bluuebunny/crossref_metadata_2025 huggingface dataset:
The prognostic value of transthoracic echocardiography findings in hospitalized adult patients with COVID-19: A single-center retrospective analysis
Authors: Muliawan Hary Sakti , Agarwal Raksheeth , Nugraha Raka Aldy , Priyonugroho Gatut , Hertine Siti , Wicaksono Sony Hilal , Almazini Prima , Zamroni Dian
Published: August 2022

Background

Cardiac involvement in coronavirus disease 2019 (COVID-19) is associated with poor outcomes. Transthoracic echocardiography (TTE) can be used to assess cardiac structure and function non-invasively, and has been shown to influence management in COVID-19.

Objectives

We aim to investigate the prognostic value of TTE findings in hospitalized adults with confirmed COVID-19.

Methods

All consecutive hospitalized adult patients with confirmed COVID-19 who underwent TTE assessment between 3rd April 2020 – 6th April 2021 were included. Comprehensive clinical data including TTE findings were collected from electronic medical records. Patients with mild-moderate and severe-critical COVID-19 were compared. Within the severe-critical group, patients who survived hospitalization and died were compared. Further analyses were conducted after matching for age >60 years, obesity, and diabetes.

Results

A total of 488 COVID-19 patients were included in this study; 202 with mild-moderate and 286 severe-critical disease. All mild-moderate patients and 152 severe-critical patients survived hospitalization. In the matched cohorts, TTE findings associated with severe-critical COVID-19 included left ventricular (LV) hypertrophy (OR: 1.91; CI: 1.21 – 3.02), LV diastolic dysfunction (OR: 1.55; CI: 1.00 – 2.38), right ventricular (RV) dysfunction (OR: 3.86; CI: 1.06 – 14.08), wall motion abnormalities (WMAs) (OR: 2.76; CI: 1.28 – 5.96), and any TTE abnormalities (OR: 2.99; CI: 1.73 – 5.17). TTE findings associated with mortality included RV dysfunction (OR: 3.53; CI: 1.12 – 11.19) and WMAs (OR: 2.63; CI: 1.26 – 5.49).

Conclusion

TTE is a non-invasive modality that can potentially be used for risk-stratification of hospitalized COVID-19 patients. These findings must be confirmed in larger prospective studies.
Autonomous Screening for Diabetic Macular Edema Using Deep Learning Processing of Retinal Images
Authors: Bressler Idan , Aviv Rachelle , Margalit Danny , Cohen Gal Yaakov , Ianchulev Tsontcho , Savant Shravan V. , Ramsey David J. , Dvey-Aharon Zack
Published: August 2022

Background

Diabetic Macular Edema (DME) is a complication of diabetes which, when untreated, leads to vision loss. Screening for signs of diabetic eye disease, including DME, is recommended for all patients with diabetes at least every one to two years, however, compliance with this standard is low.

Methods

A deep learning model was trained for DME detection using the EyePACS dataset. Data was randomly assigned, by participant, into development (n= 14,246) and validation (n= 1,583) sets. Analysis was conducted on the single image, eye, and patient levels. Model performance was evaluated using sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC). Independent validation was further performed on the IDRiD dataset, as well as new data.

Findings

At the image level, sensitivity of 0.889 (CI 95% 0.878, 0.900), specificity of 0.889 (CI 95% 0.877, 0.900), and AUC of 0.954 (CI 95% 0.949, 0.959) were achieved. At the eye level, sensitivity of 0.905 (CI 95% 0.890, 0.920), specificity of 0.902 (CI 95% 0.890, 0.913), and AUC of 0.964 (CI 95% 0.958, 0.969) were achieved. At the patient level, sensitivity of 0.901 (CI 95% 0.879, 0.917), specificity of 0.900 (CI 95% 0.883, 0.911), and AUC of 0.962 (CI 95% 0.955, 0.968) were achieved.

Interpretation

DME can be detected from color fundus imaging with high performance on all analysis metrics. Automatic DME detection may simplify screening, leading to more encompassing screening for diabetic patients. Further prospective studies are necessary.

Funding

Funding was provided by AEYE Health Inc.
Persistent Presence of Spike protein and Viral RNA in the Circulation of Individuals with Post-Acute Sequelae of COVID-19
Authors: Craddock Vaughn , Mahajan Aatish , Krishnamachary Balaji , Spikes Leslie , Chalise Prabhakar , Dhillon Navneet K.
Published: August 2022

SARS-CoV-2, the causative agent of COVID-19 disease has resulted in the death of millions worldwide since the beginning of the pandemic in December 2019. While much progress has been made to understand acute manifestations of SARS-CoV-2 infection, less is known about post-acute sequelae of COVID-19 (PASC). We investigated the levels of circulating SARS-CoV-2 components, Spike protein and viral RNA, in patients hospitalized with acute COVID-19 and in patients with and without PASC. In hospitalized patients with acute COVID-19 (n=116), we observed a positive correlation of Spike protein with D-dimer, length of hospitalization, and peak WHO score while viral RNA correlated with a tissue injury marker, lactate dehydrogenase (LDH). When comparing patients with post-COVID symptoms (n=33) and patients without (n=14), we found that Spike protein and viral RNA were more likely to be present in patients with PASC and in some cases at higher levels compared to acute COVID-19 patients. We also observed that the percent positivity of circulating viral RNA increased in the PASC positive individuals compared to acute COVID-19 group while Spike protein positivity remained the same. Additionally, we report that part of the circulating Spike protein is linked to extracellular vesicles without any presence of viral RNA in these vesicles. In conclusion, our findings suggest that Spike protein and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC, regardless of their presence or absence during the acute COVID-19 phase. These results may help in understanding the reason(s) for why patients experience PASC symptoms and may offer potential therapeutic targets.
NO2 pollution decrease in big cities of Latin America during COVID-19 pandemic
Authors: Poullain Matias , Guerrieri Juan Martin , Miller Manuel Eduardo , Utgés María Eugenia , Santini María Soledad , Acosta Mariana Manteca , Fernández Agustín , Marsico Franco Leonel
Published: August 2022

NO2 is a mainly anthropogenic gas that affects population health and its exposure is associated with several respiratory diseases. Its tropospheric concentration is associated with vehicle emissions. During 2020, COVID-19 lockdowns have impeded population’s mobility, hence constructing an almost ideal situation to study their relationship with tropospheric NO2 concentration. We used TROPOMI (TROPOspheric Monitoring Instrument) satellite images, Google mobility reports and vehicule count in order to study these relationships in six big Latin American metropolitan areas: México DF, São Paulo, Buenos Aires, Rio de Janeiro, Lima and Bogotá. In all of them, tropospheric NO2 concentration decreased during 2020 compared to 2019, particularly during April 2020. Temperature differences alone could not explain the NO2 concentration differences between February and April 2020. The daily vehicle count in Buenos Aires was a significantly important variable in order to explain NO2 concentration variations (p < 0.001) and it could be replaced by the daily Google’s residential variation without significant information loss (p ≃ 1). This study strengthens previous research findings about NO2 concentration reduction during COVID-19 lockdowns and shows the relationship between human mobility and air pollution in the particular context of Latin America big cities.
Structural evolution of trypsinogen gene redundancy confers risk for pancreas diseases
Authors: Lou Haiyi , Wang Yimin , Xie Bo , Bai Xinyue , Gao Yang , Zhang Rui , Xu Shuhua
Published: August 2022

Trypsin is an important enzyme secreted by the pancreas for digesting proteins. The precursors of major human trypsin are encoded by trypsinogen genes PRSS1 and PRSS2. Here, we leveraged multi-omic data to study their evolutionary and functional impact. We estimated that the primate trypsinogen gene was duplicated from a single copy to multiple-copy 24-34 million years ago (Mya). Compared to six protein-coding genes in non-human great apes, the human ancestral state was a 5-copy with three being pseudogenized. Interestingly, a derived 3-copy form emerged in Africans ∼260 Kya and dominated in non-Africans as one of the two major haplotypes. Although no longer encoding proteins, the pseudogene enhancers still function on pancreatic PRSS2 expression, leading to ∼15% up-regulation for the 5-copy than the 3-copy haplotype. Notably, the 3-copy structure was under positive selection in East Asians, where lower trypsin might be adaptive during high-starch diet shift for protecting the pancreas from autodigestion, as also supported by the identified causality of the haplotype structure to pancreatitis risk. Our efforts in elucidating the structural evolution of trypsinogen genes advance our understanding of the genetic basis and molecular mechanism of human pancreas diseases.
Randomized Clinical Trials or Convenient Controls: TREWS or FALSE?
Authors: Nemati Shamim , Shashikumar Supreeth P. , Holder Andre L. , Wardi Gabriel , Owens Robert L.
Published: August 2022

We read with interest the Adams et al.1 report of the TREWS machine learning (ML)-based sepsis early warning system. The authors conclude that large-scale randomized trials are needed to confirm their observations, but assert that their findings indicate the potential for the TREWS system to identify sepsis patients early and improve patient outcomes, including a significant decrease in mortality. However, this conclusion is based upon a comparison of those whose alert was confirmed vs. not confirmed within 3 hours, rather than random allocation to TREWS vs. no TREWS. Using data from over 650,000 patient encounters across two distinct healthcare systems, we show that the findings of Adams et al. are likely to be severely biased due to the failure to adjust for ‘processes of care’-related confounding factors.
A study to assess the impact of cobas Liat point-of-care PCR assays (SARS-CoV-2 and Influenza A/B) on patient clinical management in the emergency department of the University of California at Davis Medical Center
Authors: May Larissa , Robbins Elissa M. , Canchola Jesse A. , Chugh Kamal , Tran Nam K.
Published: August 2022

Background

Rapid detection of SARS-CoV-2 is crucial for reduction of transmission and clinical decision-making. The cobas® SARS-CoV-2 & Influenza A/B nucleic acid test for use on the cobas Liat® System is a rapid (20 minutes) point-of-care (POC) polymerase chain reaction (PCR) method.

Methods

This unblinded, pre-post study enrolled consecutive patients with symptoms/signs consistent with SARS-CoV-2 infection presenting to the University of California, Davis emergency department (ED). Outcomes following implementation of the cobas Liat SARS-CoV-2 & Influenza A/B test (intervention period: December 2020–May 2021) were compared with previous standard-of-care using centralized laboratory PCR methods (control period: April 2020–October 2020).

Results

Electronic health records of 8879 symptomatic patients were analyzed, comprising 4339 and 4540 patient visits and 538 and 638 positive SARS-CoV-2 PCR test results in the control and intervention periods, respectively. Compared with the control period, turnaround time (TAT) was shorter in the intervention period (median 0.98 vs 12.3 hours; p<0.0001). ED length of stay (LOS) was generally longer in the intervention period compared with the control period, but for those SARS-CoV-2-negative who were admitted, ED LOS was shorter (median 12.53 vs 17.93 hours; p<0.0001). Overall, the rate of anti-infective prescribing was also lower in the intervention period than in the control period (antibiotics only: 38.11% vs 44.55%; p<0.0001 and antivirals only: 3.13% vs 0.94%; p<0.0001).

Conclusion

This real-world study confirms faster TAT with a POC PCR method in an emergency care setting and highlights the importance of rapid SARS-CoV-2 detection to aid patient management and inform treatment decisions.

Clinical Relevance

This study reports data collected from a quasi-experimental pre-post study using the electronic health records of patients presenting to the emergency department (ED) of the University of California at Davis Medical Center with symptoms or signs consistent with SARS-CoV-2 infection during their ED visit. The primary objective of this study was to determine if implementation of the point-of-care (POC) cobas® Liat® SARS-CoV-2 & Influenza A/B test for use on the cobas Liat System reduced the diagnostic turnaround time and/or length of stay for ED patients with suspected SARS-CoV-2 infection compared with the previous standards of care (batch-wise diagnostic testing using the cobas 6800 System and on-demand urgent testing on the GenMark Dx® ePlex® system in a centralized clinical laboratory). Ultimately, these data help to inform how implementation of POC molecular testing methods impact patient management.
Outcomes of a resource-adapted Wilms tumor treatment protocol in Lilongwe, Malawi, 2016-2021: successes and enduring barriers to cure
Authors: Holmes David M. , Matatiyo Apatsa , Mpasa Atupele , Huibers Minke H. W. , Manda Geoffrey , Tomoka Tamiwe , Mulenga Maurice , Namazzi Ruth , Mehta Parth , Zobeck Mark , Mzikamanda Rizine , Chintagumpala Murali , Allen Carl , Nuchtern Jed G. , Borgstein Eric , Aronson Daniel C. , Ozuah Nmazuo , Nandi Bip , McAtee Casey L.
Published: August 2022

Purpose

Wilms tumor is a common renal cancer of childhood with long-term survival rates exceeding 80% in high-resource countries, yet survival remains below 50% in the low-resource settings of Africa. We assessed outcomes of a resource-adapted treatment protocol at a Malawian hospital to identify actionable factors affecting survival.

Methods

We assessed clinical outcomes with a single-center retrospective cohort study of children diagnosed between 2016 and 2021 in Lilongwe, Malawi.

Findings

We identified 136 patients with Wilms tumor, most commonly with stage III (25.7%) or IV disease (25.7%). Two-year overall survival (OS) was: Stage I, 78%; Stage II, 27%; Stage III, 62%; Stage IV, 23%, Stage V, 0%. Event-free survival (EFS) was: Stage I, 60%; Stage II, 0%; Stage III, 51%; Stage IV, 13%; Stage V, 0%. After death, treatment abandonment was the most common event comprising EFS, occurring in 26.5% of patients. Among 43% of patients who completed therapy, 2-year OS was 80% and EFS was 69%. Relapse was documented in 9.6% of patients. Radiotherapy was indicated for 40.4% patients, among whom only three received it due to regional unavailability. Factors associated with OS were severe acute malnutrition (Hazard ratio, HR, 1.9), increasing tumor stage (HR, 1.5), and inferior vena cava involvement (HR, 2.7). On multivariable analysis, only tumor stage remained associated with outcome.

Interpretation

Implementing a curative resource-adapted treatment protocol in an extremely resourced-constrained environment was feasible in Malawi and resulted in relatively favorable outcomes in low-stage disease, particularly among those who completed therapy. However, factors such as late-stage disease, frequent abandonment, and absent radiotherapy represent ongoing implementation barriers that should be the focus of continued research funding and intervention in Africa.
Trends in psychological distress in Great Britain, 1991-2019: evidence from three representative surveys
Authors: Zhang Anwen , Gagne Thierry , Walsh David , Ciancio Alberto , Proto Eugenio , McCartney Gerry
Published: August 2022

Background

Previously improving UK mortality trends stalled around 2012 due to economic policy changes. This paper examines whether trends in psychological distress across three population surveys show similar trends.

Methods

We report the percentages reporting psychological distress (4+ in the 12-item General Health Questionnaire (GHQ-12)) from Understanding Society (Great Britain, 1991-2019), Scottish Health Survey (SHeS, 1995-2019) and Health Survey for England (HSE, 2003-2018) for the population overall, and stratified by sex, age and area deprivation. Summary inequality indices were calculated and segmented regressions fitted to identify turning points after 2010.

Results

Psychological distress was higher in Understanding Society than in the SHeS or HSE. There was a slight improvement between 1992 and 2015 in Understanding Society (with prevalence declining from 20.6% to 18.6%) with some fluctuations. After 2015 there is some evidence of an overall deterioration in psychological distress across surveys. Prevalence worsened notably among those aged 16-34 years after 2010 (all three surveys), and aged 35-64 years in Understanding Society and SHeS after 2015. In contrast, the prevalence declined in those aged 65+ years in Understanding Society after around 2008, with less clear trends in the other surveys. The prevalence was around twice as high in the most deprived compared to the least deprived areas, and higher in women, with trends by deprivation and sex similar to the populations overall.

Conclusion

Psychological distress worsened amongst working-age adults after around 2015 across British population surveys, mirroring the mortality trends. This indicates a widespread health crisis that pre-dates the COVID-19 pandemic.
The microtubule-associated protein SlMAP70 interacts with SlIQD21 and regulates fruit shape formation in tomato
Authors: Bao Zhiru , Guo Ye , Deng Yaling , Zang Jingze , Zhang Junhong , Ouyang Bo , Qu Xiaolu , Bürstenbinder Katharina , Wang Pengwei
Published: August 2022

The shape of tomato fruits is closely correlated to microtubule organization and the activity of microtubule associated proteins (MAP), but insights into the mechanism from a cell biology perspective are still largely elusive. Analysis of tissue expression profiles of different microtubule regulators revealed that functionally distinct classes of MAPs are highly expressed during fruit development. Among these, several members of the plant-specific MAP70 family are preferably expressed at the initiation stage of fruit development. Transgenic tomato lines overexpressing SlMAP70 produced elongated fruits that show reduced cell circularity and microtubule anisotropy, while SlMAP70 loss-of-function mutant showed an opposite effect with flatter fruits. Microtubule anisotropy of fruit endodermis cells exhibited dramatic rearrangement during tomato fruit development, and SlMAP70-1 is likely implicated in cortical microtubule organization and fruit elongation throughout this stage by interacting with SUN10/SlIQD21a. The expression of SlMAP70 (or co-expression of SlMAP70 and SUN10/SlIQD21a) induces microtubule stabilization and prevents its dynamic rearrangement, both activities are essential for fruit shape establishment after anthesis. Together, our results identify SlMAP70 as a novel regulator of fruit elongation, and demonstrate that manipulating microtubule stability and organization at the early fruit developmental stage has a strong impact on fruit shape.
Optical O2 sensors also respond to redox active molecules commonly secreted by bacteria
Authors: Flamholz Avi I. , Saccomano Samuel , Cash Kevin , Newman Dianne K.
Published: August 2022

From a metabolic perspective, molecular oxygen (O2) is arguably the most significant constituent of Earth’s atmosphere. Nearly every facet of microbial physiology is sensitive to the presence and concentration of O2, which is the most favorable terminal electron acceptor used by biological organisms and also a dangerously reactive oxidant. As O2 has such sweeping implications for physiology, researchers have developed diverse approaches to measure O2 concentrations in natural and laboratory settings. Recent improvements to phosphorescent O2 sensors piqued our interest due to the promise of optical measurement of spatiotemporal O2 dynamics. However, we found that our preferred bacterial model, Pseudomonas aeruginosa PA14, secretes more than one molecule that quenches such sensors, complicating O2 measurements in PA14 cultures and biofilms. Assaying supernatants from cultures of 9 bacterial species demonstrated that this phenotype is common: all supernatants quenched a soluble O2 probe substantially. Phosphorescent O2 probes are often embedded in solid support for protection, but an embedded probe called O2NS was quenched by most supernatants as well. Measurements using pure compounds indicated that quenching is due to interactions with redox-active small molecules including phenazines and flavins. Uncharged and weakly-polar molecules like pyocyanin were especially potent quenchers of O2NS. These findings underscore that optical O2 measurements made in the presence of bacteria should be carefully controlled to ensure that O2, and not bacterial secretions, is measured, and motivate the design of custom O2 probes for specific organisms to circumvent sensitivity to redox-active metabolites.

Importance

When they are closely-packed, as in biofilms, colonies, and soils, microbes can consume O2 faster than it diffuses. As such, O2 concentrations in natural environments can vary greatly over time and space, even on the micrometer scale. Wetting soil, for example, slows O2 diffusion higher in the soil column, which, in concert with microbial respiration, greatly diminishes [O2] at depth. Given that variation in [O2] has outsized implications for microbial physiology, there is great interest in measuring the dynamics of [O2] in microbial cultures and biofilms. We demonstrate that certain classes of bacterial metabolites frustrate optical measurement of [O2] with phosphorescent sensors, but also that some species (e.g. E. coli) do not produce problematic secretions under the conditions tested. Our work therefore offers a strategy for identifying organisms and culture conditions in which optical quantification of spatiotemporal [O2] dynamics with current sensors is feasible.
SARS-CoV-2 genomic diversity in households highlights the challenges of sequence-based transmission inference
Authors: Bendall Emily , Paz-Bailey Gabriela , Santiago Gilberto A. , Porucznik Christina A. , Stanford Joseph B. , Stockwell Melissa S. , Duque Jazmin , Jeddy Zuha , Veguilla Vic , Major Chelsea , Rivera-Amill Vanessa , Rolfes Melissa A. , Dawood Fatimah S. , Lauring Adam S.
Published: August 2022

Background

The reliability of sequence-based inference of SARS-CoV-2 transmission is not clear. Sequence data from infections among household members can define the expected genomic diversity of a virus along a defined transmission chain.

Methods

SARS-CoV-2 cases were identified prospectively among 2,369 participants in 706 households. Specimens with an RT-PCR cycle threshold ≤30 underwent whole genome sequencing. Intrahost single nucleotide variants (iSNV) were identified at ≥5% frequency. Phylogenetic trees were used to evaluate the relationship of household and community sequences.

Results

There were 178 SARS-CoV-2 cases in 706 households. Among 147 specimens sequenced, 106 yielded a whole genome consensus with coverage suitable for identifying iSNV. Twenty-six households had sequences from multiple cases within 14 days. Consensus sequences were indistinguishable among cases in 15 households, while 11 had ≥1 consensus that differed by 1-2 mutations. Sequences from households and the community were often interspersed on phylogenetic trees. Identification of iSNV improved inference in 2 of 15 households with indistinguishable consensus sequences and 6 of 11 with distinct ones.

Conclusions

In multiple infection households, whole genome consensus sequences differed by 0-1 mutations. Identification of shared iSNV occasionally resolved linkage, but the low genomic diversity of SARS-CoV-2 limits the utility of “sequence-only” transmission inference.

High depth of coverage whole genome sequencing can identify SARS-CoV-2 transmission chains in settings where there is strong epidemiologic linkage but is not reliable as a stand-alone method for transmission inference.
Patient Reported Outcomes of Medical Cannabis for Managing Pain in Charcot-Marie-Tooth Disease
Authors: Canals Priscilla C. , Aguilar Alexia G. , Carter Gregory T. , Shields C. Miyabe , Westerkamp Andrew , D’Elia Meg , Aldrich Joy , Moore Robert N. , Moore Allison T. , Piper Brian J.
Published: August 2022

Background and aims

Chronic pain is a major part of the disease burden in Charcot-Marie-Tooth (CMT) disease. Current pharmacotherapies to manage symptoms of CMT disease, particularly pain, are inadequate. This exploratory study examined the patient reported efficacy of medical cannabis among CMT patients.

Methods

Participants (N = 56; 71.4% female; Age = 48.9, SD = 14.6; 48.5% CMT1) were recruited though the Hereditary Neuropathy Foundation’s Global Registry for Inherited Neuropathies. The online survey contained 52 multiple choice questions about demographics, medical cannabis use, symptomology, efficacy, and adverse effects.

Results

When asked about how much relief they experience from using cannabis as a method of symptom relief, respondents reported an average of 69.6% (SEM + 2.6). Women were more likely to report experiencing pain than men (p < .05). Participants who perceived support from their providers were more likely to inform them of their cannabis use (p < .05).

Interpretation

Patients reported that cannabis was effective to manage symptoms. More prospective and controlled research needs to be conducted to better serve and optimize the potential use of cannabis to treat CMT.

Graphical Abstract

Patient Reported Outcomes of Medical Cannabis for Managing Pain in Patients with Charcot-Marie-Tooth Disease

Priscilla C. Canals, Alexia G. Aguilar, Gregory T. Carter, Marion McNabb, Andrew M. Westerkamp, Miyabe Shields, Meg D’Elia, Joy Aldrich, Robert N. Moore, Allison T. Moore, Brian J. Piper*

There is no prior research of medical cannabis experiences among Charcot-Marie-Tooth (CMT) patients.

CMT patients (N=56) were recruited though the Hereditary Neuropathy Foundation’s Global Registry for Inherited Neuropathies and completed an online survey.

Symptom relief from using cannabis was moderately-high (70% + 3).

CMT patients that received support from their providers were significantly more likely to inform them of their cannabis use.

These descriptive results should be verified using prospective and randomized controlled trials.
ProteasomeID: quantitative mapping of proteasome interactomes and substrates forin vitroandin vivostudies
Authors: Bartolome Aleksandar , Heiby Julia C. , Fraia Domenico Di , Heinze Ivonne , Knaudt Hannah , Späth Ellen , Omrani Omid , Minetti Alberto , Hofmann Maleen , Kirkpatrick Joanna M. , Dau Therese , Ori Alessandro
Published: August 2022

Proteasomes are essential molecular machines responsible for the degradation of proteins in eukaryotic cells. Altered proteasome activity has been linked to neurodegeneration, auto-immune disorders and cancer. Despite the relevance for human disease and drug development, no method currently exists to monitor proteasome composition and interactionsin vivoin animal models. To fill this gap, we developed a strategy based on tagging of proteasomes with promiscuous biotin ligases and generated a new mouse model enabling the quantification of proteasome interactions by mass spectrometry. We show that biotin ligases can be incorporated in fully assembled proteasomes without negative impact on their activity. We demonstrate the utility of our method by identifying novel proteasome-interacting proteins, charting interactomes across mouse organs, and showing that proximity-labeling enables the identification of both endogenous and small molecule-induced proteasome substrates.
Structural Basis of Mammalian Respiratory Complex I Inhibition by Medicinal Biguanides
Authors: Bridges Hannah R. , Blaza James N. , Yin Zhan , Chung Injae , Pollak Michael N. , Hirst Judy
Published: August 2022

The molecular mode of action of metformin, a biguanide used widely in the treatment of diabetes, is incompletely characterized. Here we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We explain the unique selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel and an additional binding site is in a pocket on the intermembrane space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable rational design of novel medicinal biguanides.

One-Sentence Summary

Biguanides inhibit complex I by binding in the quinone channel, and exert an independent localized chaotropic effect.
Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable
Authors: Sarieva Kseniia , Kagermeier Theresa , Khakipoor Shokoufeh , Atay Ezgi , Yentür Zeynep , Becker Katharina , Mayer Simone
Published: August 2022

Maternal immune activation (MIA) during the critical windows of gestation is correlated with long- term neurodevelopmental deficits in the offspring, including increased risks for autism spectrum disorder (ASD) in humans. Interleukin 6 (IL-6) derived from the gestational parent is one of the major molecular mediators, by which MIA alters the developing brain. In this study, we established a human three-dimensional (3D) in vitro model of MIA by treating induced pluripotent stem cell- derived dorsal forebrain organoids with a constitutively active form of IL-6, Hyper-IL-6. We validated our model by showing that dorsal forebrain organoids express the molecular machinery necessary for responding to Hyper-IL-6 and activate STAT signaling upon Hyper-IL-6 treatment. RNA sequencing analysis revealed the upregulation of major histocompatibility complex class I (MHCI) genes, which have been implicated with ASD. Immunohistochemical analysis as well as single-cell RNA-sequencing revealed a small increase in the proportion of radial glia cells. Single-cell transcriptomic analysis revealed the highest number of differentially expressed genes in radial glia cells with downregulation of genes related to protein translation in line with data from mouse models of MIA. Additionally, we identified differentially expressed genes not found in mouse models of MIA which might drive species-specific responses to MIA. Together, we establish a human 3D model of MIA, which can be used to study the cellular and molecular mechanisms underlying the increased risk for developing disorders such as ASD.
A truncating mutation of Magel2 in the rat modelled for the study of Schaaf-Yang and Prader-Willi syndromes alters select behavioral and physiological outcomes
Authors: Reznik Derek L , Yang Mingxiao V , de la Haza Pedro Albelda , Jain Antrix , Spanjaard Melanie , Theiss Susanne , Schaaf Christian P , Malovannaya Anna , Strong Theresa V , Veeraragavan Surabi , Samaco Rodney C
Published: August 2022

Truncating mutations of the maternally imprinted, paternally expressed MAGEL2 gene are the predicted genetic cause of several rare neurodevelopmental disorders including Schaaf-Yang (SYS), Chitayat-Hall and Opitz Trigonocephaly C syndromes. MAGEL2 is also deleted or inactivated in Prader-Willi syndrome (PWS). Previous studies in mice have utilized Magel2 gene deletion models to examine the consequences of its absence. In this study, we report the generation, molecular validation, and phenotypic characterization of a novel rat model with a truncating Magel2 mutation generating a mutant peptide sequence more closely modeling variants associated with SYS-causing mutations. Within the hypothalamus, a brain region wherein mouse and human MAGEL2 is paternally-expressed, we demonstrate at the level of transcript and peptide detection that Magel2 in the rat exhibits a paternal, parent-of-origin effect. In the evaluation of behavioral features across several domains, juvenile Magel2 mutant rats display select alterations in anxiety-like behavior and sociability measures. Moreover, the analysis of peripheral organ systems detected alterations in body composition, cardiac structure and function, and breathing irregularities in Magel2 mutant rats. Several of these findings are concordant with reported mouse phenotypes, signifying the conservation of MAGEL2 function across rodent species for specific behavioral outcome measures. We conclude that our comprehensive analysis demonstrating impairments across multiple domains demonstrates the tractability of this model system for the study of truncating MAGEL2 mutations.
Coxsackievirus B3 elicits a sex-specific CD8+T cell response in female mice
Authors: Dhalech Adeeba H. , Condotta Stephanie A. , Corn Caleb , Richer Martin J. , Robinson Christopher M.
Published: August 2022

Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, which is often attributed to a weaker immune response. In contrast, a heightened immune response in females enables better pathogen elimination but leaves females more predisposed to autoimmune diseases. Unfortunately, the underlying basis for sex-specific immune responses remains poorly understood. Here, we show a sex-specific difference in the CD8+T cell response to an enteric virus, Coxsackievirus B3 (CVB3). We found that CVB3 induced expansion of CD8+T cells in female mice but not in male mice. CVB3 also increased the proportion and number of CD11ahiCD62LloCD8+T cells in female mice, indicative of activation. Further, this response was independent of the inoculation route and type I interferon. Using a recombinant CVB3 virus expressing a model CD8+T cell epitope, we found that the expansion of CD8+T cells is viral-specific and not due to bystander activation. These data demonstrate that CVB3 induces a sex-dependent CD8+T cell response and highlight the importance of sex-specific immune responses to viral pathogens.
Human iPSC Derived Enamel Organoid Guided by Single-Cell Atlas of Human Tooth Development
Authors: Alghadeer A , Hanson-Drury S , Ehnes D , Zhao YT , Patni AP , O’Day D , Spurrell CH , Gogate AA , Phal A , Zhang H , Devi A , Wang Y , Starita L , Doherty D , Glass I , Shendure J , Baker D , Regier MC , Mathieu J , Ruohola-Baker H
Published: August 2022

Tooth enamel secreted by ameloblasts is the hardest material in the human body, acting as a shield protecting the teeth. However, the enamel is gradually damaged or partially lost in over 90% of adults and cannot be regenerated due to a lack of ameloblasts in erupted teeth. Here we use sci-RNA-seq to establish a spatiotemporal single-cell atlas for the developing human tooth and identify regulatory mechanisms controlling the differentiation process of human ameloblasts. We reveal key signaling pathways involved between the support cells and ameloblasts during fetal development and recapitulate those findings in a novel human ameloblast in vitro differentiation from iPSCs. We furthermore develop a mineralizing enamel organ-like 3D organoid system. These studies pave the way for future regenerative dentistry and therapies toward genetic diseases affecting enamel formation.
Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps
Authors: Remesh Soumya G. , Merz Gregory E. , Brilot Axel F. , Chio Un Seng , Rizo Alexandrea N. , Pospiech Thomas H. , Lui Irene , Laurie Mathew T. , Glasgow Jeff , Le Chau Q. , Zhang Yun , Diwanji Devan , Hernandez Evelyn , Lopez Jocelyne , Pawar Komal Ishwar , Pourmal Sergei , Smith Amber M. , Zhou Fengbo ,   QCRG Structural Biology Consortium, DeRisi Joseph , Kortemme Tanja , Rosenberg Oren S. , Glasgow Anum , Leung Kevin K. , Wells James A. , Verba Kliment A.
Published: August 2022

The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-Spike-RBD and prevent viral entry into host cells (“receptor traps”). Here we determine cryo-EM structures of our receptor traps in complex with full length Spike. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high affinity (0.53 - 4.2nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron- and Delta-pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.
Genomic analyses of wild argali, domestic sheep, and their hybrids provide insights into chromosome evolution, phenotypic variation, and germplasm innovation
Authors: Li Xin , He San-Gang , Li Wen-Rong , Luo Ling-Yun , Yan Ze , Mo Dong-Xin , Wan Xing , Lv Feng-Hua , Yang Ji , Xu Ya-Xi , Deng Juan , Zhu Qiang-Hui , Xie Xing-Long , Xu Song-Song , Liu Chen-Xi , Peng Xin-Rong , Han Bin , Li Zhong-Hui , Chen Lei , Han Jian-Lin , Ding Xue-Zhi , Dingkao Renqing , Chu Yue-Feng , Wu Jin-Yan , Wang Li-Min , Zhou Ping , Liu Ming-Jun , Li Meng-Hua
Published: August 2022

Understanding the genetic mechanisms of phenotypic variation in hybrids between domestic animals and their wild relatives may aid germplasm innovation. Here, we report the high-quality genome assemblies of a male Pamir argali (O. ammon polii, 2n = 56), a female Tibetan sheep (O. aries, 2n = 54), and a male hybrid of Pamir argali and domestic sheep, and the high-throughput sequencing of 425 ovine animals, including the hybrids of argali and domestic sheep. We detected genomic synteny between Chromosome 2 of sheep and two acrocentric chromosomes of argali. We revealed consistent satellite repeats around the chromosome breakpoints, which could have resulted in chromosome fusion. We observed many more hybrids with karyotype 2n = 54 than with 2n = 55, which could be explained by the selfish centromeres, the possible decreased rate of normal/balanced sperm, and the increased incidence of early pregnancy loss in the aneuploid ewes or rams. We identified genes and variants associated with important morphological and production traits (e.g., body weight, cannon circumference, hip height, and tail length) that show significant variations. We revealed a strong selective signature at the mutation (c.334C > A, p.G112W) in TBXT and confirmed its association with tail length among sheep populations of wide geographic and genetic origins. We produced an intercross population of 110 F2 offspring with varied number of vertebrae and validated the causal mutation by whole-genome association analysis. We verified its function using CRISPR-Cas9 genome editing. Our results provide insights into chromosomal speciation and phenotypic evolution and a foundation of genetic variants for the breeding of sheep and other animals.
Sustaining multilinguality: case studies of two multilingual digital libraries
Authors: Wu Anping , Chen Jiangping
Published: August 2022

Purpose

This study aims to understand the technical and operational challenges encountered by multilingual digital libraries and their strategies to solve problems in sustaining multilinguality services for digital libraries.

Design/methodology/approach

Using the multiple-case method, this study investigated two digital libraries that have sustained multilinguality for over a decade: the World Digital Library and the Digital Library of the Caribbean.

Findings

This study identified eight factors that contributed to the success of the two multilingual digital libraries and eight technical and operational challenges they have faced. A framework for digital libraries to sustain multilinguality is proposed. This framework illustrates the challenges and strategies to address the challenges in 11 aspects: creation, leadership, collaboration, content, metadata, translation, funding, technology, preservation, staffing and copyright.

Research limitations/implications

This study focused on two multilingual digital libraries administered in the USA, though they do not fully represent multilingual digital libraries in the USA. Therefore, the findings from the study may not apply to multilingual digital libraries the USA or other countries. As on-site interviews of both digital libraries were conducted at the beginning of 2019, the timeframe of this study is up to that date.

Practical implications

With more users worldwide seeking information online, more digital libraries will be providing multilingual services. This study provides guidelines to digital library developers and archivists for building and sustaining their digital libraries or archives. The experience and lessons learned from these two digital libraries may also help to better understand challenges and use effective strategies in building and sustaining multilinguality.

Social implications

The users and communities of digital libraries will be able to learn the benefits and challenges as related to building and sustaining digital library services. These services always need support to better serve their users and communities.

Originality/value

As the first multiple-case research that investigates in-depth challenges and approaches of digital libraries in sustaining multilinguality, this study presents a general picture of how the two digital libraries have succeeded in sustaining multilinguality. Theoretically, the study enriches the literature by providing a more comprehensive sustainability framework for multilinguality. This framework specifies possible aspects to consider for gaining sustainability of multilingual digital libraries and offers useful guidelines and insights for the digital library community to build multilingual services.
Theorizing the impact of network characteristics on multitier sustainable supply chain governance: a power perspective
Authors: Gruchmann Tim
Published: August 2022

Purpose

While the literature on multitier supply chain management traditionally assumes that first-tier suppliers belong to the visible proportion of the supply base, intermediaries might limit focal firms' visible horizon already at this stage. High power asymmetries promoting centrality and complexity in the supply network are seen as a particular root cause that limits the impact of governance mechanisms for sustainability. To map the space for governance mechanisms in a network-sensitive context more comprehensively, the study analyzes supply network characteristics from a power perspective.

Design/methodology/approach

This research is conceptual. To better understand power imbalances and mutual dependencies from network centrality and complexity, network configurations were constructed drawing on resource dependence theory. These configurations allow deducing the impact of (non-)mediated governance mechanisms for a sustainable development in the supply network. An agenda to stimulate future empirical and model-based research is accordingly presented.

Findings

The research shows that those networks with densely interconnected first-tier suppliers promote network centrality and complexity, leading to an inverted U-shape relationship between the focal firm's exertion of coercive power and the sustainability performance in the supply network. The findings allow a more comprehensive theoretical grounding for mapping governance approaches in a network-sensitive context and provide insights on how to avoid negative effects from power asymmetries.

Practical implications

The findings suggest the need for accompanying, indirect governance mechanisms already at the stage of first-tier suppliers based on non-mediated forms of power, such as referent power, also promoting disintermediation. Purchasing companies may also consider using digital platform technologies that foster disintermediation, such as blockchain technology.

Originality/value

By studying intermediaries from a power and network perspective, the conceptualization adds to the discussion on governance in multitier sustainable supply chain networks in various industries. Furthermore, it contributes to the increasing efforts of middle-range theorizing in logistics and supply chain management. The results partially challenge previous assumptions on the moderating role of specific network characteristics.
From work meaningfulness to playful work design: the role of epistemic curiosity and perceived Leader's autonomous support
Authors: Khan Muhammad Awais
Published: August 2022

Purpose

Building on the self-determination theory (SDT), the purpose of this study is to empirically examine the influence of work meaningfulness (WM) on employees' involvement in playful work design (PWD) in the context of software development firms in Pakistan.

Design/methodology/approach

For the present study, a two-wave employee survey (online questionnaire) was used for data collection. The data were collected through an adopted questionnaire from employees working in software development firms in Pakistan. structural equation modeling and Hayes Process Macro of SPSS were used to analyze data collected from 305 respondents.

Findings

The findings of this study show that work meaningfulness and epistemic curiosity (EC) positively and significantly influence employee playful work design strategies. Moreover, the relationship between work meaningfulness and playful work design was partially mediated by employee epistemic curiosity. This mediating role of epistemic curiosity is strengthened by the presence of the perceived leader's autonomous support (LAS).

Research limitations/implications

Employees improve their personal work experience through playful work design. Theoretically, this study contributes to the body of knowledge on the factors (work meaningfulness, epistemic curiosity and leader's autonomous support) that can influence employees' self-determination to design fun and competition into their work. This study contributes to the theory by introducing the antecedents (work meaningfulness and epistemic curiosity), of employee playful work design and explores the role of epistemic curiosity as a mediator and the leader's autonomous support as a moderator through SDT perspective.

Practical implications

For practitioners, this study pinpoints that software development firms can consider improving employees' perception of work meaningfulness, which can lead them to become epistemically curious to proactively design their work experience for their psychological need fulfillment, well-being and better functioning. Moreover, leader's autonomous support can support involvement in playful work design.

Originality/value

The current study is the first investigation in the Asian context to study the antecedents of playful work design and a critical boundary condition. This study extends the literature on the antecedents of employee playful work design and explores the role of epistemic curiosity as a mediator and the leader's autonomous support as a moderator specifically through a self-determination perspective.