bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Changes in Cognitive Function in a Nationwide Cohort Study of Patients With Lymphoma Treated With Chemotherapy
Authors: Janelsins Michelle C , Mohamed Mostafa , Peppone Luke J , Magnuson Allison , Belcher Elizabeth K , Melnik Marianne , Dakhil Shaker , Geer Jodi , Kamen Charles , Minasian Lori , Reagan Patrick M , Mohile Supriya G , Morrow Gary R , Ahles Tim A , Heckler Charles E
Published: July 2021

Background

Cancer-related cognitive decline (CRCD) is an important clinical problem, but limited research exists on assessment of cognitive function in patients with lymphoma.

Methods

The overall objective of this nationwide, prospective, observational study conducted in the National Cancer Institute Community Clinical Oncology Research Program (NCORP) was to assess changes in memory, attention, and executive function in patients with lymphoma from pre- (A1) to postchemotherapy (A2) and to 6 months postchemotherapy (A3). Individuals without cancer served as noncancer controls, paired to patients by age and sex, and assessed at the same time-equivalent points. Longitudinal linear mixed models (LMM) including A1, A2, and A3 and adjusting for age, education, race, sex, cognitive reserve score, baseline anxiety, and depressive symptoms were fit. We assessed changes in patients compared with control participants without cancer and assessed differences in cognitive function in those patients with Hodgkin vs non-Hodgkin disease and by disease subtype. All statistical tests were 2-sided.

Results

Patients with lymphoma (n = 248) and participants without cancer serving as controls (n = 212) were recruited from 19 NCORP sites. From pre- to postchemotherapy and from prechemotherapy to 6 months follow-up, patients reported more cognitive problems over time compared with controls (Functional Assessment of Cancer-Therapy-Cognitive Function [FACT-Cog] perceived cognitive impairment effect size (ES) = 0.83 and 0.84 for A1 to A2 and A1 to A3, respectively; P < .001; single-item cognitive symptoms ES range = 0.55 to 0.70 inclusive of A1 to A2 and A1 to A3; P < .001); the complaints were more pronounced in women with lymphoma compared with men with lymphoma (FACT-Cog Perceived Cognitive Impairment (PCI) score group-by-time-by-sex interaction, P = .007). Patients with lymphoma also performed statistically significantly less well on tests of verbal memory and delayed recall, attention and executive function, and telephone-based category fluency.

Conclusion

Patients with lymphoma experience worse patient-reported and objectively assessed cognitive function from prechemotherapy to 6-month follow-up compared with age- and sex-paired controls without cancer assessed at similar time intervals.
Consequentialism and the Responsibility of Children: A Forward-Looking Distinction between the Responsibility of Children and Adults
Authors: Brandenburg Daphne
Published: July 2021

In this paper I provide a forward-looking account of the difference between the responsibility of children and the responsibility of adults. I do so by means of criticizing agency-cultivation accounts of responsibility. According to these accounts, the justification for holding a person to a norm is the cultivation of their moral agency, and children are, just like adults, considered responsible to the extent that they can have their moral agency cultivated in this manner. Like many forward-looking accounts, these accounts claim that the purpose of holding adults to norms is similar to the purpose of holding children to norms. I argue that the justifications for holding adults to norms are different because of the particular ways in which adults can be in moral disagreement with one another, and the consequences that this has. Moral disagreement is relevant to consequentialist accounts because it impacts on whether and how we can secure beneficial outcomes via holding someone to a norm. One of the upshots of this analysis is that the forward-looking justification for holding adults to norms is qualitatively different from how and why we should hold children to norms.
Y6 and its derivatives: molecular design and physical mechanism
Authors: Wei Qingya , Yuan Jun , Yi Yuanping , Zhang Chunfeng , Zou Yingping
Published: July 2021

Y6 and its derivatives have advanced the efficiency of organic solar cells to 15%-18%. This perspective reveals the device and photo physics features of Y-series based devices and proposed some guidelines for future molecular design.
Predictors of Readmission Following Discharge of Patients With Gram-Negative Bacteremia: A Retrospective Cohort Study
Authors: Porat Yanay , Nashashibi Jeries , Poran Itamar , Paul Mical
Published: July 2021

Background

Short-term readmission is an important outcome reflecting the poor trajectory of sepsis survivors. The aim of this study was to identify the major risk factors for 30-day readmission among patients with gram-negative bacteremia.

Methods

This was a retrospective cohort study including all consecutive adults hospitalized in the medical departments in a referral hospital in Israel with gram-negative bacteremia between 2011 and 2020, who were discharged alive. Predictors for 30-day readmission were investigated, considering death after discharge as a competing event. Cephalosporin resistance was our predictor of interest. Subdistribution hazard ratios (HRs) of the cumulative incidence function were investigated using the Fine and Gray multivariable competing-risk regression model. The prediction models were cross-validated using the k-fold method.

Results

Among 2196 patients surviving hospitalization with gram-negative bacteremia, the mean age was 70 ± 16 years and 432 (19.6%) were readmitted within 30 days. Variables associated with readmission hazards were Arab ethnicity, active malignancy, conditions requiring immunosuppression, anxiolytics or hypnotics, anticoagulant or antiplatelet therapy, discharge with a nasogastric tube, higher predischarge heart rate, duration of antibiotic therapy during hospitalization, and bacteremia caused by cephalosporin-resistant bacteria (HR, 1.23 [95% confidence interval {CI}, .99–1.52]). The area under the receiver operating characteristic curve for this model was 75.5% (95% CI, 71.3%–79.1%). In secondary models, cephalosporin resistance, inappropriate empirical antibiotic treatment, and lower predischarge albumin were significantly associated with readmission.

Conclusions

Thirty-day readmissions among patients with gram-negative bacteremia surviving the index admission were high. Readmission was related to comorbidities and infections caused by multidrug-resistant infections.

Main point: Among 2196 adults surviving hospitalization with gram-negative bacteremia, 432 (19.6%) were rehospitalized within 30 days. Comorbidities, inappropriate empirical antibiotic treatment, bacteremia caused by cephalosporin-resistant bacteria, predischarge heart rate, and albumin were associated with readmissions.
Can Shorts Predict Returns? A Global Perspective
Authors: Boehmer Ekkehart , Huszár Zsuzsa R , Wang Yanchu , Zhang Xiaoyan , Zhang Xinran
Published: July 2021

Using multiple short-sale measures, we examine the predictive power of short sales for future stock returns in 38 countries from July 2006 to December 2014. We find that the days-to-cover ratio and the utilization ratio measures have the most robust predictive power for future stock returns in the global capital market. Our results display significant cross-country and cross-firm differences in the predictive power of alternative short-sale measures. The predictive power of shorts is stronger in countries with nonprohibitive short sale regulations and for stocks with relatively low liquidity, high shorting fees, and low price efficiency.
Neutrophil extracellular traps in giant cell arteritis biopsies: presentation, localization and co-expression with inflammatory cytokines
Authors: Palamidas Dimitris Anastasios , Argyropoulou Ourania D , Georgantzoglou Natalia , Karatza Elli , Xingi Evangelia , Kapsogeorgou Efstathia K , Anagnostopoulos Constantinos D , Lazaris Andreas C , Ritis Konstantinos , Goules Andreas V , Kambas Konstantinos , Tzioufas Athanasios G
Published: July 2021

Objectives

To explore the presence of neutrophil extracellular traps (NETs) in inflamed temporal artery biopsies (TABs) of patients with GCA.

Methods

Ten patients with GCA [five with limited and five with associated generalized vascular involvement, as defined by 18F-fluorodeoxyglucose PET with CT (PET/CT)] and eight with PMR were studied. The presence, location, quantitation and decoration of NETs with IL-6, IL-1β and IL-17A were assessed in TABs at the time of disease diagnosis by tissue immunofluorescence and confocal microscopy. Paired serum levels of IL-6 and IL-17A were also evaluated in all patients.

Results

All temporal artery biopsies from GCA, but not PMR, patients had NETs located mainly in the adventitia, adjacent to the vasa vasorum. NETs decorated with IL-6 were present in 8/10 TABs of GCA patients, of whom 5 were PET/CT(+) and 3 PET/CT(–) patients. IL-17A(+) NETs were observed in all GCA patients. IL-1β(+) NETs were not detected in any GCA patient. No relation was found between serum IL-6 and IL-17A levels and NETs containing IL-6 and/or IL-17A.

Conclusions

NETs bearing pro-inflammatory cytokines are present in inflamed GCA-TABs. Future studies with a larger number of patients from different centres will show whether the findings regarding neutrophils/NETs in the TAB are consistent and disclose their clinical impact.
Acclimation of hydraulic and morphological traits to water deficit delays hydraulic failure during simulated drought in poplar
Authors: Lemaire Cédric , Blackman Chris J , Cochard Hervé , Menezes-Silva Paulo Eduardo , Torres-Ruiz José M , Herbette Stéphane
Published: July 2021

The capacity of trees to tolerate and survive increasing drought conditions in situ will depend in part on their ability to acclimate (via phenotypic plasticity) key hydraulic and morphological traits that increase drought tolerance and delay the onset of drought-induced hydraulic failure. However, the effect of water-deficit acclimation in key traits that determine time to hydraulic failure (THF) during extreme drought remains largely untested. We measured key hydraulic and morphological traits in saplings of a hybrid poplar grown under well-watered and water-limited conditions. The time for plants to dry-down to critical levels of water stress (90% loss of stem hydraulic conductance), as well as the relative contribution of drought acclimation in each trait to THF, was simulated using a soil–plant hydraulic model (SurEau). Compared with controls, water-limited plants exhibited significantly lower stem hydraulic vulnerability (P50stem), stomatal conductance and total canopy leaf area (LA). Taken together, adjustments in these and other traits resulted in longer modelled THF in water-limited (~160 h) compared with well-watered plants (~50 h), representing an increase of more than 200%. Sensitivity analysis revealed that adjustment in P50stem and LA contributed the most to longer THF in water-limited plants. We observed a high degree of trait plasticity in poplar saplings in response to water-deficit growth conditions, with decreases in stem hydraulic vulnerability and leaf area playing a key role in delaying the onset of hydraulic failure during a simulated drought event. These findings suggest that understanding the capacity of plants to acclimate to antecedent growth conditions will enable better predictions of plant survivorship during future drought.
The seroprevalence of severe acute respiratory syndrome coronavirus 2 in Delhi, India: a repeated population-based seroepidemiological study
Authors: Sharma Nandini , Sharma Pragya , Basu Saurav , Saxena Sonal , Chawla Rohit , Dushyant Kumar , Mundeja Nutan , Marak Zeasaly , Singh Sanjay , Singh Gautam , Rustagi Ruchir
Published: July 2021

Background

Three rounds of a repeated cross-sectional serosurvey to estimate the change in seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were conducted from August to October 2020 in the state of Delhi, India, in the general population ≥5 y of age.

Methods

The selection of participants was through a multistage sampling design from all 11 districts and 280 wards of the city-state, with multistage allocation proportional to population size. The blood samples were screened using immunoglobulin G (IgG) enzyme-linked immunosorbent assay kits.

Results

We observed a total of 4267 (N=150 46), 4311 (N=17 409) and 3829 (N=15 015) positive tests indicative of the presence of IgG antibody to SARS-CoV-2 during the August, September and October 2020 serosurvey rounds, respectively. The adjusted seroprevalence declined from 28.39% (95% confidence interval [CI] 27.65 to 29.14) in August to 24.08% (95% CI 23.43 to 24.74) in September and 24.71% (95% CI 24.01 to 25.42) in October. On adjusted analysis, participants with lower per capita income, living in slums or overcrowded households and those with diabetes comorbidity had significantly higher statistical odds of having antibody positivity (p<0.01).

Conclusions

Nearly one in four residents in Delhi, India ≥5 y of age had the SARS-CoV-2 infection during August–October 2020.
Ontogeny as a way to understand morphology of nasal capsule structures in Pipidae, with focus onPipa arrabali(Lissamphibia: Anura)
Authors: Araújo O G S , Pugener L A , Haddad C F B , Da Silva H R
Published: July 2021

After more than one-hundred years of studies, there is still no consensus regarding the names for the nasal elements in Pipidae and their correspondence to that of other frogs. Names vary depending on authors’ preferences for an explanatory process associated with the observed state of the structure. Some of the names indicate absence, while others indicate fusion. As naming morphological structures relates to some sort of consensus regarding systematics’ knowledge, one would expect results of the two activities to go hand-in-hand. Within the monophyletic Pipidae, one would expect that the names of structures would be all settled. However, the situation is the contrary. Our efforts to pursue such a research and properly name the involved structures resulted in a deeper understanding of the evolution within the taxa involved. Herein we present the results of the study of embryos and juveniles of P. arrabali; based on which we offer additional evidence for the proper naming of the involved elements of the nasal region. Furthermore, using key structures as topographical markers, and by comparing our evaluation to those presented by previous researchers, we have sorted out the compound nature of some key structures and present a proper naming for the morphology investigated.
Quantifying the Limitations of Clinical and Technology-based Flap Monitoring Strategies using a Systematic Thematic Analysis
Authors: Kwasnicki Richard M. , Noakes Alex J. , Banhidy Norbert , Hettiaratchy Shehan
Published: July 2021

Background:

Multiple techniques exist to monitor free flap viability postoperatively, varying with practical and personal preference, yet the limitations of each technique remain unquantified. This systematic review aims to identify the most commonly reported limitations of these techniques in clinical practice.

Methods:

A systematic review was conducted according to PRISMA guidelines using MEDLINE, EMBASE, and Web of Science with search criteria for postoperative free flap monitoring techniques. Search results were independently screened using defined criteria by two authors and a senior clinician. Limitations of the techniques found in the discussion section of eligible articles were recorded and categorized using thematic analysis.

Results:

A total of 4699 records were identified. In total, 2210 articles met the eligibility criteria and were subsequently reviewed, with 195 papers included in the final analysis. The most frequently reported limitations of clinical monitoring were interpretation requiring expertise (25% of related papers), unsuitability for buried flaps (21%), and lack of quantitative/objective values (19%). For noninvasive technologies, the limitations were lack of quantitative/objective values (21%), cost (16%), and interpretation requiring expertise (13%). For invasive technologies, the limitations were application requiring expertise (25%), equipment design and malfunction (13%), and cost (13%).

Conclusions:

This is the first systematic review to quantify the limitations of different flap monitoring techniques, as reported in the literature. This information may enhance the choice in monitoring strategy for a reconstructive service, and inform the development and refinement of new flap monitoring technologies.
An Alternative Dermal Template for Reconstruction of Complex Upper Extremity Wounds
Authors: Wu-Fienberg Yuewei , Wu Shannon S. , Gatherwright James , Chepla Kyle J.
Published: July 2021

The management of upper extremity soft-tissue defects with full-thickness skin loss and denuded tendon and/or bone traditionally requires vascularized tissue reconstruction. Herein, we present patient outcomes utilizing Novosorb Bio-degradable Temporizing Matrix (PolyNovo, Wilmington, Del.), a novel bilaminar dermal regenerative template, followed by skin grafting, for reconstruction of complex upper extremity injuries with exposed tendon and/or bone. We retrospectively reviewed all patients treated at our Level I trauma center with upper extremity trauma and exposed tendon and/or bone who had application of Novosorb Bio-degradable Temporizing Matrix over a 1-year period. At the time of surgery, all nonviable tissue was debrided, and the product was applied according to the manufacturer’s instructions. If required, split thickness skin grafting was performed once neodermis appeared perfused, or after the sealing layer delaminated spontaneously. Six patients (four men, two women) with an average age of 49.8 (35–60) years were included in the study. Average defect size measured 97 cm2 (10–440). Average time to complete healing was 45 days (27–57). Three patients reepithelialized spontaneously and did not require grafting; average defect size in these patients was 26 cm2 (10–42). There were no infections and no loss of the dermal matrix or skin graft, when performed. All patients healed without complication after grafting and did not require further surgical treatment. Therefore, we contend that Novosorb BTM is a dermal regenerative template that shows potential as an alternative option to flap reconstruction in select patients after upper extremity trauma and soft-tissue defects with exposed tendon and/or bone. Further studies will be required to refine indications and evaluate outcomes.
Reconstruction of Chronic Wounds Secondary to Injectable Drug Use with a Biodegradable Temporizing Matrix
Authors: Cheng Christopher , Kwiecien Grzegorz J. , Rowe David J. , Gatherwright James R. , Chepla Kyle J.
Published: July 2021

Injectable drug use in the upper extremity often leads to chronic wounds complicated by osteomyelitis. Conventional reconstructive options are often not feasible and/or are contraindicated in this patient population. We have started using a synthetic, biodegradable temporizing matrix (BTM) for the treatment of these patients. We hypothesize that BTM is a safe, low-risk, and low-morbidity alternative reconstructive option. We report outcomes after staged debridement and BTM application followed by split-thickness skin grafting for two patients with large, chronic bilateral forearm wounds with concomitant osteomyelitis confirmed by MRI and biopsy. No acute surgical complications were encountered and at a mean follow-up of 13 months, both patients had maintained stable soft-tissue coverage. Reconstruction using BTM is a novel treatment option that can simplify the reconstruction, reduce donor-site morbidity, and optimize success for patients with chronic wounds resulting from injectable drug use. Initial outcomes are promising; however, further comparative studies are needed to better evaluate long-term outcomes of this technique.
Acute Renal Failure following Novel Subcutaneous Fat Reduction with Injected Ice Slurry
Authors: McMahan Daniel L. , Dehbozorgi Hangameh , Lam Quy N. , Le Calvin , Richardson Justin , Villacres Alexandra , Albaalbaki Fysal
Published: July 2021

A new fat-freezing injection may pose significant health risks. Subcutaneous injection of partially frozen normal saline and glycerol has been shown to significantly reduce adipose tissue. This article reports the first human case and adverse reactions following this new procedure.
Anti-GABA-B receptor encephalitis with small cell lung cancer presenting with septic shock during immunotherapy
Authors: Lv Zi-Yang , Li Xin , Song Tao , Ma Ling-Ran , Xiang Guang-Hong , Chai Zhi-Yong , Liu Jia-Jia , Zhou Gao-Ya , Wang Shan
Published: July 2021

Introduction:

Most patients with anti-γ-aminobutyric acid-B (anti-GABA-B) receptor encephalitis present with cancer and have a poor response to immunotherapy. Moreover, septic shock, a subset of sepsis, is rarely reported in these patients during immunotherapy.

Patient concerns:

A 55-year-old man presented with epileptic seizure and cognitive impairment. He was previously healthy and had no family history of psychiatric disorders but had a history of smoking and emphysema.

Diagnoses:

Combined with the symptoms and antibody testing, anti-GABA-B encephalitis with anti-Hu antibody was diagnosed. During immunotherapy, he presented with septic shock. Further investigations and pathological examination confirmed the diagnosis of small cell lung cancer.

Interventions:

The patient was treated with five days of intravenous immunoglobulin (0.4/kg/d), ten days of methylprednisolone (1.0 g once a day and half the dose every three days), plus ten days of oxycarbazepine (0.3 g b.i.d.) and magnesium valproate (0.25 g b.i.d.). He received nine days of conventional treatment for septic shock in addition to meropenem (1 g intravenously every 8 hours) and etimicin (0.3 g intravenously per day). After that, he received one month of prednisone 30 mg with dose reduction 5 mg every two weeks, oxcarbazepine 0.3 g b.i.d. and valproic acid 0.25 g b.i.d. for antiepileptic treatment, olanzapine 5 mg qd + qn for antipsychotic symptoms.

Outcomes:

He was able to communicate with others normally and also had improved memory and clear thinking. Mini-Mental State Examination and Modified Rankin Scale were 23/30 and 1. At discharge, the titer of anti-GABA-B receptor antibody in serum (1:10) was significantly lower than the titer in serum on the day of admission (1: 100).

Conclusion:

Anti-GABA-B receptor encephalitis patients with cancer can respond well to immunotherapy. Personalized treatment should be considered to avoid complications like septic shock in anti-GABA-B receptor encephalitis with cancer during immunotherapy.
The New Molecules Are Changing the Course of Pediatric Chronically Active Ulcerative Colitis: A Series of Pediatric Cases
Authors: Martín-Masot Rafael , Ortiz Pérez Pilar , Torcuato Rubio Encarnación , Blasco Alonso Javier , Herrador López Marta , Gallego Fernández Carmen , Navas-López Víctor Manuel
Published: July 2021

Chronically active ulcerative colitis (UC) constitutes a challenge in an era where medical therapeutic options have increased while experience with colectomies has decreased. The change in the therapeutic paradigm of the disease means that patients with chronically active UC are being managed waiting to find their therapeutic target. We present 2 cases of children with chronically active UC who did not respond to intravenous steroids nor sequential therapy. A response was obtained with ustekinumab and tofacitinib, 2 drugs widely used in adults but still with little evidence in children. Highlighting the important role of patients and their families helped decision-making, facilitating the work of the medical team. With multidisciplinary management and close follow-up, they have been able to avoid surgery entering complete clinical remission.
Delayed Diagnosis of X-linked Lymphoproliferative Syndrome Type 2 in a 17-year-old Male With Severe Crohn’s Disease and Recurrent Skin Infections
Authors: Zacharias Stephanie A. , Seshadri Priyanka , Hwang Sharon , Baker Laura , Powell Jonathan , Fernando del Rosario J. , Molle-Rios Zarela
Published: July 2021

X-linked lymphoproliferative syndrome type 2 (XLP2) is a rare genetic primary immunodeficiency disease caused by mutations in the XIAP gene that lead to deficiency of the X-linked inhibitor of apoptosis protein. XLP2 is characterized by dysregulated immune responses and can result in an inflammatory bowel disease (IBD)-like phenotype, a form of monogenic IBD. Patients with XLP2 often succumb to fulminant hemophagocytic lymphohistiocytosis or Epstein-Barr virus infections. Hematopoietic stem cell transplantation (HSCT) is currently the only definitive treatment for XLP2. We report an adolescent with a delayed diagnosis of XLP2 in the setting of severe Crohn’s disease diagnosed at age 9 years and recurrent skin infections. He is under evaluation for HSCT. Gastroenterologists must recognize monogenic IBD in patients of all ages with severe disease and signs of an underlying primary immunodeficiency disease. Patients with suspected monogenic IBD should undergo immunologic and genetic analysis at diagnosis to initiate potentially life-saving treatment.
Preface
Authors: Kratochvíl Lukáš , Stöck Matthias
Published: July 2021

This preface introduces the two parts of a theme issue on vertebrate sex chromosome evolution (title below). We invited and edited 22 articles concerning the following main topics (Part 1): sex determination without sex chromosomes and/or governed by epigenetics; origin of sex-determining genes; reasons for differentiation of sex chromosomes and differences in their rates of differentiation as well as (Part 2): co-option of the same linkage groups into sex chromosomes; is differentiation of sex chromosomes a unidirectional pathway?; consequences of differentiated sex chromosomes; differences in differentiation of sex chromosomes under male versus female heterogamety; evolution of sex chromosomes under hybridization and polyploidy.

This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
The timing of genetic degeneration of sex chromosomes
Authors: Charlesworth Deborah
Published: July 2021

Genetic degeneration is an extraordinary feature of sex chromosomes, with the loss of functions of Y-linked genes in species with XY systems, and W-linked genes in ZW systems, eventually affecting almost all genes. Although degeneration is familiar to most biologists, important aspects are not yet well understood, including how quickly a Y or W chromosome can become completely degenerated. I review the current understanding of the time-course of degeneration. Degeneration starts after crossing over between the sex chromosome pair stops, and theoretical models predict an initially fast degeneration rate and a later much slower one. It has become possible to estimate the two quantities that the models suggest are the most important in determining degeneration rates—the size of the sex-linked region, and the time when recombination became suppressed (which can be estimated using Y–X or W–Z sequence divergence). However, quantifying degeneration is still difficult. I review evidence on gene losses (based on coverage analysis) or loss of function (by classifying coding sequences into functional alleles and pseudogenes). I also review evidence about whether small genome regions degenerate, or only large ones, whether selective constraints on the genes in a sex-linked region also strongly affect degeneration rates, and about how long it takes before all (or almost all) genes are lost.

This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.
Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant
Authors: Li Baisheng , Deng Aiping , Li Kuibiao , Hu Yao , Li Zhencui , Xiong Qianling , Liu Zhe , Guo Qianfang , Zou Lirong , Zhang Huan , Zhang Meng , Ouyang Fangzhu , Su Juan , Su Wenzhe , Xu Jing , Lin Huifang , Sun Jing , Peng Jinju , Jiang Huiming , Zhou Pingping , Hu Ting , Luo Min , Zhang Yingtao , Zheng Huanying , Xiao Jianpeng , Liu Tao , Che Rongfei , Zeng Hanri , Zheng Zhonghua , Huang Yushi , Yu Jianxiang , Yi Lina , Wu Jie , Chen Jingdiao , Zhong Haojie , Deng Xiaoling , Kang Min , Pybus Oliver G. , Hall Matthew , Lythgoe Katrina A. , Li Yan , Yuan Jun , He Jianfeng , Lu Jing
Published: July 2021

We report the first local transmission of the SARS-CoV-2 Delta variant in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of the quarantined subjects indicated that the viral loads of Delta infections, when they first become PCR+, were on average ∼1000 times greater compared to A/B lineage infections during initial epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. We performed high-quality sequencing on samples from 126 individuals. Reliable epidemiological data meant that, for 111 transmission events, the donor and recipient cases were known. The estimated transmission bottleneck size was 1-3 virions with most minor intra-host single nucleotide variants (iSNVs) failing to transmit to the recipients. However, transmission heterogeneity of SARS-CoV-2 was also observed. The transmission of minor iSNVs resulted in at least 4 of the 30 substitutions identified in the outbreak, highlighting the contribution of intra-host variants to population level viral diversity during rapid spread. Disease control activities, such as the frequency of population testing, quarantine during pre-symptomatic infection, and level of virus genomic surveillance should be adjusted in order to account for the increasing prevalence of the Delta variant worldwide.
Dataset on the mass spectrometry-based proteomic profiling of mouse embryonic fibroblasts from a wild type and DYT-TOR1A mouse model of dystonia, basally and during stress
Authors: Shroff Kunal , Caffall Zachary F. , Soderblom Erik J. , Waitt Greg , Ho Tricia , Calakos Nicole
Published: July 2021

Here, we present quantitative subcellular compartment-specific proteomic data from wildtype and DYT-TOR1A heterozygous mouse embryonic fibroblasts (MEFs) basally and following thapsigargin treatment [1]. In this experiment, we generated MEFs from wild type and a heterozygous DYT-TOR1A mouse model of dystonia. Subsequently, these MEF cultures were treated with either 1 μM thapsigargin or dimethylsulfoxide vehicle for six hours. Following treatment, the cells were fractionated into nuclear and cytosolic fractions. Liquid chromatography, tandem mass spectrometry (LC/MS/MS)-based proteomic profiling identified 65,056 unique peptides and 4801 unique proteins across all samples. The data presented here provide subcellular compartment-specific proteomic information within a dystonia model system both basally and under cellular stress. These data can inform future experiments focused on studying the function of TorsinA, the protein encoded by TOR1A, and its potential role in nucleocytoplasmic transport and proteostasis. In addition, the information in this article can also inform future mechanistic studies investigating the relationship between DYT-TOR1A dystonia and the cellular stress response to advance understanding of the pathogenesis of dystonia.
Interhemispheric functional connectivity in the primary motor cortex distinguishes between training on a physical and a virtual surgical simulator
Authors: Dutta Anirban , Kamat Anil , Makled Basiel , Norfleet Jack , Intes Xavier , De Suvranu
Published: July 2021

Functional brain connectivity using functional near-infrared spectroscopy (fNIRS) during a pattern cutting (PC) task was investigated in physical and virtual simulators.

14 right-handed novice medical students were recruited and divided into separate cohorts for physical (N=8) and virtual (N=6) PC training. Functional brain connectivity measured were based on wavelet coherence (WCOH) from task-related oxygenated hemoglobin (HBO2) changes from baseline at left and right prefrontal cortex (LPFC, RPFC), left and right primary motor cortex (LPMC, RPMC), and supplementary motor area (SMA). HBO2 changes within the neurovascular frequency band (0.01-0.07Hz) from long-separation channels were used to compute average inter-regional WCOH metrics during the PC task. The coefficient of variation (CoV) of WCOH metrics and PC performance metrics were compared. WCOH metrics from short-separation fNIRS time-series were separately compared.

Partial eta squared effect size (Bonferroni correction) between the physical versus virtual simulator cohorts was found to be highest for LPMC-RPMC connectivity. Also, the percent change in magnitude-squared WCOH metric was statistically (p<0.05) different for LPMC-RPMC connectivity between the physical and the virtual simulator cohorts. Percent change in WCOH metrics from extracerebral sources was not different at the 5% significance level. Also, higher CoV for both LPMC-RPMC magnitude-squared WCOH metric and PC performance metrics were found in physical than a virtual simulator.

We conclude that interhemispheric connectivity of the primary motor cortex is the distinguishing functional brain connectivity feature between the physical versus the virtual simulator cohorts. Brain-behavior relationship based on CoV between the LPMC-RPMC magnitude-squared WCOH metric and the FLS PC performance metric provided novel insights into the neuroergonomics of the physical and virtual simulators that is crucial for validating Virtual Reality technology.
Assessing Reproducibility of High-throughput Experiments in the Case of Missing Data
Authors: Singh Roopali , Zhang Feipeng , Li Qunhua
Published: July 2021

High-throughput experiments are an essential part of modern biological and biomedical research. The outcomes of high-throughput biological experiments often have a lot of missing observations due to signals below detection levels. For example, most single-cell RNA-seq (scRNA-seq) protocols experience high levels of dropout due to the small amount of starting material, leading to a majority of reported expression levels being zero. Though missing data contain information about reproducibility, they are often excluded in the reproducibility assessment, potentially generating misleading assessments.

In this paper, we develop a regression model to assess how the reproducibility of high-throughput experiments is affected by the choices of operational factors (e.g., platform or sequencing depth) when a large number of measurements are missing. Using a latent variable approach, we extend correspondence curve regression (CCR), a recently proposed method for assessing the effects of operational factors to reproducibility, to incorporate missing values. Using simulations, we show that our method is more accurate in detecting differences in reproducibility than existing measures of reproducibility. We illustrate the usefulness of our method using a single-cell RNA-seq dataset collected on HCT116 cells. We compare the reproducibility of different library preparation platforms and study the effect of sequencing depth on reproducibility, thereby determining the cost-effective sequencing depth that is required to achieve sufficient reproducibility.
Inferring the demographic history of tetraploid species from genomic data
Authors: Roux Camille , Vekemans Xavier , Pannell John
Published: July 2021

Genomic patterns of diversity and divergence are impacted by certain life history traits, reproductive systems and demographic history. The latter is characterised by fluctuations in population sizes over time, as well as by temporal patterns of introgression. For a given organism, identifying a demographic history that deviates from the standard neutral model allows a better understanding of its evolution, but also helps to reduce the risk of false positives when screening for molecular targets of natural selection. Tetraploid organisms and beyond have demographic histories that are complicated by the mode of polyploidisation, the mode of inheritance and different scenarios of gene flow between subgenomes and diploid parental species. Here we provide guidelines for experimenters wishing to address these issues through a flexible statistical framework: approximate Bayesian computation (ABC). The emphasis is on the general philosophy of the approach to encourage future users to exploit the enormous flexibility of ABC beyond the limitations imposed by generalist data analysis pipelines.
Evolution of a confluent gut epithelium under cyclic stretching
Authors: Gérémie Lauriane , Ilker Efe , Bernheim-Dennery Moencopi , Cavaniol Charles , Viovy Jean-Louis , Vignjevic Danijela Matic , Joanny Jean-François , Descroix Stéphanie
Published: July 2021

The progress of food in the gastrointestinal (GI) tract is driven by a peristaltic motion generated by the muscle belt surrounding the GI tract. In turn, the response of the intestinal epithelial cells to the peristaltic stresses affects the dynamics of the epithelial structure. In this work, we study the effect of cyclic stretching (0.125 Hz, 10% strain) on the spatial organization of the intestinal epithelium using intestinal cells deposited on a flat elastomeric substrate to mimic the peristaltic motion in vitro. A confluent monolayer of Caco-2 cells is grown on a PDMS chip to probe the morphological and orientational response of the tissue to cyclic stretching. The PDMS chips are either covalently or non-covalently coated with laminin to recapitulate the basement membrane. We observe a significant orientational response where the cells rearrange their long axes perpendicular to the stretching direction for both coating conditions. The experiment is modeled by a vertex model where the cells store elastic energy with varying strain and effectively have a rotational diffusive motion through rearrangements of their shapes. The model also predicts a transition between the perpendicular orientation and orientation at an oblique angle determined by the level of the cell elastic anisotropy. It provides a general framework to study cell response and relaxation dynamics under cyclic stretching across different cell types. We also discuss potential relevance of peristalsis in determining planar cell polarity in 3D architectures.
Scalable full-transcript coverage single cell RNA sequencing with Smart-seq3xpress
Authors: Hagemann-Jensen Michael , Ziegenhain Christoph , Sandberg Rickard
Published: July 2021

Plate-based single-cell RNA-sequencing methods with full-transcript coverage typically excel at sensitivity but are more costly and time-consuming. Here, we miniaturized and streamlined the Smart-seq3 protocol for drastically reduced cost and increased throughput. Applying Smart-seq3xpress to 16,349 human peripheral blood mononuclear cells revealed a highly granular atlas complete with both common and rare cell types whose identification previously relied on additional protein measurements or the integration with a reference atlas.
Structural basis for carbapenamC-alkylation by TokK, a B12-dependent radical SAM enzyme
Authors: Knox Hayley L. , Sinner Erica K. , Townsend Craig A. , Boal Amie K. , Booker Squire J.
Published: July 2021

Cobalamin- or B12-dependent radicalS-adenosylmethionine (SAM) enzymes acting during carbapenem antibiotic biosynthesis carry out radical-mediated methyl transfers that underlie the therapeutic usefulness of these essential medicines. Here we present x-ray crystal structures of TokK, which are representative of this functional class, containing its two metallocofactors and determined in the presence and absence of carbapenam substrate. The structures give the first visualization of a cobalamin-dependent radical SAM methylase that employs the radical mechanism shared by a vast majority of these enzymes. The structures provide insight into the stereochemistry of initial C6 methylation and suggests that substrate positioning governs the rate of each methylation event.

One Sentence Summary

Structural insight into a cobalamin-dependent radical SAM methylase that performs three sequential radical-mediated methylations to install the C6 side chain of a carbapenem antibiotic.
Enhancing Precision in Bioprinting Utilizing Fuzzy Systems
Authors: Sedigh Ashkan , DiPiero Dayna , Shine Kristy M. , Tomlinson Ryan E.
Published: July 2021

Bioprinting facilitates the generation of complex, three-dimensional (3D), cell-based constructs for a variety of applications. Although multiple bioprinting technologies have been developed, extrusion-based systems have become the dominant technology due to the diversity of substrate materials (bioinks) that can be accommodated, either individually or in combination. However, each bioink has unique material properties and extrusion characteristics that limit bioprinting precision, particularly when generating constructs from different bioinks. Here, we aimed to achieve high precision (i.e. repeatability) across samples by generating bioink-specific printing parameters using a systematic approach. We hypothesized that a fuzzy system could be used as a “black box” method to tackle the inherent vagueness and imprecision in 3D bioprinting data and uncover the optimal printing parameters for a specific bioink that would result in high accuracy and precision. Our fuzzy model was used to approximate and quantify the precision and ease of printability for two common bioinks - type I collagen and Pluronic F127, with or without dilution in αMEM culture media. The model consisted of three inputs (pressure, speed, and dilution percent of bioink) and a single output (layer width). Using this system, we introduce the Bioink Precision Index (BPI), a metric that can be used to quantify and compare the precision of any bioink. Here, we show that printing with parameters optimized using BPI increases the precision for collagen (+15%) and Pluronic F127 (+29%) as compared to the manufacturer’s recommended printing parameters.
A dynamic 1/f noise protocol to assess visual attention without biasing perceptual processing
Authors: Hanning Nina M. , Deubel Heiner
Published: July 2021

Psychophysical paradigms measure visual attention via localized test items to which observers must react or whose features have to be discriminated. These items, however, potentially interfere with the intended measurement as they bias observers’ spatial and temporal attention to their location and presentation time. Furthermore, visual sensitivity for conventional test items naturally decreases with retinal eccentricity, which prevents direct comparison of central and peripheral attention assessments. We developed a stimulus that overcomes these limitations. A brief oriented discrimination signal is seamlessly embedded into a continuously changing 1/f noise field, such that observers cannot anticipate potential test locations or times. Using our new protocol, we demonstrate that local orientation discrimination accuracy for 1/f filtered signals is largely independent of retinal eccentricity. Moreover, we show that items present in the visual field indeed shape the distribution of visual attention, suggesting that classical studies investigating the spatiotemporal dynamics of visual attention via localized test items may have obtained a biased measure. We recommend our protocol as an efficient method to evaluate the behavioral and neurophysiological correlates of attentional orienting across space and time.

Significance statement

Where (and when) we pay attention can be experimentally quantified via visual sensitivity: Attending to a certain visual signal results in better detection and feature discrimination performance. This approach is widely used, but poses an unrecognized dilemma: The test signal itself, typically a grating or letter stimulus, biases observers’ perception and expectations – and thus also the attention measurement. We developed a stimulus that manages without test items. The signal to measure attention is seamlessly embedded in a dynamic 1/f noise field, so that neither spatial nor temporal information about signal presentation is conveyed. Unlike with conventional approaches, perception and expectations in this new protocol remain unbiased, and the undistorted spatial and temporal spread of visual attention can be measured.
Effects of Frontoparietal Theta tACS on Verbal Working Memory: Behavioral and Neurophysiological Analysis
Authors: Hu Zhenhong , Samuel Immanuel B.H. , Meyyappan Sreenivasan , Rana Ke Bo Chandni , Ding Mingzhou
Published: July 2021

Left-lateralized frontoparietal theta oscillations are thought to play an important role in verbal working memory. We causally tested this idea by stimulating the frontoparietal theta network at individual theta frequencies (4 to 8 Hz) during verbal working memory and observing the subsequent behavioral and neurophysiological effects. Weak electric currents were delivered via two 4×1 HD electrode arrays centered at F3 and P3. Three stimulation configurations, including in-phase, anti-phase, or sham, were tested on three different days in a cross-over design. On each test day, the subject underwent three experimental sessions: pre-, during- and post-stimulation sessions. In all sessions, the subject performed a Sternberg verbal working memory task with three levels of memory load (load 2, 4 and 6), imposing three levels of cognitive demand. Analyzing behavioral, EEG, and pupillometry data from the post-stimulation sessions, we report three results. First, in-phase stimulation improved task performance only in subjects with higher working memory capacity (WMC) and under higher memory load (load 6). Second, in-phase stimulation enhanced frontoparietal theta synchrony during working memory retention only in subjects with higher WMC under higher memory loads (load 4 and load 6), and the enhanced frontoparietal theta synchronization is mainly driven by enhanced frontal→parietal theta Granger causality. Third, the pupil diameter was not different irrespective of whether the preceding stimulation was in-phase, anti-phase, or sham. These findings suggest that theta tACS effects on verbal working memory were load- and subject-dependent, rooted in tACS-induced changes in frontoparietal network interactions, and not driven by changes in arousal levels.
Targeting the nervous system of the parasitic worm, Haemonchus contortus, with quercetin.
Authors: Goel Vanshita , Chakroborty Neloy Kumar , Sharma Sunidhi , Singla Lachhman Das , Choudhury Diptiman
Published: July 2021

High Prevalence of infection rate, limited choice of drugs, and emerging resistance against these leads to a pressing need for the development of new antihelminthic drugs and drug targets. However, limited understanding of the physiology of worms has delayed the process substantially. Here, for the first time, we are reporting the tissue morphology of Haemonchus contortus, and target its nervous system with quercetin, a naturally occurring flavonoid. Quercetin showed anthelmintic activity against all developmental stages of the nematode. Histological analysis demonstrated damage of various body parts including isthmus, brut, pseudocoele, and other organs. Mechanistic studies revealed the generation of oxidative stress and alteration of the stress response enzyme activities. Importantly, the time-dependent imaging of ROS generation revealed the neuronal system as the primary target of quercetin in adult worms, which eventually leads to the paralysis and death of the worms. This work demonstrates the neuronal system as a novel drug target for quercetin.