models were used to assess aging-based change in blood pressure and negative affect reactivity over the course of the 6-year follow-up.

Results

Aging is associated with increased diastolic blood pressure reactivity to social conflict and task demand (β
social_conflict = 0.48, p = .007; β
task_demand = 0.19, p = .005), increases in negative affect reactivity to social conflict and task strain (β
social_conflict = 0.10, p < .001; β
task_strain = 0.08, p = .016), and increases in systolic blood pressure reactivity to task-based stress (β
task_strain = 1.29, p = .007; β
task_demand = 0.23 p = .032).

Conclusion

Findings suggest age-based increases in affective and cardiovascular reactivity to natural stressors.
Psychological Predictors of Response to Open-Label Versus Double-Blind Placebo in a Randomized Controlled Trial in Irritable Bowel Syndrome
Authors: Ballou Sarah , Haas Julia W. , Iturrino Johanna , Nee Judy , Kirsch Irving , Rangan Vikram , Cheng Vivian , Lembo Anthony , Kaptchuk Ted J. , Kelley John M.
Published: April 2022

Objective

There is growing evidence that open-label placebo (OLP) may be an efficacious treatment of chronic and functional conditions. However, patient-level predictors of response to OLP have not been clearly identified. The aim of this study is to evaluate the psychological predictors of response to OLP and to compare this to double-blind placebo (DBP) and no-pill control (NPC).

Methods

This study is a secondary analysis of data collected in a 6-week randomized controlled trial evaluating placebo effects in irritable bowel syndrome (IBS). The primary outcome was change in IBS severity. Hierarchical linear regression identified predictors of placebo response in general and compared them between those randomized to OLP, DBP, and NPC. Predictor variables included personality traits, generalized anxiety, depression, visceral sensitivity (a measure of symptom-specific anxiety), and pain catastrophizing.

Results

A total of 210 participants (mean age = 42.3 years, 73.3% female) were included. Regression models revealed that visceral sensitivity was a predictor of response to OLP and NPC but not DBP. Interestingly, the effects were opposite, with high visceral sensitivity predicting less improvement in NPC and more improvement in OLP. Pain catastrophizing was a negative predictor of response to OLP (i.e., high pain catastrophizing was associated with less improvement in OLP). Neither visceral sensitivity nor pain catastrophizing played a significant role for response to DBP.

Conclusions

IBS participants who score low on the Pain Catastrophizing Scale but high on the Visceral Sensitivity Index seem to benefit particularly from OLP. Our study suggests that different psychological mechanisms may be involved in DBP and OLP interventions.
Coronary Artery Calcifications Are Associated With More Severe Multiorgan Failure in Patients With Severe Coronavirus Disease 2019 Infection
Authors: Martens Bibi , Driessen Rob G.H. , Brandts Lloyd , Hoitinga Puck , van Veen Fauve , Driessen Mariëlle , Weberndörfer Vanessa , Kietselaer Bas , Ghossein-Doha Chahinda , Gietema Hester A. ,   MaastrICCht Collaborators, Vernooy Kevin , van der Horst Iwan C.C. , Wildberger Joachim E. , van Bussel Bas C.T. , Mihl Casper
Published: April 2022

Purpose:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is regarded as a multisystemic disease. Patients with preexisting cardiovascular disease have an increased risk for a more severe disease course. This study aimed to investigate if a higher degree of coronary artery calcifications (CAC) on a standard chest computed tomography (CT) scan in mechanically ventilated patients was associated with a more severe multiorgan failure over time.

Materials and Methods:

All mechanically ventilated intensive care unit patients with SARS-CoV-2 infection who underwent a chest CT were prospectively included. CT was used to establish the extent of CAC using a semiquantitative grading system. We categorized patients into 3 sex-specific tertiles of CAC: lowest, intermediate, and highest CAC score. Daily, the Sequential Organ Failure Assessment (SOFA) scores were collected to evaluate organ failure over time. Linear mixed-effects regression was used to investigate differences in SOFA scores between tertiles. The models were adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, cardiovascular risk factors, and chronic liver, lung, and renal disease.

Results:

In all, 71 patients were included. Patients in the highest CAC tertile had, on average, over time, 1.8 (0.5-3.1) points higher SOFA score, compared with the lowest CAC tertile (P=0.005). This association remained significant after adjustment for age, sex, and APACHE II score (1.4 [0.1-2.7], P=0.042) and clinically relevant after adjustment for cardiovascular risk factors (1.3 [0.0-2.7], P=0.06) and chronic diseases (1.3 [−0.2 to 2.7], P=0.085).

Conclusion:

A greater extent of CAC is associated with a more severe multiorgan failure in mechanically ventilated coronavirus disease 2019 patients.
Deletion of FRT-sites by no-SCAR recombineering in Escherichia coli
Authors: Rangarajan Aathmaja Anandhi , Yilmaz Cihan , Schnetz Karin
Published: April 2022

Lambda-Red recombineering is the most commonly used method to create point mutations, insertions or deletions in

Escherichia coli

and other bacteria, but usually an Flp recognition target (FRT) scar-site is retained in the genome. Alternative scarless recombineering methods, including CRISPR/Cas9-assisted methods, generally require cloning steps and/or complex PCR schemes for specific targeting of the genome. Here we describe the deletion of FRT scar-sites by the scarless Cas9-assisted recombineering method no-SCAR using an FRT-specific guide RNA, sgRNAFRT, and locus-specific ssDNA oligonucleotides. We applied this method to construct a scarless

E. coli

strain suitable for gradual induction by l-arabinose. Genome sequencing of the resulting strain and its parent strains demonstrated that no additional mutations were introduced along with the simultaneous deletion of two FRT scar-sites. The FRT-specific no-SCAR selection by sgRNAFRT/Cas9 may be generally applicable to cure FRT scar-sites of

E. coli

strains constructed by classical λ-Red recombineering.
Novel Privacy Considerations for Large Scale Proteomics
Authors: Hill Andrew C. , Litkowski Elizabeth M. , Manichaikul Ani , Lange Leslie , Pratte Katherine A. , Kechris Katerina J. , DeCamp Matthew , Coors Marilyn , Ortega Victor E. , Rich Stephen S. , Rotter Jerome I. , Gerzsten Robert E. , Clish Clary B. , Curtis Jeffery , Hu Xiaowei , Ngo Debby , O’Neal Wanda K , Meyers Deborah , Bleecker Eugene , Hobbs Brian D. , Cho Michael H. , Banaeikashani Farnoush , Bowler Russell P.
Published: April 2022

Introduction

Privacy protection is a core principle of genomic research but needs further refinement for high-throughput proteomic platforms.

Methods

We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS) and then calculated genotype probabilities by protein level for each protein-genotype combination (training). Using the most significant 100 proteins, we applied a naïve Bayesian approach to match proteomes to genomes for 2,812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA) with SomaScan 1.3K proteomes and also 2,646 COPDGene subjects with SomaScan 5K proteomes (testing). We tested whether subtracting mean genotype effect for each pQTL SNP would obscure genetic identity.

Results

In the four testing cohorts, we were able to correctly match 90%-95% their proteomes to their correct genome and for 95%-99% we could match the proteome to the 1% most likely genome. With larger profiling (SomaScan 5K), correct identification was > 99%. The accuracy of matching in subjects with African ancestry was lower (∼60%) unless training included diverse subjects. Mean genotype effect adjustment reduced identification accuracy nearly to random guess.

Conclusion

Large proteomic datasets (> 1,000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered deidentified. These findings suggest that large scale proteomic data be given privacy protections of genomic data, or that bioinformatic transformations (such as adjustment for genotype effect) should be applied to obfuscate identity.
Disrupting ACE2 Dimerization Mitigates the Infection by SARS-COV-2
Authors: Zhu Jiaqi , Su Yue , Tang Young
Published: April 2022

The coronavirus disease 2019 (COVID-19) pandemic has caused over 6 million death and 460 million reported cases globally. More effective antiviral medications are needed to curb the continued spread of this disease. The infection by SARS-COV-2 virus is initiated via the interaction between the receptor binding domain (RBD) of the viral glycoprotein Spike (S protein) and the N-term peptidase domain (PD) of the angiotensin-converting enzyme 2 (ACE2) expressed on host cell membrane. ACE2 forms protein homodimer primarily through its ferredoxin-like fold domain (aka. Neck-domain). We investigated whether the dimerization of ACE2 receptor plays a role in SARS-COV-2 virus infection. We report here that the ACE2 receptor dimerization enhances the recognition of SARS-COV-2 S protein. A 43 amino acid peptide based on the N-term of Neck-domain could block the ACE2 dimerization and the interaction between RBD and ACE2, and mitigate the SARS-COV-2/host cell interaction. Our study illustrated a new route to develop potential therapeutics for the prevention and treatment of SARS-COV-2 viral infection.
Wake respirometry may quantify stress and energetics of free-living animals
Authors: Rose Kayleigh , Wilson Rory P , Ramenda Claudia , Robotka Hermina , Wikelski Martin , Shepard Emily L C
Published: April 2022

Quantifying activity-specific energy expenditure in free-living animals is a major challenge as current methods require calibration in the lab and animal capture. We propose “wake respirometry”, a new method of quantifying fine-scale changes in CO2 production in unrestrained animals, using a non-dispersive infrared CO2 sensor positioned downwind of the animal i.e. in its wake. We parameterise the dispersion of CO2 in a wake using known CO2 concentrations, flow rates and wind speeds. Tests with three bird species in a wind tunnel demonstrated that the system can resolve breath-by-breath changes in CO2 concentration, with clear exhalation signatures increasing in period and integral with body size. Changes in physiological state were detectable following handling, flight and exposure to a perceived threat. We discuss the potential of wake respirometry to quantify stress and respiratory patterns in wild animals and estimate activity-specific metabolic rates through the full integration of CO2 production across the wake.
ReDisX: a Continuous Max Flow-based framework to redefine the diagnosis of diseases based on identified patterns of genomic signatures
Authors: Yip Hiu Fung , Chowdhury Debajyoti , Wang Kexin , Liu Yujie , Gao Yao , Lan Liang , Zheng Chaochao , Guan Daogang , Lam Kei Fong , Zhu Hailong , Tai Xuecheng , Lu Aiping
Published: April 2022

Diseases originate at the molecular-genetic layer, manifest through altered biochemical homeostasis, and develop symptoms later. Hence symptomatic diagnosis is inadequate to explain the underlying molecular-genetic abnormality and individual genomic disparities. The current trends include molecular-genetic information relying on algorithms to recognize the disease subtypes through gene expressions. Despite their disposition toward disease-specific heterogeneity and cross-disease homogeneity, a gap still exists to describe the extent of homogeneity within the heterogeneous subpopulation of different diseases. They are limited to obtaining the holistic sense of the whole genome-based diagnosis resulting in inaccurate diagnosis and subsequent management.

To fill those gaps, we proposed ReDisX framework, a scalable machine learning algorithm that uniquely classifies patients based on their genomic signatures. It was deployed to re-categorizes the patients with rheumatoid arthritis and coronary artery disease. It reveals heterogeneous subpopulations within a disease and homogenous subpopulations across different diseases. Besides, it identifiesGZMBas a subpopulation-differentiation marker that plausibly serves as a prominent indicator forGZMB-targeted drug repurposing.

The ReDisX framework offers a novel strategy to redefine disease diagnosis through characterizing personalized genomic signatures. It may rejuvenate the landscape of precision and personalized diagnosis, and a clue to drug repurposing.
scTAM-seq enables targeted high-confidence analysis of DNA methylation in single cells
Authors: Bianchi Agostina , Scherer Michael , Zaurin Roser , Quililan Kimberly , Velten Lars , Beekman Renée
Published: April 2022

Single-cell DNA methylation profiling currently suffers from excessive noise and/or limited cellular throughput. We developed scTAM-seq, a targeted bisulfite-free method for profiling up to 650 CpGs in up to 10,000 cells per experiment, with a dropout rate of less than seven percent. scTAM-seq focuses sequencing coverage on informative, variably methylated CpGs that in many tissues and cell types make up a minor fraction of all CpGs. By applying scTAM-seq to B cells from blood and bone marrow, we demonstrate that it can resolve DNA methylation dynamics across B-cell differentiation at unprecedented resolution, identifying intermediate differentiation states that were previously masked. scTAM-seq additionally queries surface protein expression and somatic mutations, thus enabling integration of single-cell DNA methylation information with cell atlas data, and opening applications in tumor profiling. In summary, scTAM-seq is the first high-throughput, high-confidence method for analyzing DNA methylation at single-CpG resolution across thousands of single cells.
A potent synthetic nanobody with broad-spectrum activity neutralizes SARS-Cov-2 virus and Omicron variant through a unique binding mode
Authors: Zhao Dongping , Liu Liqin , Liu Xinlin , Zhang Jinlei , Yin Yuqing , Luan Linli , Jiang Dingwen , Yang Xiong , Li Lei , Xiong Hualong , Xing Dongming , Zheng Qingbing , Xia Ningshao , Tao Yuyong , Li Shaowei , Huang Haiming
Published: April 2022

The major challenge to control COVID pandemic is the rapid mutation rate of the SARS-Cov-2 virus, leading to the escape of the protection of vaccines and most of the neutralizing antibodies to date. Thus, it is essential to develop neutralizing antibodies with broad-spectrum activity targeting multiple SARS-Cov-2 variants. Here, we reported a synthetic nanobody (named C5G2) obtianed by phage display and subsequent antibody engineering. C5G2 has a single digit nanomolar binding affinity to RBD domain and inhibits its binding to ACE2 with an IC50 of 3.7 nM. Pseudovirus assay indicated that the monovalent C5G2 could protect the cells from the infection of SARS-Cov-2 wild type virus and most of the virus of concern, i.e. Alpha, Beta, Gamma and Omicron variants. Strikingly, C5G2 has the highest potency against Omicron among all the variants with the IC50 of 4.9ng/mL. The Cryo-EM structure of C5G2 in complex with the Spike trimer showed that C5G2 bind to RBD mainly through its CDR3 at a conserved region that not overlapping with the ACE2 binding surface. Additionally, C5G2 bind simultaneously to the neighboring NTD domain of spike trimer through the same CDR3 loop, which may further increase its potency against the virus infection. Third, the steric hindrance caused by FR2 of C5G2 could inhibit the binding of ACE2 to RBD as well. Thus, this triple-function nanobody may be served as an effective drug for the prophylaxis and therapy against Omicron as well as future variants.
Elp1 is required for development of visceral sensory peripheral and central circuitry
Authors: Tolman Zariah , Chaverra Marta , George Lynn , Lefcort Frances
Published: April 2022

Cardiovascular instability and a blunted respiratory drive in hypoxic conditions, are hallmark features of the genetic sensory and autonomic neuropathy, familial dysautonomia (FD). FD results from a mutation in the gene ELP1, whose encoded protein is a scaffolding subunit of the six subunit Elongator complex. In mice, we and others have shown that Elp1 is essential for the normal development of neural crest derived-dorsal root ganglia (DRG) sensory neurons. Whether Elp1 is also required for development of ectodermal placode-derived visceral sensory receptors which are required for normal baroreception and chemosensory responses, has not been investigated. Using mouse models for FD, our data indicate that in fact the entire circuitry underlying baroreception and chemoreception is impaired due to a requirement for Elp1 not only in the visceral sensory neuron ganglia, but also for normal peripheral target innervation, and in their CNS synaptic partners in the medulla. Thus Elp1 is required in both placode- and neural crest-derived sensory neurons and its reduction aborts the normal development of neuronal circuitry essential for autonomic homeostasis and interoception.

Summary statement

Due to faulty afferent sensory signaling, patients with Familial dysautonomia (FD) have a diminished sensory arm of the baroreflex which would normally modulate blood pressure, and they have a blunted response to hypoxia and hypercapnia (Norcliffe-Kaufmann et al. 2010). Using mouse models for FD, we reveal here the underlying pathology which may underlie these severely impaired homeostatic reflex pathways in FD.
Long-range morphogen gradient formation by cell-to-cell signal propagation
Authors: Dickmann Johanna E. M. , Rink Jochen C. , Jülicher Frank
Published: April 2022

Morphogen gradients are a central concept in developmental biology. Their formation often involves the secretion of morphogens from a local source, that spread by diffusion in the cell field, where molecules eventually get degraded. This implies limits to both the time and length scales over which morphogen gradients can form which are set by diffusion coefficients and degradation rates. Towards the goal of identifying plausible mechanisms capable of extending the gradient range, we here use theory to explore properties of a cell-to-cell signaling relay. Inspired by the millimeter-scale Wnt-expression and signaling gradients in flatworms, we consider morphogen-mediated morphogen production in the cell field. We show that such a relay can generate stable morphogen and signaling gradients that emanate from a source of morphogen at a boundary. This gradient formation can be related to an effective diffusion and an effective degradation that result from morphogen production due to signaling relay. If the secretion of morphogen produced in response to the relay is polarized, it further gives rise to an effective drift. We find that signaling relay can generate long-ranged gradients in relevant times without relying on extreme choices of diffusion coefficients or degradation rates, thus exceeding the limits set by physiological diffusion coefficients and degradation rates. A signaling relay is hence an attractive principle to conceptualize long-ranged gradient formation by slowly diffusing morphogens that are relevant for patterning in adult contexts such as regeneration and tissue turn-over.
Linker histone H1 regulates defense priming and immunity in plants
Authors: Sheikh Arsheed H. , Nawaz Kashif , Tabassum Naheed , Trapp Marilia , Alhoraibi Hanna , Rayapuram Naganand , Hirt Heribert
Published: April 2022

Linker H1 histones play an important role in animal and human pathogenesis, but their function in plant immunity is poorly understood. Here, we analyzed mutants of the three canonical variants of Arabidopsis H1 histones, namely H1.1, H1.2 and H1.3. We observed that double h1.1h1.2 and triple h1.1h1.2h1.3 (3h1) mutants were resistant to Pseudomonas syringae and Botrytis cinerea infections. Transcriptome analysis of 3h1 mutant plants showed that histone H1s play a key role in regulating the expression of early and late defense genes upon pathogen challenge. Moreover, 3h1 mutant plants showed enhanced production of reactive oxygen species and activation of mitogen activated protein kinases upon pathogen-associated molecular pattern (PAMP) treatment. However, 3h1 mutant plants were insensitive to priming with flg22, a well-known bacterial PAMP (pathogen-associated molecular pattern) which induces enhanced resistance in WT plants. The defective defense response in 3h1 was correlated with the enhanced DNA methylation and reduced H3K56ac levels upon priming. Our data place H1 as a molecular gatekeeper in governing dynamic changes in the chromatin landscape of defense genes during plant pathogen interaction.
RNA-protein interactome at the Hepatitis E virus internal ribosome entry site
Authors: Kumar Shiv , Verma Rohit , Saha Sandhini , Agrahari Ashish , Shukla Shivangi , Anurag  , Maiti Tushar Kanti , Asthana Shailendra , Ranjith-Kumar C.T. , Surjit Milan
Published: April 2022

Multiple processes exist in a cell to ensure continuous production of essential proteins either through cap-dependent or cap-independent translation processes. Viruses depend on the host translation machinery for viral protein synthesis. Therefore, viruses have evolved clever strategies to utilize the host translation machinery. Earlier studies have shown that genotype 1-Hepatitis E virus (g1-HEV) utilizes both cap-dependent and cap-independent translation machineries for its replication and proliferation. Cap-independent translation in g1-HEV is driven by an eighty seven nucleotide-long RNA element which acts as a noncanonical, internal ribosome entry site like (IRESl) element. Here, we have identified the RNA-protein interactome of the HEV IRESl element and characterized the functional significance of some of its components. Our study reveals indispensable roles of host ribosomal protein RPL5 and DHX9 (RNA helicase A) in mediating efficient translation from the IRESl element and establish the function of HEV IRESl as a bonafide internal ribosome entry site.

Author summary

Protein synthesis is a fundamental process for survival and proliferation of all living organisms. Majority of cellular proteins are produced through cap-dependent translation. Cells also utilize a variety of cap-independent translation processes to synthesize essential proteins during stress. Viruses depend on the host cell translation machinery to synthesize their own proteins. Hepatitis E virus is a major cause of hepatitis worldwide. The viral genome is a capped positive strand RNA. Viral non-structural and structural proteins are synthesized through a cap-dependent translation process. An earlier study from our laboratory reported the presence of a fourth ORF in genotype 1-HEV, which produced the ORF4 protein using a cap-independent internal ribosome entry site-like (IRESl) element. In the current study, we identified the host proteins that associate with the HEV-IRESl RNA and generated the RNA-protein interactome. Through a variety of experimental approaches, our data proves that HEV-IRESl is a bonafide internal ribosome entry site.
Key mutations on spike protein altering ACE2 receptor utilization and potentially expanding host range of emerging SARS-CoV-2 variants
Authors: Wang Qiong , Ye Sheng-Bao , Zhou Zhi-Jian , Li Jin-Yan , Lv Ji-Zhou , Hu Bodan , Yuan Shuofeng , Qiu Ye , Ge Xing-Yi
Published: April 2022

Increasing evidence supports inter-species transmission of SARS-CoV-2 variants from human to domestic or wild animals during the ongoing COVID-19 pandemic, which is posing great challenges to epidemic control. Clarifying the host range of emerging SARS-CoV-2 variants will provide instructive information for the containment of viral spillover. The spike protein (S) of SARS-CoV-2 is the key determinant of receptor utilization, and therefore amino acid mutations on S will probably alter viral host range. Here, in order to evaluate the impact of S mutations, we constructed 20 Hela cell lines stably expressing ACE2 orthologs from different animals, and prepared 27 pseudotyped SARS-CoV-2 carrying different spike mutants, among which 20 bear single mutation and the other 7 were cloned from emerging SARS-CoV-2 variants, including D614G, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.135), Lambda (B.1.429) and Mu (B.1.525). Using pseudoviral reporter assay, we identified that the substitutions of T478I and N501Y enabled the pseudovirus to utilize chicken ACE2, indicating potential infectivity to avian species. Furthermore, the S mutants of real SARS-CoV-2 variants comprising N501Y showed significantly acquired abilities to infect cells expressing mouse ACE2, indicating a critical role of N501Y in expanding SARS-CoV-2 host range. In addition, A262S and T478I significantly enhanced the utilization of various mammals ACE2. In summary, our results indicated that T478I and N501Y substitutions were two S mutations important for receptor adaption of SARS-CoV-2, potentially contributing to spillover of the virus to many other animal hosts. Therefore, more attention should be paid to SARS-CoV-2 variants with these two mutations.
The ADAM17 sheddase complex regulator iTAP modulates inflammation, epithelial repair, and tumor growth
Authors: Badenes Marina , Burbridge Emma , Oikonomidi Ioanna , Amin Abdulbasit , de Carvalho Érika , Kosack Lindsay , Domingos Pedro , Faísca Pedro , Adrain Colin
Published: April 2022

The metalloprotease ADAM17 catalyzes the shedding of key signalling molecules from the cell surface, including the inflammatory cytokine TNF (tumour necrosis factor) and activating ligands of the EGFR (epidermal growth factor receptor). ADAM17 exists within an assemblage called the “sheddase complex” containing a rhomboid pseudoprotease (iRhom1 or iRhom2). iRhoms control multiple aspects of ADAM17 biology, including its vesicular trafficking, maturation from its precursor pro-form, activation on the cell surface and specificity for subsets of proteolytic targets. Previous studies from our laboratory and others identified the FERM domain-containing protein Frmd8/iTAP as an iRhom-binding protein. iTAP is required to maintain the cell surface stability of the sheddase complex, thereby preventing the precocious shunting of ADAM17 and iRhom2 to lysosomes and their consequent degradation. As pathophysiological role(s) of iTAP have not been addressed, here we sought to characterize the impact of loss of iTAP on ADAM17-associated phenotypes in mice. Our data show that iTAP KO mice exhibit defects in ADAM17 activity in inflammatory and intestinal epithelial barrier repair functions, but do not exhibit the collateral effects associated with global loss of ADAM17. Furthermore, we show that iTAP promotes cancer cell growth in a cell-autonomous manner, and by modulating the tumor microenvironment. Our work suggests that pharmacological intervention at the level of iTAP may be beneficial to target ADAM17 activity in specific compartments during chronic inflammatory diseases or cancer, avoiding the deleterious impact on vital functions associated with the widespread inhibition of ADAM17 in normal tissues.