bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictability and Stability Testing to Assess Clinical Decision Instrument Performance for Children After Blunt Torso Trauma
Authors: Kornblith Aaron E. , Singh Chandan , Devlin Gabriel , Addo Newton , Streck Christian J. , Holmes James F. , Kuppermann Nathan , Grupp-Phelan Jacqueline , Fineman Jeffrey , Butte Atul J. , Yu Bin
Published: March 2022

Objective

The Pediatric Emergency Care Applied Research Network (PECARN) has developed a clinical-decision instrument (CDI) to identify children at very low risk of intra-abdominal injury. However, the CDI has not been externally validated. We sought to vet the PECARN CDI with the Predictability Computability Stability (PCS) data science framework, potentially increasing its chance of a successful external validation.

Materials & Methods

We performed a secondary analysis of two prospectively collected datasets: PECARN (12,044 children from 20 emergency departments) and an independent external validation dataset from the Pediatric Surgical Research Collaborative (PedSRC; 2,188 children from 14 emergency departments). We used PCS to reanalyze the original PECARN CDI along with new interpretable PCS CDIs we developed using the PECARN dataset. External validation was then measured on the PedSRC dataset.

Results

Three predictor variables (abdominal wall trauma, Glasgow Coma Scale Score <14, and abdominal tenderness) were found to be stable. Using only these variables, we developed a PCS CDI which had a lower sensitivity than the original PECARN CDI on internal PECARN validation but performed the same on external PedSRC validation (sensitivity 96.8% and specificity 44%).

Conclusion

The PCS data science framework vetted the PECARN CDI and its constituent predictor variables prior to external validation. In this case, the PECARN CDI with 7 predictors, and our PCS-based CDI with 3 stable predictors, had identical performance on independent external validation. This suggests that both CDIs will generalize well to new populations, offering a potential strategy to increase the chance of a successful (costly) prospective validation.
Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings
Authors: Icick Romain , Shadrin Alexey , Holen Børge , Karadag Naz , Lin Aihua , Hindley Guy , O’Connell Kevin , Frei Oleksandr , Bahrami Shahram , Høegh Margrethe Collier , Cheng Weiqiu , Fan Chun C. , Djurovic Srdjan , Dale Anders M. , Lagerberg Trine Vik , Smeland Olav B. , Andreassen Ole A.
Published: March 2022

Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. We aimed to characterize the sharedvs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD), a relevant transdiagnostic factor, using large genome-wide association studies (GWASs) data. We hypothesize that cross-analyzing these phenotypes would shed light on their unique and shared polygenicity, increase our knowledge regarding the genetic basis of the comorbidity between AUD and mood disorders, and boost discovery for jointly-associated loci. Summary statistics for MOOD, AC and AUD GWASs (Ns =363,705; 200,680 and 200,004; respectively) were analysed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD, respectively. To do so, we used a newly-established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify the cross-phenotype polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly-associated genomic loci. These loci were functionally characterized and mapped to genes and biological functions. We also performed validation in independent samples and phenotypic analyses. MOOD was highly polygenic (10,400 single nucleotide polymorphisms, SNPs) compared to AC and AUD (4,900 SNPs, SD =600 and 4,300 SNPs, SD =2,000; respectively). The polygenic overlap of MOOD and AC was much larger than that of MOOD and AUD (98%vs. 49%) and genetic correlation was opposite (−0.2vs. 0.23), which was confirmed in independent samples. MOOD&AUD causal SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 loci identified in the joint analysis, sixteen were novel for MOOD, AC and AUD. Similarly distinct patterns were evidenced for SNP localization, function and previous GWAS associations outside of the phenotypes that were currently studied. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated shared biological underpinnings but clearly distinct functional patterns between MOOD&AC and MOOD&AUD. Using the MOOD endophenotype, the current study suggests new mechanisms for the comorbidity of AUD with mood disorders.
Spectral imaging enables contrast agent-free real-time ischemia monitoring in laparoscopic surgery
Authors: Ayala Leonardo , Adler Tim J. , Seidlitz Silvia , Wirkert Sebastian , Engels Christina , Seitel Alexander , Sellner Jan , Aksenov Alexey , Bodenbach Matthias , Bader Pia , Baron Sebastian , Vemuri Anant , Wiesenfarth Manuel , Schreck Nicholas , Mindroc Diana , Tizabi Minu , Pirmann Sebastian , Everitt Brittaney , Kopp-Schneider Annette , Teber Dogu , Maier-Hein Lena
Published: March 2022

Laparoscopic surgery has evolved as a key technique for cancer diagnosis and therapy. While characterization of the tissue perfusion is crucial in various procedures, such as partial nephrectomy, doing so by means of visual inspection remains highly challenging. Spectral imaging takes advantage of the fact that different tissue components have unique optical properties to recover relevant information on tissue function such as ischemia. However, clinical success stories for advancing laparoscopic surgery with spectral imaging are lacking to date. To address this bottleneck, we developed the first laparoscopic real-time multispectral imaging (MSI) system featuring a compact and lightweight multispectral camera and the possibility to complement the conventional RGB (Red, Green, and Blue) surgical view of the patient with functional information at a video rate of 25 Hz. To account for the high inter-patient variability of human tissue, we phrase the problem of ischemia detection as an out-of-distribution (OoD) detection problem that does not rely on data from any other patient. Using an ensemble of invertible neural networks (INNs) as a core component, our algorithm computes the likelihood of ischemia based on a short (several seconds) video sequence acquired at the beginning of each surgery. A first-in-human trial performed on 10 patients undergoing partial nephrectomy demonstrates the feasibility of our approach for fully-automatic live ischemia monitoring during laparoscopic surgery. Compared to the clinical state-of-the-art approach based on indocyanine green (ICG) fluorescence, the proposed MSI-based method does not require the injection of a contrast agent and is repeatable if the wrong segment has been clamped. Spectral imaging combined with advanced deep learning-based analysis tools could thus evolve as an important tool for fast, efficient, reliable and safe functional imaging in minimally invasive surgery.
Molecular profiling of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in cellular and LSL-Kras G12D/+; Trp53 fl/+; Pdx1-Cre (KPC) pancreatic cancer model
Authors: Uddin Md. Hafiz , Aboukameel Amro , Li Yiwei , Khan Husain Yar , Sexton Rachel E. , Bannoura Sahar , Dyson Gregory , Al-Hallak Mohammad Najeeb , Mzannar Yosef , Mohamed Amr , Landesman Yosef , Kim Steve , Beydoun Rafic , Mohammad Ramzi M. , Shields Anthony F. , Azmi Asfar S.
Published: March 2022

The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nab-Paclitaxel (GemPac) treatment indicating the need for more effective combinations for this recalcitrant disease.

Earlier we showed that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC and the selective inhibitor of nuclear export (SINE) selinexor (Sel), synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids, patient derived tumors and had promising activity in a phase I study in patients with PDAC. Here we investigated the mechanisms of synergy by molecular profiling of Sel or Sel-GemPac treated PDAC cells,in vitroand by utilizing genetically modified LSL-Kras G12D/+; Trp53 fl/+; Pdx1-Cre (KPC) mouse model.

In KPC model, Sel given with GemPac at a sub-MTD dose enhanced the survival compared to controls (p< 0.05). Molecular analysis of residual KPC tumors showed re-organization of tumor stromal architecture, suppression of proliferation and nuclear retention of tumor suppressors. Single cell nuclear RNA sequencing (snRNAseq) revealed significant loss of cellular clusters in the Sel-GemPac treated mice including CD44 stem cell population. RNA-seq, Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) analysis showed inhibition of several tumor promoting molecules.

Prioritized RNA-seq identified molecules were validated inin vitroor in the PDAC patient samples through siRNA mediated silencing, quantitative gene expression, cytotoxicity assays and confirmed their role in observed synergy. Sel or Sel-GemPac caused broad penetration in PDAC supporting signaling networks.
The push-pull intercrop Desmodium does not repel, but intercepts and kills pests
Authors: Erdei Anna Laura , David Aneth Bella , Savvidou Eleni C. , Džemedžionaitė Vaida , Chakravarthy Advaith , Molnár Béla Péter , Dekker Teun
Published: March 2022

Over two decades ago, scientists developed a push-pull intercropping strategy that received critical acclaim for synergizing food security with ecosystem resilience in smallholder farming. The strategy suppresses Lepidopteran pests in maize through a combination of a repellent intercrop (push), commonly Desmodium spp., and an attractive, dead-end border crop (pull). Key is the intercrop’s constitutive release of volatiles that repel herbivores. Surprisingly, however, we found that Desmodium does not constitutively release volatiles, and only minimally upon herbivory. Further, in oviposition choice settings, Spodoptera frugiperda, a devastating invasive pest, was not repelled by Desmodium volatiles. In search of an alternative mechanism, we found that neonate larvae strongly preferred Desmodium over maize. However, their development stagnated and none survived. In addition, larvae were frequently seen impaled and immobilized by the dense network of silica-fortified, non-glandular trichomes. Thus, entirely different from repelling adult moths, Desmodium intercepts and decimates dispersing offspring. As a hallmark of sustainable pest control, maize-Desmodium intercropping has inspired countless efforts trying to emulate a stimulo-deterrent diversion in other cropping systems. However, detailed knowledge of the actual mechanisms is required to rationally improve the strategy, and translate the concept into other cropping systems.
Repeat Detector: versatile sizing of expanded tandem repeats and identification of interrupted alleles from targeted DNA sequencing
Authors: Taylor Alysha S. , Barros Dinis , Gobet Nastassia , Schuepbach Thierry , McAllister Branduff , Aeschbach Lorene , Randall Emma L. , Trofimenko Evgeniya , Heuchan Eleanor R. , Barszcz Paula , Ciosi Marc , Morgan Joanne , Hafford-Tear Nathaniel J. , Davidson Alice E. , Massey Thomas H. , Monckton Darren G. , Jones Lesley ,   REGISTRY Investigators of the European Huntington’s disease network, Xenarios Ioannis , Dion Vincent
Published: March 2022

Targeted DNA sequencing approaches will improve how the size of short tandem repeats is measured for diagnostic tests and pre-clinical studies. The expansion of these sequences causes dozens of disorders, with longer tracts generally leading to a more severe disease. Interrupted alleles are sometimes present within repeats and can alter disease manifestation. Determining repeat size mosaicism and identifying interruptions in targeted sequencing datasets remains a major challenge. This is in part because standard alignment tools are ill-suited for repetitive and unstable sequences. To address this, we have developed Repeat Detector (RD), a deterministic profile weighting algorithm for counting repeats in targeted sequencing data. We tested RD using blood-derived DNA samples from Huntington’s disease and Fuchs endothelial corneal dystrophy patients sequenced using either Illumina MiSeq or Pacific Biosciences single-molecule, real-time sequencing platforms. RD was highly accurate in determining repeat sizes of 609 blood-derived samples from Huntington’s disease individuals and did not require prior knowledge of the flanking sequences. Furthermore, RD can be used to identify alleles with interruptions and provide a measure of repeat instability within an individual. RD is therefore highly versatile and may find applications in the diagnosis of expanded repeat disorders and the development of novel therapies.
mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations
Authors: Holmes Alexandra O. M. , Goldman Adrian , Kalli Antreas C.
Published: March 2022

Membrane-integral pyrophosphatases (mPPases) are membrane-bound enzymes responsible for hydrolysing inorganic pyrophosphate and translocating a cation across the membrane. Their function is essential for the infectivity of clinically relevant protozoan parasites and plant maturation. Recent developments have indicated that their mechanism is more complicated than previously thought and that the membrane environment may be important for their function. In this work, we use multiscale molecular dynamics simulations to demonstrate for the first time that mPPases form specific anionic lipid interactions at 4 sites at the distal and interfacial regions of the protein. These interactions are conserved in simulations of the mPPases from Thermotoga maritima, Vigna radiata and Clostridium leptum and characterised by interactions with positive residues on helices 1, 2, 3 and 4 for the distal site, or 9, 10, 13 and 14 for the interfacial site. Due to the importance of these helices in protein stability and function, these lipid interactions may play a crucial role in the mPPase mechanism and enable future structural and functional studies.

Author summary

In this work we have been able to demonstrate conservation of lipid-interaction sites on proteins from distinct species that deviated from their evolutionary common ancestors a long time ago, as in the case of the membrane-integral pyrophosphatases from a thermophilic bacteria species and a plant species studied here. This retention of a common lipid interaction profile or “fingerprint” and our ability to predict this for other proteins in this family may indicate that they are more integral to protein function than previously thought. By identifying lipid interactions that may act to stabilise the protein structure, these properties could be exploited to gain protein structures, and the interfacial site’s potential involvement in inter-subunit communication may be useful for further investigation of the catalytic cycle of this clinically relevant membrane protein family.
Multiple carotenoid-based signals are enhanced despite poor body condition in urban male and female Northern Cardinals (Cardinalis cardinalis)
Authors: Baldassarre Daniel T. , Bedell Haley S. , Drzewiecki Kristie M. , Goodman Brooke D. , Mills Mya L. , Ramos Denis A.
Published: March 2022

If humans aim to sustainably coexist with wildlife, we must understand how our activity impacts the communication systems of urban animal populations. We know much about the effects of anthropogenic noise on bird song, but relatively little about how avian visual signals are affected by urbanization. One way such an effect may occur if urbanization alters the food available to species with color based on carotenoids, which they must obtain from their diet. Over three years, we compared a comprehensive suite of visual signals in male and female Northern Cardinals (Cardinalis cardinals) in a rural and an urban population. We predicted that urban birds would have enhanced carotenoid-based signals as they likely have access to more carotenoids from invasive plants, especially honeysuckle (Lonicera spp.), that thrive in cities. We used reflectance spectrometry, digital image analyses, and avian visual models to quantify hue, saturation, and brightness of chest (male), underwing (female), and bill (male and female) signals. Compared to rural males, urban males had redder chest feathers in one year and redder bills in every year. Urban females had more saturated underwing color than rural females in every year. These color differences were sufficient to be distinguished by the avian visual system. Urbanization did not affect female bill color. Interestingly, urban birds had significantly reduced mass-related body condition compared to rural birds. These results show that both male and female urban birds can display enhanced carotenoid-based signals despite being in relatively poor condition. The consequences of this color enhancement are unknown, but it could affect the information content of the signals and the dynamics of the social and mating systems. These results stand in stark contrast to the predominant trend in birds of decreased color in urban areas and highlight the complex and varied potential effects of urbanization on animal communication.
Comparison of influenza and COVID-19–associated hospitalizations among children < 18 years old in the United States — FluSurv-NET (October–April 2017–2021) and COVID-NET (October 2020–September 2021)
Authors: Delahoy Miranda J. , Ujamaa Dawud , Taylor Christopher A. , Cummings Charisse , Anglin Onika , Holstein Rachel , Milucky Jennifer , O’Halloran Alissa , Patel Kadam , Pham Huong , Whitaker Michael , Reingold Arthur , Chai Shua J. , Alden Nisha B. , Kawasaki Breanna , Meek James , Yousey-Hindes Kimberly , Anderson Evan J. , Openo Kyle P. , Weigel Andy , Teno Kenzie , Reeg Libby , Leegwater Lauren , Lynfield Ruth , McMahon Melissa , Ropp Susan , Rudin Dominic , Muse Alison , Spina Nancy , Bennett Nancy M. , Popham Kevin , Billing Laurie M. , Shiltz Eli , Sutton Melissa , Thomas Ann , Schaffner William , Talbot H. Keipp , Crossland Melanie T. , McCaffrey Keegan , Hall Aron J. , Burns Erin , McMorrow Meredith , Reed Carrie , Havers Fiona P. , Garg Shikha
Published: March 2022

Background

Influenza virus and SARS-CoV-2 are significant causes of respiratory illness in children.

Methods

Influenza and COVID-19-associated hospitalizations among children <18 years old were analyzed from FluSurv-NET and COVID-NET, two population-based surveillance systems with similar catchment areas and methodology. The annual COVID-19-associated hospitalization rate per 100 000 during the ongoing COVID-19 pandemic (October 1, 2020–September 30, 2021) was compared to influenza-associated hospitalization rates during the 2017–18 through 2019–20 influenza seasons. In-hospital outcomes, including intensive care unit (ICU) admission and death, were compared.

Results

Among children <18 years old, the COVID-19-associated hospitalization rate (48.2) was higher than influenza-associated hospitalization rates: 2017–18 (33.5), 2018–19 (33.8), and 2019–20 (41.7). The COVID-19-associated hospitalization rate was higher among adolescents 12–17 years old (COVID-19: 59.9; influenza range: 12.2-14.1), but similar or lower among children 5–11 (COVID-19: 25.0; influenza range: 24.3-31.7) and 0–4 (COVID-19: 66.8; influenza range: 70.9-91.5) years old. Among children <18 years old, a higher proportion with COVID-19 required ICU admission compared with influenza (26.4% vs 21.6%; p<0.01). Pediatric deaths were uncommon during both COVID-19- and influenza-associated hospitalizations (0.7% vs 0.5%; p=0.28).

Conclusions

In the setting of extensive mitigation measures during the COVID-19 pandemic, the annual COVID-19-associated hospitalization rate during 2020–2021 was higher among adolescents and similar or lower among children <12 years old compared with influenza during the three seasons before the COVID-19 pandemic. COVID-19 adds substantially to the existing burden of pediatric hospitalizations and severe outcomes caused by influenza and other respiratory viruses.

Annual hospitalization rates and proportions of hospitalized children experiencing severe outcomes were as high or higher for COVID-19 during October 2020–September 2021 compared with influenza during the three seasons before the COVID-19 pandemic, based on U.S. population-based surveillance data.
Pharmaceutical Payments to Japanese Board-Certified Infectious Disease Specialists: A Four-year Retrospective Analysis of Payments from 92 Pharmaceutical Companies between 2016 and 2019
Authors: Murayama Anju , Kamamoto Sae , Yamada Kohki , Bhandari Divya , Shoji Iori , Mamada Hanano , Kawashima Moe , Yamashita Erika , Saito Hiroaki , Kusumi Eiji , Sawano Toyoaki , Sapkota Binaya , Tanimoto Tetsuya , Ozaki Akihiko
Published: March 2022

Objective

Conflict of interest with pharmaceutical companies is one of the most contentious issues in infectious diseases. However, there is a lack of whole picture of detailed payments in Japan.

Study Design and Setting

This retrospective study assessed financial relationships between pharmaceutical companies and all infectious disease specialists board-certified by the Japanese Association for Infectious Disease, using publicly disclosed payment data from 92 pharmaceutical companies. Descriptive analyses were conducted for the payments. Payment trends were examined by the generalized estimating equations.

Results

Of 1614 board-certified infection disease specialists, 1,055 (65.4%) received a total of $17,784,070 payments, corresponding to 21,680 cases between 2016 and 2019. The mean±SD and median (interquartile range: IQR) were $16,857±$45,010 and $3,183 ($938□$11,250) in payments. All board executive members of Japanese Association of Infectious Disease received higher payments averaging $163,792. There were no significant changes in payments per specialist (annual change rate: -1.4% [95% CI: -4.7□2.3%], p=0.48) and prevalence of specialists with payments (annual change rate: -1.4% [95% CI: -3.1%□0.2%], p=0.093) over the four years.

Conclusion

There were substantial financial relationships between pharmaceutical companies and board-certified infectious disease specialists in Japan. Such personal payments must be restricted to a certain level to avoid potential conflict of interest.
Symptoms of depression and anxiety among Vietnamese immigrants in Japan during the COVID-19 pandemic: a cross-sectional web-based study
Authors: Yamashita Tadashi , Quy Pham Nguyen , Nogami Emi , Seto-Suh Erina , Yamada Chika , Iwamoto Saori , Shimazawa Kyoko , Kato Kenji
Published: March 2022

Background

Mental health among immigrants in Japan may be related to aspects of COVID-19 infection as well as pandemic-related lifestyle changes, investigating mental health status among Vietnamese residents remains an important public health concern. The mental health status of Vietnamese immigrants in Japan during the COVID-19 epidemic remains unclear. We aimed to examine the mental health status and related factors among Vietnamese immigrants in Japan during the coronavirus disease 2019 (COVID-19) pandemic using data from an online cross-sectional survey administered from September 21 to October 21, 2021.

Methods

Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scores were considered the main outcome measures. Multivariable logistic regression was used to identify factors related to symptoms of depression and anxiety, and the chosen variables were entered simultaneously in the survey.

Results

Among 621 participants (age: 26.0±4.8 years; male: 347 [55.9%]) who completed the questionnaire, 73.7% reported a decrease in income when compared with the period before the COVID-19 pandemic, and 60.4% reported being recently affected by poor socioeconomic status. Moderate to severe symptoms of depression (PHQ-9 score ≥ 10 points) and mild-to-severe symptoms of anxiety (GAD-7 score ≥5 points) were observed in 203 (32.7%) and 285 (45.9%) individuals, respectively. Factors related to depressive symptoms were age (odds ratio [OR]=0.94, p=0.043), pre-existing health conditions (OR=2.46, p<0.001), and subjective socioeconomic status (OR=2.47, p<0.001). Factors related to anxiety symptoms were being single (OR=1.72, p=0.044), pre-existing health conditions (OR=2.52, p<0.001), subjective socioeconomic status (OR=2.72, p<0.001), and a partner with whom to discuss one’s health (OR=1.66, p=0.013).

Conclusions

The current findings demonstrate that, when compared with non-Vietnamese Japanese people, people with Vietnamese backgrounds experienced a decrease in income, worsening working conditions, and poor mental health status during the COVID-19 pandemic. These findings highlight the potential contribution of low socioeconomic status and social isolation to poor mental health status.
Risks for death after admission to pediatric intensive care (PICU) - a comparison with the general population
Authors: Hamrin Tova Hannegård , Eksborg Staffan
Published: March 2022

Objective/Aim

The aim of the study was to investigate the mortality rate in children after admission to a Pediatric Intensive Care Unit (PICU), compared to the matched general Swedish population.

Design

Single-center, retrospective cohort study.

Setting

Registry study of hospital registers, a national population register and Statistics Sweden.

Patients

Children admitted to a tertiary PICU in Sweden in 2008-2016.

Interventions

None

Main Results

In total, 6,487 admissions (4,682 patients) were included in the study. During the study period 444 patients died. Median follow-up time for the entire PICU cohort was 7.2 years (IQR 5.0-9.9 years). Patients were divided into four different age groups (0–28 d, > 28 d -1 yr, > 1–4 yr, and > 4 yr) and four different risk stratification groups [Predicted Death Rate (PDR) intervals: 0–10%, > 10–25%, > 25–50%, and > 50%] at admission. Readmission was seen in 929 (19.8%) patients. The Standardized Mortality Ratios (SMRs) were calculated using the matched Swedish population as a reference group. The SMR for the entire study group was 49.8 (95% CI: 44.8-55.4). For patients with repeated PICU admissions SMR was 108.0 (95% CI: 91.9-126.9), and after four years 33.9 (95% CI: 23.9-48.0). Patients with a single admission had a SMR of 35.2 (95% CI: 30.5-40.6), and after four years 11.0 (95% CI: 7.0-17.6). The highest SMRs were seen in readmitted children with oncology/hematology (SMR=358) and neurologic (SMR=192) diagnosis. Children aged >1-4 years showed the highest SMR (325). In PDR group 0-10% children with repeated PICU admissions (n=798), had a SMR of 100.

Conclusion

SMRs were greatly elevated up to four years after PICU admission, declining from over 100 to 33 for patients with repeated PICU admissions, and from 35 to 11 for patients with a single PICU admission, compared to the matched Swedish population.
Longitudinal associations between perceived stress and anhedonia during psychotherapy
Authors: Phillips Rachel , Walsh Erin , Jensen Todd , Nagy Gabriela , Kinard Jessica , Cernasov Paul , Smoski Moria , Dichter Gabriel
Published: March 2022

Background

Chronic stress alters reward sensitivity and contributes to the emergence of anhedonia. In clinical samples, the perception of stress is a strong predictor of anhedonia. While there is substantial evidence demonstrating psychotherapy reduces perceived stress, little is known regarding the effects of treatment-related decreases in perceived stress on anhedonia.

Methods

The current study investigated reciprocal relations between perceived stress and anhedonia using a cross-lagged panel model approach in a 15-week clinical trial examining the effects of Behavioral Activation Treatment for Anhedonia (BATA), a novel psychotherapy to treat anhedonia, compared to a Mindfulness-Based Cognitive Therapy (MBCT) comparison intervention (ClinicalTrials.gov Identifiers NCT02874534 and NCT04036136).

Results

Treatment completers (n=72) experienced significant reductions in anhedonia (M=-8.94, SD=5.66) on the Snaith-Hamilton Pleasure Scale (t(71)=13.39, p<.0001), and significant reductions in perceived stress (M=-3.71, SD=3.88) on the Perceived Stress Scale (t(71)=8.11, p<.0001) following treatment. Across all treatment-seeking participants (n=87), a longitudinal autoregressive cross-lagged model revealed significant paths showing that higher levels of perceived stress at treatment Week 1 predicted reductions in anhedonia at treatment Week 4.

Conclusions

Longitudinal models illustrated that individuals with relatively high perceived stress at the start of treatment were likely to report relatively lower anhedonia a few weeks into treatment. At mid-treatment, individuals with low perceived stress were more likely to report lower anhedonia towards the end of treatment. Early treatment components are thought to reduce perceived stress, allowing for mid-to-late treatment components to exert their direct effects on anhedonia. The findings presented here demonstrate the importance of including stress-reducing components in cognitive-behavioral-based anhedonia treatments.
A novel Vps34 complex constrains loop extrusion-mediated P-H2A spreading
Authors: Chen Hui , Feng Tingting , Liu Simu , Zhu Wei-Guo
Published: March 2022

The establishment of appropriate phosphorylated histone H2AX (γH2AX) foci is required for the precise initiation of DNA damage response (DDR) signaling, which contributes to the efficient repair of DNA double-strand breaks (DSB)1. Therefore, it is important to understand exactly how γH2AX foci are established in response to DSB. Recently, an attractive mechanism has been proposed to explain this process2. DSB-anchored cohesin-mediated loop extrusion promotes H2AX-containing chromatin to pass through DSB-recruited ATM, by which H2AX is phosphorylated to form γH2AX foci on each side of the DSB. The loop extrusion-promoted enlargement of γH2AX-modified chromatin is halted upon cohesin encountering boundary factors such as CTCF. This cohesin-dependent mechanism was shown to be conserved among eukaryotic cells, because deletion of the cohesin regulator Pds5 in budding yeast also results in extended spreading of phosphorylated H2A at Ser129 (P-H2A)2. However, yeast lacks CTCF or CTCF-like boundary factors that restrict cohesion-mediated loop extrusion. Here, we report a novel vacuolar sorting protein 34 (Vps34) complex, which might function as a boundary factor that constrains cohesin-dependent loop extrusion-mediated P-H2A spreading.
Recombinant annexin A6 promotes membrane repair in a stem cell derived-cardiomyocyte model of dystrophic cardiomyopathy
Authors: Fullenkamp Dominic E. , Willis Alexander B. , Curtin Jodi L. , Amaral Ansel P. , Harris Sloane I. , Burridge Paul W. , Demonbreun Alexis R. , McNally Elizabeth M.
Published: March 2022

Heart failure is a major source of mortality in Duchenne muscular dystrophy (DMD). DMD arises from mutations that ablate expression of the protein dystrophin, which render the plasma membrane unusually fragile and prone to disruption. In DMD patients, repeated mechanical stress leads to membrane damage and cardiomyocyte loss. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer the opportunity to study specific mutations in the context of a human cell, but these models can be improved by adding physiologic stressors. We modeled the primary defect underlying DMD by applying equibiaxial mechanical strain to DMD iPSC-CMs. DMD iPSC-CMs demonstrated an increased susceptibility to equibiaxial strain after 2 hours at 10% strain relative to healthy control cells, measured as increased lactate dehydrogenase (LDH) release. After 24 hours, both DMD and healthy control iPSC-CMs showed evidence of injury with release of LDH and cardiac troponin T. We exposed iPSC-CMs to recombinant annexin A6, a protein resealing agent, and found reduced LDH and troponin release in DMD and control iPSC-CMs that had been subjected to 24 hour strain at 10%. We used aptamer protein profiling of media collected from DMD and control iPSC-CMs and compared these results to serum protein profiling from DMD patients. We found a strong correlation between the proteins in DMD patient serum and media from DMD iPSC-CMs subjected to mechanical stress. By developing an injury assay that specifically targets an underlying mechanism of injury seen in DMD-related cardiomyopathy, we demonstrated the potential therapeutic efficacy of the protein membrane resealer, recombinant annexin A6, for the treatment of DMD-related cardiomyopathy and general cardiac injury.
Fear of the new? Geckos hesitate to attack novel prey, feed near objects and enter a novel space
Authors: Szabo Birgit , Ringler Eva
Published: March 2022

Neophobia, the fear of novelty, is an ecologically important response which enables animals to avoid potentially harmful situations. Low levels of neophobia have been linked to elevated dispersal/ migration, invasiveness and living in human modified landscapes albeit only in birds and mammals. In this study, we assessed neophobia in captive Tokay geckos (Gekko gecko). We expected to find low neophobia in our geckos because they are invasive and adopt well to anthropogenic environments. This species is, however, also both predator and prey in the wild which might select for higher neophobia. We tested neophobia in three contexts: attacking novel prey, foraging near novel objects and entering a novel space. We aimed to quantify (1) neophobia in these contexts, (2) individual consistency across trials using different novel stimuli, and (3) correlation of individual responses across the three contexts. We found that geckos hesitate to attack novel prey and prey close to objects (familiar and novel). Geckos hesitated the most when entering novel space and repeatability of behaviour across contexts was low (R = 0.12) indicating that neophobia might not be a single trait. The strength of a neophobic response can indicate how anxious or curious an individual is. This test has great potential to help answer questions about how captivity, enrichment, rearing environment and cognition affect fear responses in different contexts in lizards. By studying reptiles, we can better understand the universality of what is known about the causes leading to difference in neophobia across individuals and species.
Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer’s disease
Authors: Ranasinghe Kamalini G , Verma Parul , Cai Chang , Xie Xihe , Kudo Kiwamu , Gao Xiao , Lerner Hannah , Mizuiri Danielle , Strom Amelia , Iaccarino Leonardo , La Joie Renaud , Miller Bruce L , Gorno-Tempini Maria Luisa , Rankin Katherine P , Jagust William J , Vossel Keith , Rabinovici Gil D , Raj Ashish , Nagarajan Srikantan S
Published: March 2022

Background

Neuronal and circuit level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aβ) in preclinical models of Alzheimer’s disease (AD). These relationships remain poorly understood in patients with AD.

Methods

Using empirical spectra from magnetoencephalography (MEG) and computational modeling (neural mass model; NMM) we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography (PET), in patients with AD.

Results

Patients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aβ depositions.

Conclusions

Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ in patients with AD.

Funding

This study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM & GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer’s Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL and (KGR); 2019-A-013-SUP (KGR); a grant from the Alzheimer’s Association: (PCTRB-13-288476) (KAV), and made possible by Part the CloudTM, (ETAC-09-133596); a grant from Tau Consortium (GDR & WJJ), and a gift from the S. D. Bechtel Jr. Foundation.
Vocalization categorization behavior explained by a feature-based auditory categorization model
Authors: Kar Manaswini , Pernia Marianny , Williams Kayla , Parida Satyabrata , Schneider Nathan A. , McAndrew Madelyn , Kumbam Isha , Sadagopan Srivatsun
Published: March 2022

Vocal animals produce multiple categories of calls with high between- and within-subject variability, over which listeners must generalize to accomplish call categorization. The behavioral strategies and neural mechanisms that support this ability to generalize are largely unexplored. We previously proposed a theoretical model that accomplished call categorization by detecting features of intermediate complexity that best contrasted each call category from all other categories. We further demonstrated that some neural responses in the primary auditory cortex were consistent with such a model. Here, we asked whether a feature-based model could predict call categorization behavior. We trained both the model and guinea pigs on call categorization tasks using natural calls. We then tested categorization by the model and guinea pigs using temporally and spectrally altered calls. Both the model and guinea pigs were surprisingly resilient to temporal manipulations, but sensitive to moderate frequency shifts. Critically, model performance quantitatively matched guinea pig behavior to a remarkable degree. By adopting different model training strategies and examining features that contributed to solving specific tasks, we could gain insight into possible strategies used by animals to categorize calls. Our results validate a model that uses the detection of intermediate-complexity contrastive features to accomplish call categorization.
Methionine uptake via SLC43A2 transporter is essential for regulatory T lymphocyte survival
Authors: Naaz Afsana , Saini Neetu , Padma Shree , Gahlot Pinki , Walvekar Adhish , Dutta Anupam , Davathamizhan Umamaheshwari , Sarin Apurva , Laxman Sunil
Published: March 2022

It is increasingly clear that cell death, survival or growth decisions of T lymphocyte subsets depend on interplay between cytokine-dependent and metabolic processes. What the metabolic requirements of T regulatory cells (Tregs) for their survival are, and how these requirements are satisfied remain to be fully understood. In this study, we identified a necessary requirement of methionine uptake and utilization for Tregs survival upon interleukin 2 (IL-2) deprivation. Activated Tregs have high methionine uptake and consumption to S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH). This methionine uptake is essential for Tregs survival, and is regulated by Notch1 activity. Notch1 controls the expression of the solute carrier protein SLC43A2 transporter during IL-2 deprivation. SLC43A2 is necessary for sufficient methionine uptake, and determines Tregs viability upon IL-2 withdrawal. Collectively, we identify a specifically regulated mechanism of methionine import in Tregs that is necessary for the survival of these cells. This highlights the need for methionine availability and metabolism in contextually regulating cell death in an immunosuppressive population of T lymphocytes.
Seasonality but not photoperiodism affects susceptibility of the two-spotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae) to pesticides
Authors: Yang Zhenguo , Wang Zinan , Ni Jing , Da Aisi , Xie Daoyan , Chung Henry , Luo Yanjie
Published: March 2022

Understanding how endogenous and exogenous factors such as annual seasonal rhythm and photoperiodism affect the toxicity of pesticides can help design integrated pest management strategies. The two-spotted spider mite Tetranychus urticae Koch (Acari: Tetranychidae), a worldwide phytophagous pest species distributed in areas with different time zones, is a good model to explore how the photoperiodism and seasonality affect the pesticide toxicity. In this study, we conducted a laboratory experiment from March 2017 to November 2018 where spider mites were reared at three photoperiod regimes in environmentally controlled incubators. The toxicities of two acaricides, propargite and diafenthiruon, were measured on T. urticae every month. To determine potential mechanisms underlying the changes in the acaricide toxicity, we measured body size and total GSTs activity with the toxicity measurements in 2018. Our results showed that the toxicities of the two acaricides were not significantly different among the three photoperiod regimes. However, both had a consistent trend along the season which increased in the spring and summer and decreased in the winter in all photoperiod regimes for two consecutive years, suggesting seasonality be an endogenous factor affecting the susceptibility of the spider mites to pesticide. Pearson’s correlation analyses showed only the body size had a weak negative correlation with the acaricide toxicities, suggesting a minor contribution to the higher toxicity from the smaller size of T. urticae. Our study is the first to show that seasonality can have an endogenous effect on the pesticide toxicity, and the results can inform practical insights into the pest management strategies.
Cell-surface PD-L1 expression identifies a sub-population of distal epithelial cells enriched in idiopathic pulmonary fibrosis
Authors: Ahmadvand Negah , Carraro Gianni , Jones Matthew R. , Shalashova Irina , Wilhelm Jochen , Baal Nelli , Kosravi Farhad , Chen Chengshui , Zhang JinSan , Ruppert Clemens , Guenther Andreas , Wasnick Roxana , Bellusci Saverio
Published: March 2022

Idiopathic lung fibrosis (IPF) is a fatal lung disease characterized by chronic epithelial injury and exhausted repair capacity of the alveolar compartment, associated with the expansion of cells with intermediate alveolar epithelial cell (AT2) characteristics. Using SftpcCreERT2/+: tdTomatoflox/flox mice, we previously identified a lung population of quiescent injury activated alveolar epithelial progenitors (IAAPs) marked by low expression of the AT2 lineage trace marker tdTomato (Tomlow), and characterized by high levels of Pd-l1 (Cd274) expression. This led us to hypothesize that a population with similar properties exists in the human lung. To that end, we used flow cytometry to characterize the CD274 cell surface expression in lung epithelial cells isolated from donor and end-stage IPF lungs. The identity and functional behavior of these cells were further characterized by qPCR analysis, in vitro organoid formation, and ex vivo precision-cut lung slices (PCLS). Our analysis led to the identification of a population of CD274pos cells expressing intermediate levels of SFTPC, which was expanded in IPF lungs. While donor CD274pos cells initiated clone formation, they did not expand significantly in 3D organoids in AT2-supportive conditions. However, an increased number of CD274pos cells was found in cultured PCLS. In conclusion, we demonstrate that, similar to the IAAPs in the mouse lung, a population of CD274 expressing cells exists in the normal human lung and this population is expanded in the IPF lung and in an ex vivo PCLS assay, suggestive of progenitor cell behavior.
Differential Activity of Repurposed Drugs as Receptor Binding Domain Antagonists for Omicron and Native Strains of SarsCov2
Authors: Meher Kranti , K Saranya , Reddy Arpitha , Kadiyala Gopi , Iyer Subra , Vangala Subhramanyam , Chandran Satish , Saxena Uday
Published: March 2022

Omicron strain is the latest variant of concern of SarsCov2 virus. The mutations in this strain in the S protein Receptor Binding domain (RBD) enable it to be more transmissible as well as escape neutralizing activity by antibodies in response to vaccine. Thus, Omicron specific strategies are need to counter infection by this strain.

We investigated a collection of approved drugs shown to antagonize the binding of native strain RBD to human ACE2, for their ability to antagonize binding to Omicron strain RBD.

While most of the drugs the drugs that antagonize binding to native RBD are also active for Omicron RBD but some were inactive, namely drugs that contain iodine are completely inactive against Omicron RBD. Our data strongly indicate that presence of a single iodine molecule in the drug renders it inactive against Omicron strain. Thus, there is molecular specificity of drugs for antagonizing Omicron strain RBD versus native strain RBD of this virus. Such information will pave way for specific drugs for Omicron. A pragmatic message from our data is that the often-used iodine containing mouth wash and rises may be ineffective in antagonizing receptor binding of Omicron strain.
An ultra-high-throughput method for measuring biomolecular activities
Authors: Tu Boqiang , Sundar Vikram , Esvelt Kevin M.
Published: March 2022

Large datasets of biomolecular activities are crucial for protein engineering, yet their scarcity due to limited experimental throughput hampers progress. We introduce Direct High-throughput Activity Recording and Measurement Assay (DHARMA), an innovative method enabling ultra-high-throughput measurement of biomolecular activities. DHARMA employs molecular recording techniques to link activity directly to editing rates of DNA segments contiguous with the coding sequence of biomolecule of interest. Leveraging a Bayesian inference-based denoising model, we mapped the fitness landscape of TEV protease across 160,000 variants. Using these datasets, we benchmarked popular protein models and showed the impact of data size on model performance. We also developed circuit self-optimization strategies and demonstrated DHARMA’s capability to measure a wide range of biomolecular activities. DHARMA represents a leap forward, offering the machine learning community unparalleled datasets for accurate protein fitness prediction and enhancing our understanding of sequence-to-function relationships.

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