bluuebunny/crossref_metadata_2025 huggingface dataset:
Self-Reported SARS-CoV-2 Vaccination is Consistent with Electronic Health Record Data among the COVID-19 Community Research Partnership
Authors: Tjaden Ashley H. , Fete Lida M. , Edelstein Sharon L. , Gibbs Michael , Hinkelman Amy , Runyon Michael , Santos Roberto P. , Weintraub William S. , Yukich Joshua , Uschner Diane ,   the COVID-19 Community Research Partnership Study Group
Published: May 2022

Introduction

Observational studies of SARS-CoV-2 vaccine effectiveness depend on accurate ascertainment of vaccination receipt, date, and product type. Self-reported vaccine data may be more readily available to and less expensive for researchers than assessing medical records.

Methods

We surveyed adult participants in the COVID-19 Community Research Partnership who had an authenticated EHR (N=41,484) concerning receipt of SARS-CoV-2 vaccination using a daily survey beginning in December 2020 and a supplemental survey in September-October 2021. We compared self-reported information to that available in the EHR for the following data points: vaccine brand, date of first dose, and number of doses. Self-reported data was available immediately following vaccination (in the daily survey) and at a delayed interval (in the supplemental survey).

Results

For the date of first vaccine dose, self-reported “immediate” recall was within +/- 7 days of the date reported in the “delayed” survey for 87.9% of participants. Among the 19.6% of participants with evidence of vaccination in their EHR, 95% self-reported vaccination in one of the two surveys. Self-reported dates were within +/- 7 days of documented EHR vaccination for 97.6% of the “immediate” surveys and 92.0% of the “delayed” surveys. Self-reported vaccine product details matched those in the EHR for over 98% of participants for both “immediate” and “delayed” surveys.

Conclusions

Self-reported dates and product details for COVID-19 vaccination can be a good surrogate when medical records are unavailable in large observational studies. A secondary confirmation of dates for a subset of participants with EHR data will provide internal validity.
Spatially Constrained Gene Regulation Identifies Key Genetic Contributions of Preeclampsia, Hypertension and Proteinuria
Authors: Boom Genevieve , O’Sullivan Justin M. , Schierding William
Published: May 2022

Preeclampsia (PE) is a relatively common but severe pregnancy disorder that is characterized by hypertension (HTN) and either proteinuria (PRO), or other organ damage. There are very limited effective treatments for PE, and it is associated with substantial effects on the health of both the mother and fetus. 25 genetic variants have been associated (p < 1 × 10−6) with PE in the latest genome-wide association studies (GWAS). By overlapping the regulatory impacts of the PE-associated genetic variants with the regulatory impacts of HTN- and PRO-associated genetic variants, we were able to identify shared functional impacts between PE and HTN. We identified significant variation of the mean LOUEF scores for genes targeted by cis- and trans-acting eQTLs, consistent with an enrichment for regulatory interactions with target genes intolerant to loss-of-function mutations. Signaling pathways were enriched within the protein-protein interaction networks (PPINs) that were constructed using proteins encoded by the eQTL targeted genes. Finally, tissue-specific analyses of eQTLs specific to whole blood and arteries detected dysregulation of PE-relevant regulatory pathways. Collectively, these results are consistent with a model in which predisposition to HTN and PRO lays a molecular groundwork toward risk for PE pathogenesis. These findings inform on possible therapeutic targets for future studies.
Is Cancer significant Comorbid Condition in COVID 19 Infected Patients? -A Retrospective Analysis Experienced in a Tertiary Care Center in Eastern India
Authors: Mukherjee Kalyan K , Dam Aniruddha , Chakrabarti Deepa , Jatua Debasish , Sengupta Saubhik , Dutta Rita , Majumdar Suparna , Mandal Shyam Sundar , Basu Biswarup , Bhattacharjee Pratiti , Mukherjee Dattatreya , Sengupta Sankar , Chakrabarti Jayanta
Published: May 2022

Objectives

Patients with a history of active malignancy were initially thought to be at a higher risk of having COVID-19, although available data are conflicting due to economic stress, malnutrition, fear of hospitalization or treatment discontinuation. A cohort-based study was undertaken in Indian regional cancer centre to understand cancer-covid link in patients.

Study Design

A total of 1565 asymptomatic patients were admitted based on thermal screening and evaluation from the screening form. The COVID 19 has been checked by RT-PCR method and the COVID 19 positive patients were transferred to government allocated COVID 19 hospital. The COVID 19 negative patients were transferred to general ward for further cancer treatment.

Method

Post COVID 19 testing, positive patients were transferred to COVID hospital and their outcomes were analyzed and correlated with patient’s age gender and cancer stages.

Result

Out of 1565 patients, 54 patients (3.4%) tested positive. Most of the patients are in 45-59 years age group. As female patients admitted were more in number than males, so predominance of disease is higher in female. 3 patients were symptomatic after admission and 2 were severe and were admitted to the ICU with ventilations. 8 patients died in Cancer and one patient died in COVID 19.

Conclusions

As only 3.4% patients tested positive and only one patient out of 54 had died, so cancer is found not to be a comorbid condition towards COVID 19 patients in the Indian population studied.
Artificial intelligence-based opportunistic screening for the detection of arterial hypertension through ECG signals
Authors: Angelaki Eleni , Barmparis Georgios D. , Kochiadakis George , Maragkoudakis Spyros , Savva Eirini , Kampanieris Emmanuel , Kassotakis Spyros , Kalomoirakis Petros , Vardas Panos , Tsironis Giorgos P. , Marketou Maria E.
Published: May 2022

Background

Hypertension is a major risk factor for cardiovascular disease (CVD) which often escapes the diagnosis or should be confirmed by several office visits. The electrocardiogram (ECG) is one of the most widely used diagnostic tools and could be of paramount importance in patients’ initial evaluation.

Methods

We used machine learning (ML) techniques based features derived from the electrocardiogram for detecting hypertension in a population without CVD. We enrolled 1091 subjects who were classified into hypertensive and normotensive group. We trained a random forest (RF), to predict the existence of hypertension in patients based only on a few basic clinical parameters and ECG-derived features. We also calculated Shapley additive explanations (SHAP), a sophisticated feature importance analysis, to interpret each feature’s role in the random forest’s predictions.

Results

Our RF model was able to distinguish hypertensive from normotensive patients with accuracy 84.2 %, specificity 66.7%, sensitivity 91.4%, and area under the receiver-operating curve 0.86. Age, body mass index (BMI), BMI-adjusted Cornell criteria (BMI multiplied by RaVL+SV3), R wave amplitude in aVL, and BMI-modified Sokolow-Lyon voltage (BMI divided by SV1+RV5), were the most important anthropometric and ECG-derived features in terms of the success of our model.

Conclusions

Our ML algorithm is effective in the detection of hypertension in patients using ECG-derived and basic anthropometric criteria. Our findings open new horizon in the detection of many undiagnosed hypertensive individuals who have an increased cardiovascular disease risk.
Association of cortical arousals with sleep-disordered breathing events
Authors: Zitting Kirsi-Marja , Lockyer Brandon J , Azarbarzin Ali , Sands Scott A , Wang Wei , Wellman Andrew , Quan Stuart F
Published: May 2022

Study Objectives

The American Academy of Sleep Medicine recommends scoring hypopneas in adults when there is a ≥3% oxygen desaturation Or when the event is associated with an arousal. However, there is no rule regarding the duration of the interval between the event termination and the associated arousal. The purpose of this study is to explore the timing between arousals and sleep-disordered breathing (SDB) events.

Methods

We analyzed cortical arousals (>1.6 million) and SDB events (>350,000 apneas and >1.9 million hypopneas) from 11,400 manually scored polysomnography recordings. Only arousals that started within ±30 seconds from the end of SDB events were included. We used the two local minimums on either side of the arousal distribution as the start/end times for the distribution, and to define which arousals are associated with SDB events. Finally, we calculated arousal probability near the end of SDB events.

Results

Cortical arousals with start times that fell within the two minimums were considered to be associated with SDB events. Using this definition, we found that 90% of apnea-associated arousals started no earlier than 4 seconds before and no later than 9 seconds after the end of apneas. Similarly, 90% of hypopnea-associated arousals started no earlier than 6 seconds before and no later than 14 seconds after the end of hypopneas, with the peak of the distribution coinciding with event end time. Arousal probability was highest during the first 10 seconds after the end of the event and was higher for longer events.

Conclusions

Our results suggest that 90% of SDB-associated arousals start from 6 seconds before to 14 seconds after the end of the respiratory events.
SARS-CoV-2 Omicron Variant Wave in India: Advent, Phylogeny and Evolution
Authors: Singh Urvashi B. , Deb Sushanta , Chaudhry Rama , Bala Kiran , Rani Lata , Gupta Ritu , Kumari Lata , Ahmed Jawed , Gaurav Sudesh , Perumalla Sowjanya , Nizam Md. , Mishra Anwita , Stephenraj J. , Shukla Jyoti , Bhardwaj Deepika , Nayer Jamshed , Aggarwal Praveen , Kabra Madhulika , Ahuja Vineet , Sinha Subrata , Guleria Randeep
Published: May 2022

SARS-CoV-2 evolution has continued to generate variants, responsible for new pandemic waves locally and globally. Varying disease presentation and severity has been ascribed to inherent variant characteristics and vaccine immunity. This study analyzed genomic data from 305 whole genome sequences from SARS-CoV-2 patients before and through the third wave in India. Delta variant was responsible for disease in patients without comorbidity(97%), while Omicron BA.2 caused disease primarily in those with comorbidity(77%). Tissue adaptation studies brought forth higher propensity of Omicron variants to bronchial tissue than lung, contrary to observation in Delta variants from Delhi. Study of codon usage pattern distinguished the prevalent variants, clustering them separately, Omicron BA.2 isolated in February grouped away from December strains, and all BA.2 after December acquired a new mutation S959P in ORF1b (44.3% of BA.2 in the study) indicating ongoing evolution. Loss of critical spike mutations in Omicron BA.2 and gain of immune evasion mutations including G142D, reported in Delta but absent in BA.1, and S371F instead of S371L in BA.1 could possibly be due to evolutionary trade-off and explain very brief period of BA.1 in December 2021, followed by complete replacement by BA.2.
COVID-19 vaccines effectiveness against SARS-CO-V-2 infection among persons attending RT-PCR centre at a Medical College Hospital in Telangana: A case control study
Authors: Veerapu Nagapraveen , Inmdar Dhanashree P , Ravi Kumar Baer P , Anuradha Basavaraju , Guddanti Pavitra , Issapuri Sree D , Ganta Nikhita S , Gopi Arun
Published: May 2022

Background

In January 2021, India drug regulator issued restricted emergency approval for COVAXIN and COVISHIELD which were manufactured in India. On mid-January 2021, in India, there were 10.5million confirmed cases and 0.15 million deaths.

Objectives

The objectives were to evaluate vaccine effectiveness (VE) of India made Covid-19 vaccines against SARS-CoV-2 infection.

Methods

A test negative case control study was conducted from May 2021 to December 2021 for duration of 8months among people attending an RT-PCR centre at a medical college Hospital for RT-PCR test. The baseline characteristics and RT-PCR report; and preliminary data about vaccine status were collected from the RT-PCR centre. The exposure to vaccination was enquired via Phone call or was checked with data available with the health authorities.

Results

After applying inclusion exclusion criteria, case and control definitions, a total of 380 participants (95cases and 285 controls) were included. The adjusted VE of two doses of COVISHIED vaccine against symptomatic SARS-CoV-2 infection was 52.2% (95% CI, 41.7 to 62.1) and single dose was 40.88% (95% CI, 31.26 to 51.29). The adjusted VE of two doses of COVAXIN vaccine against SARS-CoV-2 infection was 39% (95% CI, 29.40 to 49.27). The overall VE was 48.20% (95% CI, 37.90 to 58.22) for two doses of any vaccines.

Conclusions

India made vaccines were nearly 50% effective. Similar results show by different studies with a margin of 10-25% difference. Further new studies should be conducted as new variants of SARS-CoV-2 are emerging, and we don’t know how the vaccine works against the variants and booster doses were required or not.
Altered Regulation of Ia Afferent Input during Voluntary Activity after Human Spinal Cord Injury
Authors: Chen Bing , Perez Monica A.
Published: May 2022

Sensory input converging on the spinal cord contributes to the control of voluntary activity. Although sensory pathways reorganize following spinal cord injury (SCI), the extent to which sensory input from Ia afferents is regulated during voluntary activity after the injury remains largely unknown. To address this question, we examined the soleus H-reflex and conditioning of the H-reflex by stimulating homonymous and heteronymous nerves [depression of the soleus H-reflex evoked by common peroneal nerve stimulation (D1 inhibition) and the monosynaptic Ia facilitation of the soleus H-reflex evoked by femoral nerve stimulation (FN facilitation)] at rest, and during tonic voluntary activity in humans with and without chronic incomplete SCI. We found that during voluntary activity the soleus H-reflex size increased in both groups compared with rest, but to a lesser extent in SCI participants. Compared with rest, the D1 inhibition decreased during voluntary activity in controls but it was still present in SCI participants. Further, the FN facilitation increased in controls but remained unchanged in SCI participants during voluntary activity compared with rest. Changes in the D1 inhibition and FN facilitation were correlated with changes in the H-reflex during voluntary activity, suggesting an association between outcomes. These findings provide the first demonstration that the regulation of Ia afferent input from homonymous and heteronymous nerves is altered during voluntary in humans with SCI, resulting in lesser facilitatory effect on motor neurons.
Linked selection and the evolution of altruism in family-structured populations
Authors: Thomson Lia , Priego Espinosa Daniel , Brandvain Yaniv , Van Cleve Jeremy
Published: May 2022

Much research on the evolution of altruism via kin selection, group selection, and reciprocity focuses on the role of a single locus or quantitative trait. Very few studies have explored how linked selection, or selection at loci neighboring an altruism locus, impacts the evolution of altruism. While linked selection can decrease the efficacy of selection at neighboring loci, it might have other effects including promoting selection for altruism by increasing relatedness in regions of low recombination. Here, we used population genetic simulations to study how negative selection at linked loci, or background selection, affects the evolution of altruism. When altruism occurs between full siblings, we found that background selection interfered with selection on the altruistic allele, increasing its fixation probability when the altruistic allele was disfavored and reducing its fixation when the allele was favored. In other words, background selection has the same effect on altruistic genes in family-structured populations as it does on other, nonsocial, genes. This contrasts with prior research showing that linked selective sweeps can favor the evolution of cooperation, and we discuss possibilities for resolving these contrasting results.
Effects of Robotic-Assisted Gait at Different Levels of Guidance and Body Weight Support on Lower Limb Joint Angles, Angular Velocity, and Inter-Joint Coordination
Authors: Cherni Yosra , Blache Yoann , Begon Mickaël , Ballaz Laurent , Maso Fabien Dal
Published: May 2022

The Lokomat provides task-oriented therapy for patients with gait disorders. This robotic technology drives the lower limbs in the sagittal plane. However, unconstrained gait involves motions also in the coronal and transverse planes. This study aimed to compare the Lokomat with Treadmill gait through 3D-joint kinematics and inter-joint coordination. Lower limb kinematics was recorded in 18 healthy participants who walked at 3 km/h on a Treadmill or in a Lokomat with nine combinations of Guidance (30, 50, 70%) and body-weight-support (30, 50,70%). Compared to Treadmill, the Lokomat altered pelvis rotation, decreased pelvis obliquity and hip adduction, and increased ankle rotation. Moreover, the Lokomat resulted in a significantly slower velocity at the hip, knee, and ankle flexion compared to the treadmill condition. Moderate to strong correlations were observed between the Treadmill and Lokomat conditions in terms of inter-joint coordination between hip-knee (r=0.67-0.91), hip-ankle (r=0.66-0.85), and knee-ankle (r=0.90-0.95). In conclusion, this study showed that some gait determinants such as pelvis obliquity and rotation, and hip adduction are altered when walking with Lokomat in comparison to Treadmill. Kinematic deviations induced by the Lokomat were most prominent at high levels of body-weight-support. Interestingly, different levels of Guidance did not affect gait kinematics.
Unmet dental needs in children following suspension of school-based oral health services due to COVID-19
Authors: Ruff Ryan Richard , Godín Tamarinda Barry , Whittemore Rachel , Small Topaz Murray , Santiago-Galvin Nydia , Sharma Priyanka
Published: May 2022

Background

Dental caries (tooth decay) is the world’s most prevalent noncommunicable disease and can lead to pain, infection, and edentulism. Many children with caries lack access to traditional dental services. School-based caries prevention can increase access to care and reduce health inequities. Disruptions in school-based care due to pandemic control policies may result in children losing access to their primary dental care option.

Methods

The CariedAway project was a school-based caries prevention program in operation from 2019-2023 in urban schools with a high proportion of low-income, minority students. Program operations were suspended for two years due to the COVID-19 pandemic. We estimated the prevalence of untreated decay, swelling, fistula, and pulpal involvement in participants at baseline and again after restrictions were lifted.

Results

2998 children between the ages of 5 and 13 years were enrolled and received preventive care prior to pandemic shutdowns, and 1398 (47%) completed their first follow-up observation after two years. At baseline, approximately 30% had untreated caries on any dentition, 11% of children presented with evidence of having received preventive dental sealants, and no participants had swelling, fistula, or pulpal involvement. After 24 months, 12% of participants had swelling fistula, or pulpal involvement that was not treated during the pandemic period.

Conclusion

There are considerable unmet dental needs in high-risk children that may be further exacerbated by a lack of access to care during disease outbreaks.
Pulmonary function among rural residents in high air pollution area in northern Thailand
Authors: Ruchiwit Pitchayapa , Saiphoklang Narongkorn , Leelasittikul Kanyada , Pugongchai Apiwat , Poachanukoon Orapan
Published: May 2022

Background

Air pollution has become a serious environmental and health issue in several countries. This condition leads to respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). This study aimed to determine pulmonary functions and prevalence of respiratory diseases among rural residents in an area in northern Thailand with a high concentration of air pollution.

Methods

A cross-sectional study was conducted in people aged 18 years or older, living in Lamphun, Thailand in December 2021. Demographics, pre-existing diseases, respiratory symptoms, and pulmonary functions by spirometry including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiration flow (PEF), forced expiration flow rate at 25-75% of FVC (FEF25-75), and bronchodilator responsiveness (BDR; FEV1 improvement after BDR test >12% and 200 mL) were collected.

Results

A total of 127 people (78.7%male) were included. Mean age was 43.76±11.32 years. Smoking was 52.0% and 4.44±5.45 pack-years. Self-reported respiratory diseases were allergic rhinitis (7.1%), asthma (0.8%), and COPD (0.8%). Respiratory symptoms were presented in 33.1% (14.2% runny nose, 10.2% nasal obstruction, 9.4% cough, 7.9% sputum production, and 6.3% breathlessness). Lung functions showed FVC in 96.74±12.91%, FEV1 in 97.52±12.99%, PEF in 102.46±19.18%, and FEF25-75 in 96.77±29.88%. Abnormal lung functions were found in 15.7%. Small airway disease (FEF25-75<65%) was 7.1%. Restrictive defect (FVC<80%) was 6.3%. Airway obstruction (FEV1/FVC<70%) was 2.4%. There was no BDR. Compared to people with normal lung functions, the abnormal lung function group was older (48.00±8.68 years vs 42.96±11.61 years, P=0.036), and had a higher proportion of breathlessness (20.0% vs 3.7%, P=0.021).

Conclusions

Abnormal pulmonary functions, especially small airway disease, were relatively common in rural residents in a polluted air area in northern Thailand. These abnormal pulmonary functions were associated with more respiratory symptoms.

Clinicaltrials.in.th number

TCTR20211223001
Therapeutic neutralizing monoclonal antibody administration protects against lethal Yellow Fever infection
Authors: Ricciardi Michael J. , Rust Lauren N. , Pedreño-Lopez Nuria , Yusova Sofiya , Biswas Sreya , Webb Gabriela M. , Gonsales-Nieto Lucas , Voigt Thomas B. , Louw Johan J. , Laurino Fernanda D. , DiBello John R. , Raué Hans-Peter , Barber-Axthelm Aaron M. , Uttke Samantha , Raphael Lidiane M.S. , Yrizarry-Medina Aaron , Rosen Brandon C. , Agnor Rebecca , Gao Lina , Labriola Caralyn , Axthelm Michael , Smedley Jeremy , Julander Justin G. , Bonaldo Myrna C. , Walker Laura M. , Messaoudi Ilhem , Slifka Mark K. , Burton Dennis R. , Kallas Esper G. , Sacha Jonah B. , Watkins David I. , Burwitz Benjamin J.
Published: May 2022

Few countermeasures to treat Yellow Fever virus (YFV) infection are under development, because vaccines have helped to limit new infections. Unfortunately, vaccine hesitancy, supply deficits, and a paucity of therapeutic options have left individuals at risk. Here, we tested potent YFV-specific neutralizing monoclonal antibodies in rodents and non-human primates. We administered antibodies during acute pathogenic YFV infection and demonstrate that we can prevent severe disease and death. Given the severity of YFV-induced disease, our results show that these antibodies could be effective in saving lives and fill a much-needed void in managing Yellow Fever cases during outbreaks around the world.

One Sentence Summary

Therapeutic monoclonal antibodies prevent death from YFV infection.
Sex differences in coronary artery disease and diabetes revealed by scRNA-Seq and CITE-Seq of human CD4+ T cells
Authors: Saigusa Ryosuke , Vallejo Jenifer , Gulati Rishab , Suthahar Sujit Silas Armstrong , Suryawanshi Vasantika , Alimadadi Ahmad , Markings Jeff , Durant Christopher P. , Freuchet Antoine , Roy Payel , Ghosheh Yanal , Pandori William , Pattarabanjird Tanyaporn , Drago Fabrizio , McNamara Coleen A. , Shemesh Avishai , Lanier Lewis L. , Hedrick Catherine C. , Ley Klaus
Published: May 2022

Background

Despite the decades-old knowledge that diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD), the reasons for this association are only partially understood. Among the immune cells involved in CVD development, accumulating evidence supports the critical role of T cells as drivers and modifiers of this condition. CD4+ T cells are commonly found in atherosclerotic plaques. The activity and distribution of CD4+ T cell subsets differs between the sexes.

Methods

Peripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by single cell RNA sequencing (scRNA-Seq, ∼200,000 cells) combined with 49 protein markers (CITE-Seq). Coronary artery disease (CAD) was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD-. Four pairs of groups were matched for clinical and demographic parameters. To test how DM changed cell proportions and gene expression, we compared matched groups of diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 61 mostly statin-treated coronary artery disease patients with and without DM.

Results

We identified 16 clusters in CD4 T cells. The proportion of cells in CD4 cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. The proportions of cells in CD4T2, CD4T11, CD4T16 were increased and CD4T13 was decreased in CAD+ among DM+Statin+ participants. CD4T12 was increased in DM+ participants. In female participants, CD4T8, 12, and 13 were decreased compared to in male participants. In CD4 T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature.

Conclusions

We conclude that CAD and DM are clearly reflected in PBMC transcriptomes and that significant differences exist between women and men and between subjects treated with statins or not.
Parallel clonal and molecular profiling of hematopoietic stem cells using RNA barcoding
Authors: Wojtowicz Edyta E. , Mistry Jayna , Uzun Vladimir , Scoones Anita , Chin Desmond W. , Kettyle Laura , Grasso Francesca , Lord Allegra M. , Etherington Graham , Hellmich Charlotte , Woll Petter S. , Belderbos Mirjam E. , Bowles Kristian M. , Nerlov Claus , Haerty Wilfried , Bystrykh Leonid V. , Jacobsen Sten Eirik W. , Rushworth Stuart A. , Macaulay Iain C.
Published: May 2022

Anucleate cells - platelets and erythrocytes - constitute over 95% of all hematopoietic stem cell (HSC) output, but the clonal dynamics of HSC contribution to these lineages remains largely unexplored. Here, we use lentiviral RNA cellular barcoding and transplantation of HSCs, combined with single-cell RNA-seq, for quantitative analysis of clonal behavior with a multi-lineage readout - for the first time including anucleate and nucleate lineages. We demonstrate that most HSCs steadily contribute to hematopoiesis, but acute platelet depletion shifts the output of multipotent HSCs to the exclusive production of platelets, with the additional emergence of new myeloid-biased clones. Our approach therefore enables comprehensive profiling of multi-lineage output and transcriptional heterogeneity of individual HSCs, giving insight into clonal dynamics in both steady state and under physiological stress.
Expanding EMC Foldopathies: Topogenesis Deficits Alter the Neural Crest
Authors: Marquez Jonathan , Khokha Mustafa K.
Published: May 2022

The endoplasmic reticulum membrane protein complex (EMC) is essential for the insertion of a wide variety of transmembrane proteins into the plasma membrane across cell types. Each EMC is composed of Emc1-7, Emc10, and either Emc8 or Emc9. Recent human genetics studies have implicated variants in EMC genes as the basis for a group of human congenital diseases. The patient phenotypes are varied but appear to affect a subset of tissues more prominently than others. Namely, craniofacial development seems to be commonly affected. We previously developed an array of assays in Xenopus tropicalis to assess the effects of emc1 depletion on the neural crest, craniofacial cartilage, and neuromuscular function. We sought to extend this approach to additional EMC components identified in patients with congenital malformations. Through this approach we determine that EMC9 and EMC10 are important for neural crest development and the development of craniofacial structures. The phenotypes observed in patients and our Xenopus model were similar to EMC1 loss of function likely due to a similar mechanism of dysfunction in transmembrane protein topogenesis.
A CRISPR-screen in intestinal epithelial cells identifies novel factors for polarity and apical transport
Authors: Klee Katharina MC , Hess Michael W , Lohmüller Michael , Herzog Sebastian , Pfaller Kristian , Müller Thomas , Vogel Georg F , Huber Lukas A
Published: May 2022

Epithelial polarization and polarized cargo transport are highly coordinated and interdependent processes. In our search for novel regulators of epithelial polarization and protein secretion, we used a genome-wide CRISPR/Cas9 screen and combined it with an assay based on fluorescence-activated cell sorting (FACS) to measure the secretion of the apical brush border hydrolase dipeptidyl peptidase 4 (DPP4). In this way, we performed the first CRISPR screen to date in human polarized epithelial cells. Using high-resolution microscopy, we detected polarization defects and mislocalization of DPP4 to late endosomes/lysosomes after knock-down of TM9SF4, anoctamin 8, and ARHGAP33, confirming the identification of novel factors for epithelial polarization and apical cargo secretion. Thus, we provide a powerful tool suitable for studying polarization and cargo secretion in epithelial cells. In addition, we provide a dataset that serves as a resource for the study of novel mechanisms for epithelial polarization and polarized transport and facilitates the investigation of novel congenital diseases associated with these processes.
Visual system hyperexcitability and compromised V1 receptive field properties in early-stage retinitis pigmentosa in mice
Authors: Leinonen Henri , Lyon David C , Palczewski Krzysztof , Foik Andrzej T
Published: May 2022

Inherited retinal degenerative diseases are a prominent cause of blindness. Even though mutations causing death of photoreceptors are mostly known, the pathophysiology downstream in the inner retina and along the visual pathway is incompletely characterized in the earliest disease stages. Here we investigated retinal, midbrain and cortical visual function using electroretinography (ERG), the optomotor response (OMR), visual evoked potentials (VEPs), respectively, and single unit electrophysiology at the primary visual cortex (V1) in light-adapted juvenile (∼ 1-month-old) and young adult (3-month-old)RhoP23H/WTmice, representative of early-stage retinitis pigmentosa (RP). Photopic ERG revealed up to ∼ 30 % hypersensitivity to light inRhoP23H/WTmice, as measured by the light intensity required to generate half-maximal b-wave (I50parameter).RhoP23H/WTmice also showed increased optomotor responses towards low spatial frequency drifting gratings, indicative of visual overexcitation at the midbrain level. At the V1 level, VEPs and single-cell recordings revealed prominent hyperexcitability in the juvenileRhoP23H/WTmice. Mean VEP amplitudes for light ON stimuli were nearly doubled in 1-month-oldRhoP23H/WTmice compared to controls, and more than doubled for light OFF. Single-cell recordings showed a significantly increased spontaneous V1 neuron firing in theRhoP23H/WTmice, and persistent contrast and temporal sensitivities. In contrast, direction selectivity was severely compromised. Our data suggest that during early RP, the visual pathway becomes hyperexcited. This could have both compensatory and deleterious consequences for visual behavior. Further studies on the mechanisms of hyperexcitability are warranted as this could lead to therapeutic interventions for RP.

Significance statement

Lost retinal function in many blinding retinal degenerative disorders could soon be alleviated by advanced therapies that restore photoreception. However, it is unknown whether a visual system rewired downstream of the photoreceptors can process signals adequately. We studied the functional consequences of early rod death along the visual pathway in young retinitis pigmentosa (RP) mice. Photopic inner retina responses were moderately hypersensitized in the electroretinograms of RP mice. Reflex-based visual behavior and visual cortex electrophysiology showed hyperexcitability. Some aspects of complex visual processing were remarkably resistant to degeneration, whereas others were severely impacted. We conclude that the visual system adapts to lost photoreception by increasing sensitivity, but simultaneously becomes detrimentally hyperexcited. Mechanistic understanding could lead to therapeutic preservation and restoration of vision.
An algorithm for the identification of indicator taxonomic units and their use in analyses of ecosystem state
Authors: de la Vega Hernán , Falco Liliana , Saravia Leonardo , Sandler Rosana , Duhour Andrés , Velazco Víctor N , Coviella Carlos
Published: May 2022

Biological community structure can be used as an ecological state descriptor, and the sensitivity of some taxonomic groups or biological entities to environmental conditions allows for their use as ecological state indicators. This work describes a mathematical methodology developed for the identification of such taxonomic units when comparing environments or ecosystems under different anthropic impacts. Based on this methodology, a freely downloadable R package for easy use was developed, (Ecoindicators, DOI: 10.5281/zenodo.5772829). Based solely on presence or absence information, the method identifies indicator taxonomic units for each environment, estimates the belonging of any additional samples to a given environment, approximates the ecological niche of any taxonomic unit based on two or more selected environmental factors, and returns the frequency of any taxonomic unit in a selected combination of environmental factors. By using the approximation to the ecological niche of species present, given a new sample, the physicochemical parameters can be estimated by the species present in the sample. These analyses can be performed simultaneously for two or more taxonomic units. This paper provides a mathematical description of how the mathematical method was developed. One of the advantages of this method, and the referred R-package is that it can be used for any ecosystem for which there is a suitable biological dataset associated with environmental factors. In addition, both this mathematical procedure and the package referred to, can be tailored by other researchers to fit their own needs. We also expect other developers to further improve it.
Combined reference-free and multi-reference approaches uncover cryptic variation underlying rapid adaptation in microbial pathogens
Authors: Dutta Anik , McDonald Bruce A. , Croll Daniel
Published: May 2022

Background

Microbial species often harbor substantial functional diversity driven by structural genetic variation. Rapid adaptation from such standing variation in pathogens threatens global food security and human health. Genome wide association studies (GWAS) provide a powerful approach to identify genetic variants underlying recent pathogen evolution. However, the reliance on single reference genomes and single nucleotide polymorphisms (SNPs) obscures the true extent of adaptive genetic variation. Here, we show quantitatively how a combination of multiple reference genomes and reference-free approaches captures substantially more relevant genetic variation compared to single reference mapping.

Results

We performed reference-genome based association mapping across 19 reference-quality genomes covering the diversity of the species. We contrasted the results with a reference-free (i.e., K-mer) approach using raw whole genome sequencing data. We assessed the relative power of these GWAS approaches in a panel of 145 strains collected across the global distribution range of the fungal wheat pathogen Zymoseptoria tritici. We mapped the genetic architecture of 49 life history traits including virulence, reproduction and growth in multiple stressful environments. The inclusion of additional reference genome SNP datasets provides a nearly linear increase in additional loci mapped through GWAS. Variants detected through the K-mer approach explained a higher proportion of phenotypic variation than a reference genome based approach, illustrating the benefits of including genetic variants beyond SNPs.

Conclusions

Our study demonstrates how the power of GWAS in microbial species can be significantly enhanced by comprehensively capturing functional genetic variation. Our approach is generalizable to a large number of microbial species and will uncover novel mechanisms driving rapid adaptation in microbial populations.
Focal electrical stimulation on an alcohol disorder model using MRI-compatible chronic neural monopolar carbon fiber electrodes
Authors: Lopez-Castro Alejandra , Angeles-Valdez Diego , Rojas-Piloni Gerardo , Garza-Villarreal Eduardo A.
Published: May 2022

Neuromodulation interventions, such as Deep Brain Stimulation (DBS) and repeated transcranial magnetic stimulation (rTMS), are proposed as possible new complementary therapies to treat substance use disorders (SUD) such as alcohol use disorder (AUD). It is hypothesized that neuromodulation may induce neural plasticity in the reward and frontostriatal systems via electrical field induction, possibly reducing symptoms. Preclinical self-administration rodent models of AUD may help us gain insight into the effects of neuromodulation therapies on different pathology, as well as the neural mechanisms behind the positive effects. DBS, or any type of brain stimulation using intracranial electrodes in rodents, would benefit from the use of MRI to study the longitudinal effects and mechanisms of stimulation as well as novel targets, as it is a non-invasive technique that allows the analysis of structural and functional changes in the brain. To do this, there is a need for MRI-compatible electrodes that allow for MRI acquisition with minimal distortion of the magnetic field. In this protocol, we present a method for the construction and surgery of chronically implantable monopolar carbon electrodes for use in rats. Unlike conventional electrodes, carbon electrodes are resistant to high temperatures, flexible, and generate fewer artifacts in MRI compared to conventional ones. We validated its use by using a focal electrical stimulation high-frequency (20 Hz) protocol that lasted ~10 sessions. We propose that this technique can also be used for the research of the neurophysiological bases of the neuromodulatory treatment in other preclinical substance use disorders (SUD) models.
Evaluation of the DBA/2J mouse as a potential background strain for genetic models of cardiomyopathy
Authors: Hart Cora C. , Lee Young il , Hammers David W. , Sweeney H. Lee
Published: May 2022

The potential use of the D2.mdx mouse (the mdx mutation on the DBA/2J genetic background) as a preclinical model of the cardiac aspects of Duchenne muscular dystrophy (DMD) has been criticized based on speculation that the DBA/2J genetic background displays an inherent hypertrophic cardiomyopathy phenotype. Accordingly, the goal of the current study was to further examine the cardiac status of this mouse strain over a 12-month period. DBA/2J mice have been scrutinized for the presence of cardiac lesions, however, in the current study we find that DBA/2J mice contain equivalent amounts of left ventricular collagen as healthy canine and human samples. In a longitudinal echocardiography study, neither sedentary or exercised DBA/2J mice demonstrated left ventricular wall thickening or cardiac functional deficits. In summary, we find no evidence of hypertrophic cardiomyopathy, or any other cardiac pathology, and thus propose that it is an appropriate background strain for genetic modeling of cardiac diseases, including the cardiomyopathy associated with DMD.
Botrytis cinerea infection accelerates ripening and cell wall disassembly to promote disease in tomato fruit
Authors: Silva Christian , Adaskaveg Jaclyn A. , Mesquida-Pesci Saskia D. , Ortega-Salazar Isabel B. , Pattathil Sivakumar , Zhang Lisha , Hahn Michael G. , van Kan Jan A.L. , Cantu Dario , Powell Ann L.T. , Blanco-Ulate Barbara
Published: May 2022

Postharvest fungal pathogens benefit from the increased host susceptibility that occurs during fruit ripening. In unripe fruit, pathogens often remain quiescent and unable to cause disease until ripening begins, emerging at this point into destructive necrotrophic lifestyles that quickly result in fruit decay. Here, we demonstrate that one such pathogen, Botrytis cinerea, actively induces ripening processes to facilitate infections and promote disease. Assessments of ripening progression revealed that B. cinerea accelerated external coloration, ethylene production, and softening in unripe fruit, while mRNA sequencing of inoculated unripe fruit confirmed the corresponding upregulation of host genes involved in ripening processes, such as ethylene biosynthesis and cell wall degradation. Furthermore, an ELISA-based glycomics technique to assess fruit cell wall polysaccharides revealed remarkable similarities in the cell wall polysaccharide changes caused by both infections of unripe fruit and ripening of healthy fruit, particularly in the increased accessibility of pectic polysaccharides. Virulence and additional ripening assessment experiments with B. cinerea knockout mutants showed that induction of ripening is dependent on the ability to infect the host and break down pectin. The B. cinerea double knockout Δbcpg1Δbcpg2 lacking two critical pectin degrading enzymes was found to be incapable of emerging from quiescence even long after the fruit had ripened at its own pace, suggesting that the failure to accelerate ripening severely inhibits fungal survival on unripe fruit. These findings demonstrate that active induction of ripening in unripe tomato fruit is an important infection strategy for B. cinerea.

One-Sentence Summary

Physiological, transcriptional, and glycomic evidence indicates Botrytis cinerea hastens tomato fruit ripening to facilitate infection by a mechanism dependent on the fungal enzymes Bcpg1 and Bcpg2.
Protective geometry and reproductive anatomy as candidate determinants of clutch size variation in pentatomid bugs
Authors: Abram Paul K. , Guerra-Grenier Eric , Brodeur Jacques , Capko Clarissa , Aquino Michely Ferreira Santos , Beers Elizabeth H. , Blassioli-Moraes Maria Carolina , Borges Miguel , Cingolani M. Fernanda , Cusumano Antonino , De Clercq Patrick , Fernandez Celina A. , Gariepy Tara D. , Haye Tim , Hoelmer Kim , Laumann Raul Alberto , Lietti Marcela , McPherson J.E. , Punschke Eduardo , Saunders Thomas E. , Zhang Jin Ping , Hardy Ian C.W.
Published: May 2022

Many animals lay their eggs in clusters. Eggs on the periphery of clusters can be at higher risk of mortality. We asked whether the most commonly occurring clutch sizes in pentatomid bugs could result from geometrical arrangements that maximize the proportion of eggs in the cluster’s interior. Although the most common clutch sizes do not correspond with geometric optimality, stink bugs do tend to lay clusters of eggs in shapes that protect increasing proportions of their offspring as clutch sizes increase. We also considered whether ovariole number, an aspect of reproductive anatomy that may be a fixed trait across many pentatomids, could explain observed distributions of clutch sizes. The most common clutch sizes across many species correspond with multiples of ovariole number. However, there are species with the same number of ovarioles that lay clutches of widely varying size, among which multiples of ovariole number are not over-represented. In pentatomid bugs, reproductive anatomy appears to be more important than egg mass geometry in determining clutch size uniformity. In addition, within this group of animals that has lost most of its variation in ovariole number, clutches with a broad range of shapes and sizes may still be laid.
Gradient-based parameter optimization to determine membrane ionic current composition of human induced pluripotent stem cell-derived cardiomyocytes
Authors: Kohjitani Hirohiko , Koda Shigeya , Himeno Yukiko , Makiyama Takeru , Yamamoto Yuta , Yoshinaga Daisuke , Wuriyanghai Yimin , Kashiwa Asami , Toyoda Futoshi , Zhang Yixin , Amano Akira , Noma Akinori , Kimura Takeshi
Published: May 2022

1.

Premature cardiac myocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) show heterogeneous action potentials (APs), most probably because of different expression patterns of membrane ionic currents. We aim to develop a method of determining expression patterns of functional channels in terms of the whole-cell ionic conductances (Gx) using individual spontaneous AP configurations. However, it has been suggested that apparently identical AP configurations were obtained by different sets of ionic currents in a mathematical model of cardiac membrane excitation. If so, the inverse problem of Gx estimation might not be solved. We computationally tested the feasibility of the gradient-based optimization method. For realistic examination, conventional ‘cell-specific models’ were prepared by superimposing the model output of AP on each experimental AP record by the conventional manual adjustment of Gxs of the baseline model. Then, Gxs of 4 ~ 6 major ionic currents of the ‘cell-specific models’ were randomized within a range of ±5 ~ 15% and were used as initial parameter sets for the gradient-based automatic Gxs recovery by decreasing the mean square error (MSE) between the target and model output. When plotted all data points of MSE - Gx relation during the optimization, we found that the randomized population of Gxs progressively converged to the original value of the cell-specific model with decreasing MSE. To confirm the absence of any other local minimum in the global search space, we mapped the MSE by randomizing Gxs over a range of 0.1 ~ 10 times the control. No additional local minimum of MSE was obvious in the whole parameter space besides the global minimum of MSE at the default model parameter.
Tracking and perceiving diverse motion signals: Directional biases in human smooth pursuit and perception
Authors: Wu Xiuyun , Spering Miriam
Published: May 2022

Human smooth pursuit eye movements and motion perception behave similarly when observers track and judge the motion of simple objects, such as dots. But moving objects in our natural environment are complex and contain internal motion. We ask how pursuit and perception integrate the motion of objects with motion that is internal to the object. Observers (n = 20) tracked a moving random-dot kinematogram with their eyes and reported the object’s perceived direction. Objects moved horizontally with vertical shifts of 0, ±3, ±6, or ±9° and contained internal dots that were static or moved ±90° up/down. Results show that whereas pursuit direction was consistently biased in the direction of the internal dot motion, perceptual biases differed between observers. Interestingly, the perceptual bias was related to the magnitude of the pursuit bias (r = 0.75): perceptual and pursuit biases were directionally aligned in observers that showed a large pursuit bias, but went in opposite directions in observers with a smaller pursuit bias. Dissociations between perception and pursuit might reflect different functional demands of the two systems. Pursuit integrates all available motion signals in order to maximize the ability to monitor and collect information from the whole scene. Perception needs to recognize and classify visual information, thus segregating the target from its context. Ambiguity in whether internal motion is part of the scene or contributes to object motion might have resulted in individual differences in perception. The perception-pursuit correlation suggests shared early-stage motion processing or perception-pursuit interactions.