bluuebunny/crossref_metadata_2025 huggingface dataset:
The diagnostic dilemma and the treatment approach of COVID-19 pneumonia in a kidney transplant patient
Authors: Elfanish Amin , Tuschen Katharina , Anders Johanna , Neumann Lars , Wendel Andreas F. , Lüsebrink Jessica , Schildgen Verena , Schildgen Oliver , Brockmann Michael , Karagiannidis Christian , Weidemann Alexander
Published: April 2021

Introduction:

Coronavirus disease 2019 (COVID-19) pneumonia is a disease caused by the newly discovered coronavirus severe acute respiratory syndrome coronavirus-2. There is no effective treatment and the global pandemic is likely to continue for a certain time until sufficient herd immunity has been reached through the recently released vaccines. As transplant patients are presumably at a higher risk for infection and for a more severe course of disease, diagnostic validity is especially crucial. Polymerase chain reaction testing sometimes yields false-negative results, and especially in areas where medical resources are limited, diagnostic tests have to be safe and feasible yet cost effective to facilitate broad implementation.

Patient concerns:

A 46-year-old kidney transplant recipient with severe COVID-19 pneumonia requiring intubation and mechanical ventilation.

Diagnoses:

Albeit she presented with typical symptoms for at least 2 weeks, two nasopharyngeal swabs and 1 throat gargle sample were negative. Ultimately, positive stool samples confirmed the diagnosis before bronchoalveolar lavage tested positive.

Interventions:

Therapy consisted of reduction of immunosuppression and mechanical ventilation without experimental treatments.

Outcomes:

The patient recovered completely and was discharged after 60 days from the hospital.

Conclusion:

Our findings suggest that stool testing for severe acute respiratory syndrome coronavirus-2 might be a fast and cost effective way to identify and isolate COVID-19 patients, especially in areas where complex medical procedures such as bronchoscopy cannot be performed. Furthermore, the reduction of the immunosuppression and a therapy with intravenous immunoglobulin could be sufficient in kidney transplant patients without further experimental therapy.
The Development of iManage-PC, an Online Symptom Monitoring and Self-management Tool for Men With Clinically Localized Prostate Cancer
Authors: Murphy Karly M. , Sauer Christina , Yang Dershung , Hass Niina , Novakovic Kristian , Helfand Brian , Nadler Robert , Schalet Benjamin D. , Victorson David
Published: April 2021

Background

Prostate cancer (PC) often impacts 4 major aspects of health-related quality of life (HRQL): urinary, sexual, and bowel dysfunction, and anxiety. Online tools may be helpful in supporting the development of self-management skills that can improve HRQL.

Objective

The aim of this study was to develop and pilot-test an online symptom monitoring and self-management program, iManage-PC.

Methods

A literature search, input from experts, and feedback from patients were used to develop iManage-PC. A 4-week, single-arm pilot study was conducted with 96 men with prostate cancer. We evaluated system usability, acceptance, and satisfaction and examined preliminary effects on patient-reported outcomes.

Results

Rates of retention (94.8%) and adherence to symptom monitoring (95.0%-97.0%) were high. Most participants rated the tool as satisfactory and acceptable (81.2%-94.3%). Related-samples Wilcoxon signed rank tests revealed that participants reported increased self-efficacy related to their ability to manage their adverse effects (T = 1772.0, P < .001, r = 0.39), physical discomfort (T = 1259.0, P < .001, r = 0.40), and stress and worry (T = 1108.5, P = .001, r = 0.34). Global mental and physical health also improved (T = 1322.0, P = .032, r = 0.23, and T = 1409.0, P = .001, r = 0.35, respectively).

Conclusions

Future research with such tools should examine the potential role of cut-score–derived management interventions to improve engagement, symptom management self-efficacy, and HRQL.

Implications for Practice

Our findings are consistent with a growing body of literature that supports the feasibility and acceptability of remotely delivered interventions.
Comprehensive Clinical Assessment of Vestibular Function in Multiple Sclerosis
Authors: Cochrane Graham D. , Christy Jennifer B. , Motl Robert W.
Published: April 2021

Background and Purpose:

Balance disorders and dizziness are common in people with multiple sclerosis (MS), suggesting dysfunction of the vestibular system. Evaluating how people with MS perform on objective clinical vestibular tools will help broaden understanding of vestibular function in MS. This cross-sectional study's goal was to complete a robust battery of vestibular-ocular reflex (VOR), dynamic visual acuity (DVA), subjective visual vertical (SVV), and cervical and ocular vestibular-evoked myogenic potential (c/oVEMP) tests in people with and without MS.

Methods:

Forty people with relapsing-remitting MS (Expanded Disability Status Scale [EDSS] ≤6.5) and 20 controls completed the vestibular testing battery. Results were compared between groups and correlations with EDSS scores were calculated.

Results:

People with MS were less able to visually cancel their VOR and showed a larger variance in response on SVV. EDSS significantly correlated with VOR cancellation, SVV variance, and DVA lines lost; linear regression showed that VOR cancellation and SVV variance significantly predicted EDSS.

Discussion and Conclusion:

Vestibular functions requiring central integration of vestibular information, but not reflexive vestibular functions like VEMP, were impaired in people with MS and correlated with EDSS, suggesting that clinical evaluation of functions requiring central integration best evaluates MS-related vestibular dysfunction. Measures assessing central vestibular integration and not vestibular reflexes may be more sensitive to detecting vestibular deficits in people with mild to moderate MS.

Video Abstract available for more insight from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A344).
Testicular Tumors: A Contemporary Update on Morphologic, Immunohistochemical and Molecular Features
Authors: Al-Obaidy Khaleel I. , Idrees Muhammad T.
Published: April 2021

Testicular tumors are incredibly diverse and one of the most challenging areas in surgical pathology. Because of the rarity and overlapping features with numerous entities occurring in the testis and paratestis, these tumors pose a diagnostic challenge even to the most experienced general pathologists. In 2016, the latest “World Health Organization (WHO) classification of testicular tumors” was released, which incorporated several updates to the previous 2004 classification system. These updates involved several entities, including germ cell tumors, sex cord-stromal tumors, tumors containing both germ cells and sex-cord stromal cells, a miscellaneous group of testicular tumors and paratesticular tumors. In addition, significant changes were also introduced in the 2018 AJCC TNM staging (8th edition) regarding testicular tumors. The germ cell tumors are divided into 2 major groups; tumors derived from germ cell neoplasia in situ (GCNIS) and those unrelated to GCNIS. The GCNIS associated tumors include seminomatous and nonseminomatous germ cell tumors, which constitute a heterogeneous group of tumors. Non–GCNIS-associated tumors include prepubertal-type teratoma, prepubertal yolk sac tumor, mixed prepubertal-type teratoma and yolk sac tumor and spermatocytic seminoma. In the sex cord-stromal category, the tumors are classified based on their cells of origin. Most are Leydig cell tumors and Sertoli cell tumors; however, several mixed and diverse entities based on cell types are included in this group. Gonadoblastoma is the only tumor in the mixed germ cell and sex cord-stromal tumor category. Because of recent advances in molecular techniques, abundant new genetic information has emerged which helped classify the tumors based on the molecular alterations and provided insights into the tumor pathogenesis. This review focused on the updates related to testicular germ cell tumors and sex cord-stromal tumors and described the morphologic, immunohistochemical and molecular characteristics with an aim to provide a practical diagnostic approach and an update on relevant recent molecular advances.
Systems Analysis to Increase HIV Testing Delivery and HIV Diagnosis in Primary Care Clinics in South Africa
Authors: Mishra Anant , Mshweshwe-Pakela Nolundi , Kubeka Griffiths , Hansoti Bhakti , Mabuto Tonderai , Hoffmann Christopher J.
Published: April 2021

Background:

Provider-initiated testing and counseling remains highly underused in many South African health facilities. We implemented a systems analysis to investigate whether simple adjustments to HIV testing services (HTS) delivery can increase HTS provision.

Setting:

Ten primary care facilities in the Ekurhuleni District in South Africa.

Methods:

Following a baseline HTS assessment that showed limited offering of HTS by clinicians, clinic staff had the option to adopt several change approaches to increase HTS delivery using existing human resources. Approaches included adjusting HTS timing, strengthening HTS promotion, counsellor management, and implementing reward systems. Evaluation was conducted identically to the baseline study using patient exit interviews to quantify HTS engagement and value stream mapping to map patient flow through the clinic.

Results:

We conducted 2163 exit interviews and followed 352 patients for value stream mapping. After change implementation, a significantly higher proportion of patients reported being offered HTS (742/2163, 34.3% vs. 231/2206, 10.5% during the baseline period; χ2
P < 0.001) and having undertaken testing (527/2163, 24.4% vs. 197/2206, 8.9% during the baseline period; χ2
P < 0.001) with only a 3-percentage point decrease in HIV-positive yield (14.0% vs. 17.1% during the baseline period). The median time to HTS offer decreased from 77 minutes to 3 minutes after clinic arrival during the intervention (χ2
P = 0.001).

Conclusions:

A systems approach can be an effective and appropriate implementation strategy to augment HTS delivery and increase HIV diagnoses. This low-cost approach may be extended to optimize other aspects of clinic service delivery.
Brief Report: Association Between Pain, Pulmonary Function, and Respiratory Symptoms in People With HIV
Authors: Singhvi Deepti G. , Nouraie Mehdi , Kessinger Cathy , McMahon Deborah K. , Weinman Renee , Crothers Kristina , Huang Laurence , Bon Jessica , Morris Alison , Merlin Jessica
Published: April 2021

Background:

People with HIV (PWH) experience chronic pain and respiratory symptoms, which are closely related in the general population. Pain may affect the impaired pulmonary function seen in PWH beyond its association with HIV alone. Our objective was to investigate the relationship of pain severity to pulmonary function, respiratory symptoms, and sleep disturbance in PWH.

Setting:

Study sites included the University of Pittsburgh, University of California San Francisco, and University of Washington.

Methods:

Pain, dyspnea, and sleep were assessed using the Brief Chronic Pain Questionnaire, St. George's Respiratory Questionnaire, and Pittsburgh Sleep Quality Index. Participants performed prebronchodilator and postbronchodilator spirometry and 6-minute walk test. Associations between pain severity, lung function, dyspnea, and sleep were assessed with bivariate and multiple quantile regression analysis adjusted for age, sex, race, body mass index, and smoking status.

Results:

Of 159 PWH, the median age was 56 years with 30.8% women. Two-thirds experienced pain in the past week, with 40.3% reporting chronic pain. Pain severity was higher with female sex (P = 0.038), non-White race (P = 0.005), current smoking (P = 0.003), and lower CD4+ count (P = 0.035). In adjusted analysis, higher pain severity was correlated with reduced postbronchodilator forced expiratory volume in 1 second %predicted (P = 0.008), reduced postbronchodilator forced vital capacity %predicted (P = 0.019), and chronic obstructive pulmonary disease (P = 0.032). Greater pain severity was strongly associated with a higher St. George's Respiratory Questionnaire score (P < 0.001) and sleep disturbance (P < 0.001).

Conclusions:

In PWH, pain is common and associated with airflow obstruction, dyspnea, and sleep disturbance. Future studies assessing pain severity and pulmonary function over time could clarify the direction of this association and the impact on quality of life.
Patterns of Craniomaxillofacial Trauma After E-Scooter Accidents in Germany
Authors: Thoenissen Philipp , Salewski Deborah , Heselich Anja , Sader Robert , Marzi Ingo , Muehlenfeld Nils , Ghanaati Shahram
Published: April 2021

Introduction:

E-Scooters are trending as an individual transport vehicle with electric drive in Germany. But there is less data about the frequency, demographic details and possible injuries and therapy needs in context with E-scooter accidents. Therefore, the primary aim of this study was to analyze the frequency and the characteristics of facial trauma as well as the consecutive hospitalization and management after injuries with E-scooters in a German clinic specialized in craniomaxillofacial surgery.

Materials and Methods:

Retrospective data analysis of the hospital information system of patients admitted to central emergency unit driving e-scooters and injuries between June and December 2019.

Results:

A total of 28 consecutive patients were admitted to the emergency care unit of a level one trauma center from June to December 2019. 85% had a minimum of two or more facial injuries. Most common were soft tissue injuries with 64% (n = 18), fractures with 54% (n = 15) and teeth injuries with 39% (n = 11). 82% percent of injuries were related with consumption of alcohol.

Discussion:

The data show a variety of different injuries from teeth injury, wounds and facial fractures in varying degrees in a predominantly young and male cohort (mean age 33.57, 68% male) often associated with alcohol. As accidents happen especially at nighttime and on weekends personnel capacities should be provided. Still bicycle accidents and following injuries stay a major problem.
Bedside testing for precision pain medicine
Authors: Reimer Maren , Sachau Juliane , Forstenpointner Julia , Baron Ralf
Published: April 2021

Purpose of review

In recent years, the identification of therapy responders has become an increasing focus of pain research. On the basis of laboratory quantitative sensory testing, subgroups of patients were identified, which have been shown to predict treatment response. However, the high cost and time expenditure limits the use of these lab-QST protocols in clinical practice and large clinical trials.

Recent findings

Recently, different bedside testing protocols were developed as easy-to-use alternative for lab-QST. In addition, patients can be subgrouped based on their symptoms by use of patient-reported outcome measures. First results suggest that these approaches can be used to stratify patients into pathophysiological-plausible subgroups predictive for treatment response.

This review presents recently developed bedside approaches that can be implemented as stratification tools in future clinical trials to realize individualized pain medicine. Being complementary rather than replaceable, future studies should combine questionnaires and sensory testing and apply them prospectively in large clinical trials.
Visual Outcomes in Surgically Treated Intracranial Meningiomas
Authors: Zhang Yibing , Kim John , Andrews Chris , Archer Erica , Bursztyn Lulu , Grabe Hilary , Margolin Edward , Sullivan Stephen , Trobe Jonathan
Published: April 2021

Background:

Intracranial meningiomas that arise from the medial sphenoid ridge, anterior clinoid process, tuberculum sellae, or planum sphenoidale often impair vision by compressing the optic nerves and optic chiasm. Although many studies have reported visual outcome following surgery for these tumors, documentation has often been incomplete and not validated by patient self-report.

Methods:

Retrospective study of 40 patients drawn from a single, academic, medical center. We used a unique method of assessing visual outcome based on whether the change in visual function affected the preoperatively better-sighted or worse-sighted eye in the belief that this method would correlate with effects on activities of daily living (ADL). To elicit patient self-reports of those effects, we conducted telephone interviews of 25 patients with a standard questionnaire. We also assessed putative ophthalmic, imaging, and surgical predictors of visual outcome.

Results:

Visual improvement occurred in 61% of patients with preoperative monocular visual dysfunction, but only 22% of patients reported improvement in their ability to conduct ADL, and 17% lost vision. Visual outcomes were better in patients with preoperative binocular visual dysfunction, where visual improvement occurred in 73% and no patient lost vision in the preoperatively better-sighted eye. However, only 27% of patients with preoperative binocular visual dysfunction reported improvement in their ability to conduct ADL. Long duration of vision impairment, presence of optic disc pallor, large tumor size, and imaging-based preoperative optic canal involvement did not preclude a favorable visual outcome. Aggressive surgical reduction in displacement of the optic nerves was not necessary to obtain a favorable visual outcome and sometimes led to an unfavorable visual outcome.

Conclusions:

In this study, surgery often improved vision, especially in patients with preoperative binocular visual dysfunction. But patients indicated that the effect on their ability to perform ADL was more modest. Moreover, 17% of patients with preoperative monocular visual dysfunction lost vision in the only affected eye, often to a considerable degree. In those patients, surgery would be justified primarily to relieve the concern of having a large brain tumor and to prevent tumor growth. Preoperative ophthalmic and imaging features poorly predicted visual outcomes. Favorable visual outcomes occurred without aggressive surgical debulking of the tumors.
The Effect of Optic Nerve Sheath Fenestration on Intraocular Pressure in Patients With Idiopathic Intracranial Hypertension
Authors: Mullen Martin , Scofield-Kaplan Stacy M. , Ford William C. , Mancini Ronald
Published: April 2021

Background:

To evaluate the change in intraocular pressure (IOP) in patients with idiopathic intracranial hypertension (IIH) who underwent optic nerve sheath fenestration (ONSF) and to determine if radiographic evidence of posterior scleral or globe indentation influenced IOP.

Methods:

This is a retrospective analysis of IOP in IIH patients who underwent ONSF. The study included all patients from September 2010 to March 2018 operated on by a single surgeon (R.M.). IOPs preoperatively and postoperatively were recorded along with the acetazolamide dosage and whether there was evidence of posterior scleral or globe indentation on preoperative MRI.

Results:

A total of 29 patients (35 eyes) with IIH underwent ONSF. The average reduction in IOP among all patients was 1.24 mm Hg (P = 0.0218), but this increased to 2.69 mm Hg (P = 0.004) in patients who were maintained on the same dosage of acetazolamide in the preoperative and postoperative period. Furthermore, the reduction in IOP in those with posterior scleral or globe indentation was 2.5 mm Hg (P = 0.0095). When the perioperative period was evaluated, the mean decrease in IOP was 1.83 mm Hg (P = 0.0217).

Conclusions:

Reducing the cerebral spinal fluid pressure (CSFP) at the level of the intraorbital optic nerve through an ONSF can slightly reduce the IOP. In those with evidence of posterior globe or scleral indentation/flattening, the reduction in IOP was higher, which supports the theory that CSF pressure indents the globe and leads to an increase in IOP. Although these changes in IOP are small, this study provides further evidence for a connection between IOP and CSFP.
Utility of Ultrasound and Optical Coherence Tomography in Differentiating Between Papilledema and Pseudopapilledema in Children
Authors: Farazdaghi Marybeth K. , Trimboli-Heidler Carmelina , Liu Grant T. , Garcia Arielle , Ying Gui-Shuang , Avery Robert A.
Published: April 2021

Background:

Differentiating between papilledema and pseudopapilledema in children presenting with mild-to-moderate optic nerve head elevation is challenging. This study sought to determine which B-scan ultrasonography (BSUS) and optical coherence tomography (OCT) features, individually or in combination, are best able to differentiate between papilledema and pseudopapilledema in children.

Methods:

Children presenting with optic nerve head elevation of unknown etiology were eligible if they underwent BSUS and OCT performed by the same investigator. The absolute optic nerve sheath diameter (in millimeter) along with the presence/absence of a hyperreflective nodule(s) at the optic nerve head (indicative of druse) from BSUS was determined. The average circumpapillary retinal nerve fiber layer (cpRNFL), diameter of Bruch membrane opening, maximum papillary height, and the presence/absence of hyper-/hyporeflective lesions at the optic nerve head were calculated. Sensitivity and specificity were calculated to evaluate which BSUS and OCT imaging features, individually and in combination, accurately classified children as having papilledema vs pseudopapilledema.

Results:

One hundred eighty-one eyes from 94 children (mean age, 11.0 years; range, 3.2–17.9) were included; 36 eyes with papilledema and 145 eyes with pseudopapilledema. Among BSUS features, optic nerve sheath widening (>4.5 mm) demonstrated the best sensitivity (86%; 95% confidence interval [CI], 64%–96%) and specificity (88%; 95% CI, 79%–94%) for papilledema. Among OCT measures, cpRNFL thickness of ≥140 µm demonstrated the best sensitivity (83%; 95% CI, 66%–93%) and specificity (76%; 95% CI, 66%–84%) to identify papilledema. The presence of both optic nerve sheath widening (>4.5 mm) and cpRNFL thickness of ≥140 µm reduced the sensitivity (72%; 95% CI, 52%–86%) but increased specificity (95%; 95% CI, 88%–98%).

Conclusion:

BSUS (optic nerve sheath widening [>4.5 mm]) and OCT (cpRNFL thickness ≥140 µm), individually and collectively, have good diagnostic accuracy for differentiating between papilledema and pseudopapilledema. The presence of druse does not exclude the diagnosis of papilledema.
Protective effect of acute splenic irradiation in rats with traumatic brain injury
Authors: Huang Xiaofei , Lu Yuanlan , Li Lie , Sun Tianjing , Jiang Xuheng , Li Mo , Zhang Tianxi , Yu Anyong
Published: April 2021

Objective

To explore the protective effect of acute splenic irradiation against traumatic brain injury (TBI) in rats.

Methods

A rat model of TBI was established according to Feeney’s method. Splenic irradiation was performed by the reverse intensity-modulated radiation therapy (IMRT) source-axis distance (SAD) irradiation technique. Rat brain tissue samples were collected, the water content of the rat brain tissue was determined and the abundance of microglia was detected by immunofluorescence. Spleens were collected to measure the spleen index. Lung, liver, small intestine and kidney tissues were taken for hematoxylin and eosin staining to observe whether there was radiation-induced pathological damage. Peripheral blood was collected to detect tuftsin and the inflammatory factors IL-6 and IL-10.

Results

Compared with the nonirradiated TBI rat group, the 4-h spleen irradiation TBI rat group showed (1) increased behavioral scores at 3 days after TBI (P 
< 0.05), (2) reduced water content of the ipsilateral hemisphere at 3 days after TBI, (3) reduced spleen index at 3 and 7 days after TBI, (4) reduced number of microglia cells infiltrating around the lesion at 7 days after TBI, (5) reduced IL-6 levels at 3 days after TBI, (6) increased IL-10 levels at 3 and 5days after TBI and (7) Compared with the nonirradiated TBI rat group, the 8-h spleen irradiation TBI rat group showed reduced tuftsin levels at 3 and 7days after TBI.

Conclusions

Acute splenic irradiation had a protective effect in rats with TBI.
Time variation in the probability of failing to detect a case of polymerase chain reaction testing for SARS-CoV-2 as estimated from a viral dynamics model
Authors: Ejima Keisuke , Kim Kwang Su , Iwanami Shoya , Fujita Yasuhisa , Li Ming , Zoh Roger S. , Aihara Kazuyuki , Miyazaki Taiga , Wakita Takaji , Iwami Shingo
Published: April 2021

Viral tests including polymerase chain reaction (PCR) tests are recommended to diagnose COVID-19 infection during the acute phase of infection. A test should have high sensitivity; however, the sensitivity of the PCR test is highly influenced by viral load, which changes over time. Because it is difficult to collect data before the onset of symptoms, the current literature on the sensitivity of the PCR test before symptom onset is limited. In this study, we used a viral dynamics model to track the probability of failing to detect a case of PCR testing over time, including the presymptomatic period. The model was parametrized by using longitudinal viral load data collected from 30 hospitalized patients. The probability of failing to detect a case decreased toward symptom onset, and the lowest probability was observed 2 days after symptom onset and increased afterwards. The probability on the day of symptom onset was 1.0% (95% CI: 0.5 to 1.9) and that 2 days before symptom onset was 60.2% (95% CI: 57.1 to 63.2). Our study suggests that the diagnosis of COVID-19 by PCR testing should be done carefully, especially when the test is performed before or way after symptom onset. Further study is needed of patient groups with potentially different viral dynamics, such as asymptomatic cases.
A functional topography within the cholinergic basal forebrain for encoding sensory cues and behavioral reinforcement outcomes
Authors: Robert Blaise , Kimchi Eyal Y. , Watanabe Yurika , Chakoma Tatenda , Jing Miao , Li Yulong , Polley Daniel B.
Published: April 2021

Basal forebrain cholinergic neurons (BFCNs) project throughout the cortex to regulate arousal, stimulus salience, plasticity, and learning. Although often treated as a monolithic structure, the basal forebrain features distinct connectivity along its anteroposterior axis that could impart regional differences in BFCN processing. Here, we performed simultaneous bulk calcium imaging from anterior and posterior BFCNs over a one-month period of variable reinforcement learning in mice. BFCNs in both regions showed equivalently weak responses to unconditioned visual stimuli and anticipated rewards. Anterior BFCNs in the horizontal limb of the diagonal band were more responsive to reward omission, more accurately classified behavioral outcomes, and more closely tracked fluctuations in pupil-indexed global brain state. Posterior BFCNs in globus pallidus and substantia innominata were more responsive to unconditioned auditory stimuli, orofacial movements, aversive reinforcement, and showed robust associative plasticity for punishment-predicting cues. These results identify a functional topography that diversifies cholinergic modulatory signals broadcast to downstream brain regions.
Time-oriented attention improves accuracy in a paced finger tapping task
Authors: Versaci Leonardo , Laje Rodrigo
Published: April 2021

Finger tapping is a task widely used in a variety of experimental paradigms, in particular to understand sensorimotor synchronization and time processing in the range of hundreds of milliseconds (millisecond timing). Normally, subjects don’t receive any instruction about what to attend to and the results are seldom interpreted taking into account the possible effects of attention. In this work we show that attention can be oriented to the purely temporal aspects of a paced finger tapping task and that it affects performance. Specifically, time-oriented attention improves the accuracy in paced finger tapping and it also increases the resynchronization efficiency after a period perturbation. We use two markers of the attention level: auditory ERPs and subjective report of the mental workload. In addition, we propose a novel algorithm to separate the auditory, stimulus-related components from the somatosensory, response-related ones, which are naturally overlapped in the recorded EEG.
Integrating unmatched scRNA-seq and scATAC-seq data and learning cross-modality relationship simultaneously
Authors: Zhang Ziqi , Yang Chengkai , Zhang Xiuwei
Published: April 2021

It is a challenging task to integrate scRNA-seq and scATAC-seq data obtained from different batches. Existing methods tend to use a pre-defined gene activity matrix (GAM) to convert the scATAC-seq data into scRNA-seq data. The pre-defined GAM is often of low quality and does not reflect the dataset-specific relationship between the two data modalities. We propose scDART (singlecellDeep learning model forATAC-seq andRNA-seqTrajectory), a deep learning framework that integrates scRNA-seq and scATAC-seq data and learns cross-modalities relationships simultaneously. Specifically, the design of scDART allows it to preserve cell trajectories in continuous cell populations and can be applied to trajectory inference on integrated data.
The physiological basis for the computation of direction selectivity in theDrosophilaOFF pathway
Authors: Ramos-Traslosheros Giordano , Silies Marion
Published: April 2021

InDrosophila, direction-selective neurons implement a mechanism of motion computation similar to cortical neurons, using contrast-opponent receptive fields with ON and OFF subunits. It is not clear how the presynaptic circuitry of direction-selective neurons in the OFF pathway supports this computation, because all major inputs are OFF-rectified neurons. Here, we reveal the biological substrate for motion computation in the OFF pathway. Three interneurons, Tm2, Tm9 and CT1, also provide information about ON stimuli to the OFF direction-selective neuron T5 across its receptive field, supporting a contrast-opponent receptive field organization. Consistent with its prominent role in motion detection, variability in Tm9 receptive field properties is passed on to T5, and calcium decrements in Tm9 in response to ON stimuli are maintained across behavioral states, while spatial tuning is sharpened by active behavior. Together, our work shows how a key neuronal computation is implemented by its constituent neuronal circuit elements to ensure direction selectivity.
Adipose gene expression profiles reveal novel insights into the adaptation of northern Eurasian semi-domestic reindeer (Rangifer tarandus)
Authors: Weldenegodguad Melak , Pokharel Kisun , Niiranen Laura , Soppela Päivi , Ammosov Innokentyi , Honkatukia Mervi , Lindeberg Heli , Peippo Jaana , Reilas Tiina , Mazzullo Nuccio , Mäkelä Kari A. , Nyman Tommi , Tervahauta Arja , Herzig Karl-Heinz , Stammler Florian , Kantanen Juha
Published: April 2021

Reindeer (Rangifer tarandus) are semi-domesticated animals adapted to the challenging arctic conditions of northern Eurasia. Adipose tissues play a crucial role in animals living in northern environments by altering gene expression in their tissues to regulate energy homeostasis and thermogenic activity. Here, we performed transcriptome profiling by RNA sequencing of adipose tissues from three different anatomical depots: metacarpal (bone marrow), perirenal, and prescapular fat in Finnish and Even reindeer (in Sakha) during two seasonal time points (spring and winter). On average 36.5 million pair-ended clean reads were obtained for each sample, and a total of 16,362 genes were expressed in our data. Gene expression profiles in metacarpal tissue were distinct and clustered separately from perirenal and prescapular adipose tissues. Notably, metacarpal adipose tissue appeared to have a significant role in the regulation of the energy metabolism of reindeer in spring when their nutritional condition is poor after winter. During spring, when the animals are in less optimal condition, genes associated with the immune system (e.g.,CCL2,CCL11,CXCL14,IGSF3,IGHM,IGLC7,IGKC,JCHAIN,andIGSF10) were upregulated in the perirenal and prescapular adipose tissue, while genes involved in energy metabolism (e.g.,ACOT2,APOA1,ANGPTL1,ANGPTL8,ELOVL7,MSMO1,PFKFB1, andST3GAL6) were upregulated in metacarpal tissue. Even reindeer harboured relatively fewer significantly differentially expressed genes than Finnish reindeer, irrespective of the season, possibly owing to climatic and management differences. Moreover, blood and tissue parameters reflecting general physiological and metabolic status showed less seasonal variation in Even reindeer than in Finnish reindeer. This study identified adipose candidate genes potentially involved in immune response, fat deposition, energy metabolism, development, cell growth, and organogenesis. Taken together, this study provides new information on the mechanisms by which reindeer adapt to less optimal arctic conditions.
Ultra-rare constrained missense variants in the epilepsies: Shared and specific enrichment patterns in neuronal gene-sets
Authors: Koko Mahmoud , Krause Roland , Sander Thomas , Bobbili Dheeraj Reddy , Nothnagel Michael , May Patrick , Lerche Holger ,   Epi25 Collaborative
Published: April 2021

Background

Burden analysis in epilepsy has shown an excess of deleterious ultra-rare variants (URVs) in few gene-sets, such as known epilepsy genes, constrained genes, ion channel or GABAAreceptor genes. We set out to investigate the burden of URVs in a comprehensive range of gene-sets presumed to be implicated in epileptogenesis.

Methods

We investigated several constraint and conservation-based strategies to study whole exome sequencing data from European individuals with developmental and epileptic encephalopathies (DEE,n= 1,003), genetic generalized epilepsy (GGE,n= 3,064), and non-acquired focal epilepsy (NAFE,n= 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. The burden of 12 non-synonymous URVs types in 92 gene-sets was compared between epilepsy cases (DDE, GGE, NAFE) and controls using logistic regression analysis.

Results

Burden analysis of brain-expressed genes revealed an excess of different URVs types in all three epilepsy categories which was largest for missense variants in highly constrained sites (constrained missense variants). The URVs burden was prominent in neuron-specific, synaptic and developmental genes as well as genes encoding ion channels and receptors, and it was generally higher for DEE and GGE compared to NAFE. The patterns of URVs burden in gene-sets expressed in inhibitory vs. excitatory neurons or receptors suggested a high burden in both groups in DEE but a differential involvement of inhibitory genes in GGE, while excitatory genes were predominantly affected in NAFE. Top ranking susceptibility genes from a recent genome-wide association study (GWAS) of generalized and focal epilepsies displayed a higher URVs burden in constrained coding regions in GGE and NAFE, respectively.

Conclusions

Using exome-based gene-set burden analysis, we demonstrate that missense URVs affecting mainly constrained sites are enriched in neuronal genes in both common and rare severe epilepsy syndromes. Our results indicate a differential impact of these URVs in genes expressed in inhibitory vs. excitatory neurons and receptors in generalized vs. focal epilepsies. The excess of URVs in top-ranking GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies.
Food web aggregation: effects on key positions
Authors: Giacomuzzo Emanuele , Jordán Ferenc
Published: April 2021

Providing standard definitions of what should be considered as a node in food webs is still an unsolved problem. Especially for comparative and predictive food web modelling, a more systematic understanding is needed for the effects of trophic aggregation procedures. Aggregation is unavoidable during data management. Therefore, it is crucial to know whether food web properties are conserved during this process.

Here, we study how different aggregation methods change the positional importance of species in food webs. In particular, we investigated the effects of various aggregation algorithms on 24 indices of importance. Our work was carried out on 76 aquatic food webs coming from the Ecopath with Ecosim database (EcoBase). We considered six main types of aggregation, according to the way that the nodes were clustered. These were (i) hierarchical clustering based on the Jaccard index, (ii) hierarchical clustering based on the regular equivalence index (REGE), (iii) maximisation of directed modularity, (iv) maximisation of modularity according to modules in which species fed on the same preys, (v) maximisation of modularity according to modules in which species are fed upon by the same predators, and (vi) clustering through the group model.

Hierarchical clustering based on the Jaccard index and REGE index outperformed the other four methods on maintaining the relative importance of species for all the indices of importance (except for the contrastatus index (s′) and betweenness centrality (BC)). The choice between these two methods should follow our research question and the importance index we are interested in studying. The other four aggregation methods change more the centrality of species, especially the one based on maximising directed modularity. When using these aggregation algorithms, one has to keep in mind that the network will not only be smaller but also provides different information.
Single-molecule imaging of IQGAP1 regulating actin filament dynamics in real time
Authors: Hoeprich Gregory J. , Shekhar Shashank , Goode Bruce L.
Published: April 2021

IQGAP is a conserved family of actin-binding proteins with essential roles in cell motility, cytokinesis, and cell adhesion, yet it has remained poorly understood how IQGAP proteins directly regulate actin filament dynamics. To close this gap, we used single-molecule and single-filament TIRF microscopy to directly visualize IQGAP regulating actin dynamics in real time. To our knowledge, this is the first study to do so. Our results show that full-length human IQGAP1 forms dimers that stably bind to filament sides and transiently cap barbed ends. These interactions organize actin filaments into thin bundles, suppress barbed end growth, and inhibit filament disassembly. Surprisingly, each activity depends on distinct combinations of IQGAP1 domains and/or dimerization, suggesting that different mechanisms underlie each functional effect on actin. These observations have important implications for how IQGAP functions as a direct actin regulator in vivo, and how it is deployed and regulated in different biological settings.
Network controllability enrichment analysis reveals that SARS-CoV-2 infection tends to target indispensable nodes of a directed human protein-protein interaction network
Authors: Lee Ho-Joon
Published: April 2021

The COVID-19 disease has been a global threat caused by the new coronavirus species, SARS-CoV-2, since early 2020 with an urgent need for therapeutic interventions. In order to provide insight into human proteins targeted by SARS-CoV-2, here we study a directed human protein-protein interaction network (dhPPIN) based on our previous work on network controllability of virus targets. We previously showed that human proteins targeted by viruses tend to be those whose removal in a dhPPIN requires more control of the network dynamics, which were classified as indispensable nodes. In this study we introduce a more comprehensive rank-based enrichment analysis of our previous dhPPIN for SARS-CoV-2 infection and show that SARS-CoV-2 also tends to target indispensable nodes in the dhPPIN using multiple proteomics datasets, supporting validity and generality of controllability analysis of viral infection in humans. Also, we find differential controllability among SARS-CoV-2, SARS-CoV-1, and MERS-CoV from a comparative proteomics study. Moreover, we show functional significance of indispensable nodes by analyzing heterogeneous datasets from a genome-wide CRISPR screening study, a time-course phosphoproteomics study, and a genome-wide association study. Specifically, we identify SARS-CoV-2 ORF3A as most frequently interacting with indispensable proteins in the dhPPIN, which are enriched in TGF-beta signaling and tend to be sources nodes and interact with each other. Finally, we built an integrated network model of ORF3A-interacting indispensable proteins with multiple functional supports to provide hypotheses for experimental validation as well as therapeutic opportunities. Therefore, a sub-network of indispensable proteins targeted by SARS-CoV-2 could serve as a prioritized network of drug targets and a basis for further functional and mechanistic studies from a network controllability perspective.
Production of antibodies in egg whites of chickens
Authors: Vaillant Angel Justiz , Ferrer-Cosme Belkis
Published: April 2021

Background

IgM, which participates in the primary immune response, is the primary antibody in egg whites. There is scant information about the production of antibodies in egg whites. This study describes the preparation of antibodies against bacterial antigens.

Methods

Enzyme-linked immunosorbent assay (ELISA) was used to detect the presence of anti-egg white antibodies. The antibodies were purified using affinity chromatography. Statistical analyses were performed using SPSS version 22. Statistical significance was set at P<0.05.

Results

Large amounts of anti-protein A antibodies were produced in chicken egg whites. The generation of anti-SpA antibodies was demonstrated by affinity chromatography from 9 d post-immunization egg white samples. Inhibition of agglutination was observed in samples containing anti-SpA antibodies, and agglutination at the bottom of the wells was observed in the negative samples.

Conclusion

Anti-protein A antibodies (IgM) were produced in the egg whites of the immunized hens. Bacterial growth in blood agar plates was observed only in specimens plated with egg whites from pre-immunized birds. Protein A-affinity chromatography was helpful for the characterization of anti-protein A antibodies. Inhibition of these antibodies was observedin vitro.
Stabilisation of Antithetic Control via Molecular Buffering
Authors: Hancock Edward J. , Oyarzún Diego A.
Published: April 2021

A key goal in synthetic biology is the construction of molecular circuits that robustly adapt to perturbations. Although many natural systems display perfect adaptation, whereby stationary molecular concentrations are insensitive to perturbations, itsde novoengineering has proven elusive. The discovery of the antithetic control motif was a significant step toward a universal mechanism for engineering perfect adaptation. Antithetic control provides perfect adaptation in a wide range of systems, but it can lead to oscillatory dynamics due to loss of stability, and moreover, it can lose perfect adaptation in fast growing cultures. Here, we introduce an extended antithetic control motif that resolves these limitations. We show that molecular buffering, a widely conserved mechanism for homeostatic control in nature, stabilises oscillations and allows for near-perfect adaptation during rapid growth. We study multiple buffering topologies and compare their performance in terms of their stability and adaptation properties. We illustrate the benefits of our proposed strategy in exemplar models for biofuel production and growth rate control in bacterial cultures. Our results provide an improved circuit for robust control of biomolecular systems.
Deep Mutagenesis of a Transporter for Uptake of a Non-Native Substrate Identifies Conformationally Dynamic Regions
Authors: Ellis Heather J , Chan Matthew , Selvam Balaji , Walter Evan , Devlin Christine A , Szymanski Steven K , Henry Loren Keith , Shukla Diwakar , Procko Erik
Published: April 2021

The serotonin transporter, SERT, catalyzes serotonin reuptake at the synapse to terminate neurotransmission via an alternating access mechanism, and SERT inhibitors are the most widely prescribed antidepressants. Here, deep mutagenesis is used to determine the effects of nearly all amino acid substitutions on human SERT surface expression and transport of the fluorescent substrate APP+, identifying many mutations that enhance APP+ import. Comprehensive simulations of the entire ion-coupled import process reveal that while binding of the native substrate, serotonin, reduces free energy barriers between conformational states to promote SERT dynamics, the conformational free energy landscape in the presence of APP+ instead resembles Na+ bound-SERT, with a higher free energy barrier for transitioning to an inward-facing state. The deep mutational scan for SERT-catalyzed import of APP+ finds mutations that promote the necessary conformational changes that would otherwise be facilitated by the native substrate. Indeed, hundreds of gain-of-function mutations for APP+ import are found along the permeation pathway, most notably mutations that favor the formation of a solvent-exposed intracellular vestibule. The mutagenesis data support the simulated mechanism in which the neurotransmitter and a symported sodium share a common cytosolic exit pathway to achieve coupling. Furthermore, the mutational landscape for SERT surface expression, which likely filters out misfolded sequences, reveals that residues along the permeation pathway are mutationally tolerant, providing plausible evolutionary pathways for changes in transporter properties while maintaining folded structure.
Shared and specific functions of Arfs 1–5 at the Golgi revealed by systematic knockouts
Authors: Pennauer Mirjam , Buczak Katarzyna , Prescianotto-Baschong Cristina , Spiess Martin
Published: April 2021

The ADP-ribosylation factors (Arfs) are small GTPases regulating membrane traffic in the secretory pathway. They are closely related and appear to have overlapping functions, regulators, and effectors. The functional specificity of individual Arfs and the extent of redundancyin vivoare still largely unknown. We addressed these questions by CRISPR/Cas9-mediated genomic deletion of the human class I (Arfs 1 and 3) and class II (Arfs 4 and 5) Arfs, either individually or in combination. Cells lacking individual Arfs or certain combinations were viable with only a slight growth defect when lacking Arf1 or Arf4. However, Arf1 and 4, and Arf4 and 5 could not be deleted simultaneously. Hence, class I Arfs are not essential and Arf4 alone was found to be sufficient for cell viability. Remarkably, two single knockouts produced specific and distinct phenotypes. Upon deletion of Arf1, the Golgi complex was enlarged and recruitment of vesicle coats decreased, confirming a major role of Arf1 in coat formation at the Golgi. Cell lines deleted for Arf4 exhibited secretion of ER resident proteins, indicating a specific defect in coatomer-dependent ER protein retrieval by the KDEL receptors. The knockout cell lines will be a useful tool to study other Arf-dependent processes.