bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐cell transcriptomics reveal temporal dynamics of critical regulators of germ cell fate during mouse sex determination
Authors: Mayère Chloé , Neirijnck Yasmine , Sararols Pauline , Rands Chris M. , Stévant Isabelle , Kühne Françoise , Chassot Anne‐Amandine , Chaboissier Marie‐Christine , Dermitzakis Emmanouil T. , Nef Serge
Published: March 2021

Despite the importance of germ cell (GC) differentiation for sexual reproduction, the gene networks underlying their fate remain unclear. Here, we comprehensively characterize the gene expression dynamics during sex determination based on single‐cell RNA sequencing of 14 914 XX and XY mouse GCs between embryonic days (E) 9.0 and 16.5. We found that XX and XY GCs diverge transcriptionally as early as E11.5 with upregulation of genes downstream of the bone morphogenic protein (BMP) and nodal/Activin pathways in XY and XX GCs, respectively. We also identified a sex‐specific upregulation of genes associated with negative regulation of mRNA processing and an increase in intron retention consistent with a reduction in mRNA splicing in XY testicular GCs by E13.5. Using computational gene regulation network inference analysis, we identified sex‐specific, sequential waves of putative key regulator genes during GC differentiation and revealed that the meiotic genes are regulated by positive and negative master modules acting in an antagonistic fashion. Finally, we found that rare adrenal GCs enter meiosis similarly to ovarian GCs but display altered expression of master genes controlling the female and male genetic programs, indicating that the somatic environment is important for GC function. Our data are available on a web platform and provide a molecular roadmap of GC sex determination at single‐cell resolution, which will serve as a valuable resource for future studies of gonad development, function, and disease.
Isovolemic Degradation of Polycaprolactone Particles and Calculation of Their Original Size from Human Biopsy
Authors: Kim JongSeo
Published: March 2021

Background:

Polycaprolactone (PCL) implants show isovolemic degradation during phase-1 degradation; they maintain their volume as their molecular weight decreases. Phase-2 begins with PLC volume being reduced by bulk degradation with autocatalysis. Isovolemic degradation of PCL particles during phase 1 and their longevity should be established in humans. PCL particle size can be mathematically calculated through cross-sectioned PCL particles in biopsy slides.

Methods:

Biopsy specimens were obtained from humans after giving them a subdermal injection for 4 years to measure cross-section diameters of PCL particles. In all (160) biopsy slides, all cross-sections of PCL particles were measured in size in microscopic photographs, and the real size of PCL particles was calculated through Equation of a circle (Equation

circle
) and mean value theorem for integrals (Integral

Theorem
). Diameters of Ellansé particles were measured with particle size analyzer.

Results:

On average, the calculated PCL particle size using Integral

Theorem
was 42.83 (immediately), then 43.18(1), 42.62(2), 40.90(3), and 34.46 µm(4 years), respectively. These results were similar to the diameters calculated using the Equation

circle
. PCL size remained unchanged until 3 years, which began to decrease from the fourth year, making the transition point in between. In particle size analyzer, the mean diameter was 42.42 µm.

Conclusions:

PCL particle size was mathematically calculated for 4 years in an in vivo biopsy study. Until 3 years after the injection, PCL particle diameter remained at 95.47% and showed phase-1 isovolemic degradation. From 4 years after the injection, particles decreased in size, showing phase-2 bulk degradation. PCL particles were smooth and circular for 3 years, and from the fourth year, the surface became very rough. The Ellansé-M longevity was longer than 4 years.
Multiple Thrombi during Microvascular Anastomosis Caused by Decreased Antithrombin Activity: A Case Report
Authors: Uchibori Takafumi , Takanari Keisuke , Nakamura Ryota , Kambe Miki , Ebisawa Katsumi , Nakamura Yutaka , Mogi Kousuke , Kamei Yuzuru
Published: March 2021

With recent advances in microsurgical instruments and technique, microvascular anastomosis has become a universal surgical technique; however, thrombosis still presents in a number of cases. Tension, twisting, and compression to the anastomotic site are the main causes of thrombus; however, disorder of the coagulation–fibrinolysis system also need to be considered. To date, only few reports exist regarding thrombosis caused by disorder of coagulant system in microvascular anastomosis. Here we report our 3 cases in which multiple thrombus formation occurred intraoperatively caused by decrease of antithrombin (AT) activity. AT activity was measured twice a day after vascular anastomosis: after surgery and up to 3 days after surgery. Thrombosis was not observed in any of the 3 patients intraoperatively after the transfusion, or thrombosis was not observed in any of 3 patients intraoperatively after the transfusion or postoperatively, and no other complications were observed. In these 3 cases, the thrombus was not caused by technical error or other previously described factors. The observed intraoperative decrease in AT activity was thought to be caused by thrombus formation. It is important that microsurgeons are reminded that disorders of the coagulation–fibrinolysis system could cause thrombosis.
The PRS Rainbow Classification for Assessing Postbariatric Contour Deformities
Authors: de Vries Claire E. E. , van den Berg Lisa , Monpellier Valerie M. , Hoogbergen Maarten M. , Mink van der Molen Aebele B. , de Castro Steve M. M. , van der Lei Berend
Published: March 2021

Background:

There is a need for a reliable classification system to grade contour deformities and to inform reimbursement of body contouring surgery after massive weight loss. We developed the PRS Rainbow Classification, which uses select photographs to provide standardized references for evaluating patient photographs, to classify contour deformities in postbariatric patients. To assess the reliability of the PRS Rainbow Classification to classify contour deformities in massive weight loss patients.

Methods:

Ten independent experienced plastic surgeons, 7 experienced medical advisors of the healthcare insurance company, and 10 laypersons evaluated 50 photographs per anatomical region (arms, breast, abdomen, and medial thighs). Each participant rated the patient photographs on a scale of 1–3 in an online survey. The inter-observer and the intra-observer reliabilities were determined using intra-class correlation coefficients (ICCs). The ICC analyses were performed for each anatomical region.

Results:

Inter-observer reliability was moderate to good in the body regions “arms,” “abdomen,” “medial thighs,” with mean ICC values of 0.678 [95% confidence interval (CI), 0.591–0.768], 0.685 (95% CI, 0.599–0.773), and 0.658 (95% CI, 0.569–0.751), respectively. Inter-observer reliability was comparable within the 3 different professional groups. Intra-observer reliability (test–retest reliability) was moderate to good, with a mean overall ICC value of 0.723 (95% CI, 0.572–0.874) for all groups and all 4 body regions.

Conclusions:

The moderate to good reliability found in this study validates the use of the PRS Rainbow Classification as a reproducible and reliable classification system to assess contour deformities after massive weight loss. It holds promise as a key part of instruments to classify body contour deformities and to assess reimbursement of body contouring surgery.
A Systematic Review of Tranexamic Acid in Plastic Surgery: What’s New?
Authors: Elena Scarafoni Esteban
Published: March 2021

Background:

Blood loss associated with surgical interventions can lead to several complications. Therefore, minimizing perioperative bleeding is critical to improve overall survival. Several interventions have been found to successfully reduce surgical bleeding, including the antifibrinolytic agent. After aprotinin was withdrawn from the market in 2008, TXA remained the most commonly used medication. The safety and efficacy of TXA has been well studied in other specialties. TXA has been rarely used in plastic surgery, except in craniofacial procedures. Since the last review, the number of articles examining the use of TXA has doubled; so the aim of this systematic review is to update the readers on the current knowledge and clinical recommendations regarding the efficacy of TXA in plastic surgical procedures.

Methods:

A systematic literature search was conducted in Medline, SciELO, Cochrane, and Google Scholar to evaluate all articles that discussed the use of TXA in plastic surgery in the fields of aesthetic surgery, burn care, and reconstructive microsurgery.

Results:

A total of 233 publications were identified using the search criteria defined above. After examination of titles and abstracts, and exclusion of duplicates, a total of 23 articles were selected for analysis.

Conclusions:

The literature shows a clear benefit of using TXA to decrease blood loss regardless of the administration route, with no risk of thrombosis events. Also, TXA elicits a potent anti-inflammatory response with a decrease in postoperative edema and ecchymosis, which improves recovery time. Further investigations are needed to standardize the optimal administration route and dosage of TXA.
Pilonidal Cyst Excision: Primary Midline Closure with versus without Closed Incision Negative Pressure Therapy
Authors: Gabor Silvio , de Lima Favaro Murillo , Pimentel Pedroso Ruy Francisco , Duarte Bárbara Henriqueta Ferreira , Novo Rafaela , Iamarino Ana Paula , Ribeiro Marcelo Augusto Fontenelle
Published: March 2021

Background:

Pilonidal cysts are a painful condition that primarily affect young adult men. In the literature, numerous operative techniques for resolving pilonidal cysts are described, with variable outcomes. The objective of this study was to compare primarily closed midline incisions managed with or without the use of closed incision negative pressure therapy after pilonidal cyst excision.

Methods:

Twenty-one patients underwent excision and midline primary closure. Postoperative care composed of closed incisional negative pressure therapy (study group; n = 10) or gauze dressings (control group; n = 11). In both groups, the sutures were partially removed on day 14 and completely removed on day 21. Compared outcomes included the duration of hospitalization, pain on the day of surgical procedure, and on postoperative day 7, and time-to-healing.

Results:

The median hospital stay was about 9 hours and 23 hours in the study and control groups, respectively (P < 0.05). The median pain scores on the day of operation were 1.20/10 in the study group and 3.36/10 in the control group (P < 0.05). On day 7, study group showed median pain score 0.9/10 and control group showed 2.63/10 (P < 0.05). The mean healing time was 23.8 and 57.9 days in the ciNPT group and gauze group, respectively (P < 0.05).

Conclusion:

These outcomes supported the incorporation of closed incision negative pressure therapy into our surgical treatment protocol for pilonidal cysts.
Building a Multidisciplinary Academic Surgical Gender-affirmation Program: Lessons Learned
Authors: Manrique Oscar J. , Bustos Samyd S. , Bustos Valeria P. , Mascaro Andres A. , Ciudad Pedro , Forte Antonio J. , Del Corral Gabriel , Kim Esther A. , Langstein Howard N.
Published: March 2021

Background:

Every day, we see more patients present to hospitals and clinics seeking gender-affirmation care to ameliorate the symptoms of gender dysphoria. However, to provide a multidisciplinary approach, it is important to offer an integrated clinical program that provides mental health assessment, endocrine therapy, physical therapy, research, and the full spectrum of surgical services devoted to transgender patients. This article describes our experience on building a specialized, multidisciplinary, academic state-of-the-art gender-affirmation program.

Methods:

Herein, we describe the main and critical components on how to build a multidisciplinary academic gender-affirmation program. We share our lessons learned from this experience and describe how to overcome some of the obstacles during the process.

Results:

Building a multidisciplinary academic gender-affirmation program requires an invested team, as each and every member is essential for feedback, referrals, and to improve patient’s experience. Institutional support is essential and by far the most important component to overcome some of the obstacles during the process. Having all team members working under the same institution provides all the critical components needed to improve outcomes and patient satisfaction. In addition, the collection of prospective data with a well-structured research team will provide information needed to improve clinical services and standardize clinical protocols, while leaving space for innovation.

Conclusions:

This article describes the steps and experience needed to build a multidisciplinary holistic academic gender-affirmation program. We provide our lessons learned during the process that will help guide those who intend to start an academic gender-affirmation program.
Treatment of Trichiasis by Releasing Follicle Roots of Eyelashes: A New Technique
Authors: Karademir Sacit , Agaoglu Galip
Published: March 2021

Trichiasis is an acquired condition in which eyelashes are misdirected toward the ocular surface, resulting in eye irritation and ocular morbidities. Different treatment modalities have been described, including surgical and non-surgical methods. The goal of this article is to present a novel technique for treatment of trichiasis, with a brief review of treatment options. Through a supratarsal incision, each misdirected eyelash follicle root was reached and freed from surrounding tissues by meticulous dissection. Then, hair shafts on the lid margin were redirected upward and glued to 2 bars extending horizontally across the upper eyelid. Two years after operation, the corrected eyelashes maintained their normal upward direction. To the best of our knowledge, this is the first reported case of chronic trichiasis treated by this technique. The main advantage of the technique, unlike most of the other treatment methods, is that follicles of the affected eyelashes are not removed or destroyed, which is appreciated from the aesthetic point of view, especially in female patients. We believe that any plastic surgeon with basic knowledge of blepharoplasty and hair transplantation can perform this technique without much difficulty. So far, there is no recurrence; however, long-term follow-up with a large series of patients is required for drawing better conclusions.
The effect of NSAIDs on postfracture bone healing: a meta-analysis of randomized controlled trials
Authors: Al Farii Humaid , Farahdel Leila , Frazer Abbey , Salimi Ali , Bernstein Mitchell
Published: March 2021

Objectives:

To determine whether nonsteroidal anti-inflammatory drugs (NSAIDs) have an adverse effect on bone healing by evaluating all available human randomized controlled trials (RCTs) on this subject.

Data Sources:

A comprehensive search of electronic databases (PubMed, MEDLINE, and Cross-References) until October 2018 comparing the occurrence of nonunion in patients who received NSAIDs to the control group through RCTs.

Study Selection:

Inclusion criteria were English-only studies, and the type of studies was restricted to RCTs.

Data Extraction:

Two authors independently extracted data from the selected studies, and the data collected were compared to verify agreement.

Data Synthesis:

Nonunion was the main outcome evaluated in each study. Regression analysis was used to estimate the relative risk comparing the duration and the type of NSAIDs by calculating the odds ratio (OR) for dichotomous variables. Studies were weighed by the inverse of the variance of the outcome, and a fixed-effects model was used for all analyses.

Conclusions:

Six RCTs (609 patients) were included. The risk of nonunion was higher in the patients who were given NSAIDs after the fracture with an OR of 3.47. However, once the studies were categorized into the duration of treatment with NSAIDs, those who received NSAIDs for a short period (<2 weeks) did not show any significant risk of nonunion compared to those who received NSAIDs for a long period (>4 weeks). Indomethacin was associated with a significant higher nonunion rate and OR ranging from 1.66 to 9.03 compared with other NSAIDs that did not show a significant nonunion risk.
Postviral Depression
Authors: COLLINS MADISON L. , CHENEY GRACE A. , YEHL JENNIFER L. , SULLIVAN GREGORY A. , STEWART JONATHAN T. , CATALANO GLENN
Published: March 2021

A previously healthy 68-year-old man rapidly developed a severe melancholic depression following influenza infection. There is an evolving understanding of the complex and possibly bidirectional relationship between depression and inflammation. We review the literature concerning this relationship in the context of viral infection and discuss possible implications for treatment.
Consistency of the Antidepressant Effect of Intranasal Esketamine in Phase 3 Clinical Trials
Authors: PRESKORN SHELDON H.
Published: March 2021

This column reviews the development of intranasal esketamine with particular emphasis on the consistency of the clinical trial results. In the process, it illustrates methodological issues important in the approval process by an agency such as the United States Food and Drug Administration. Topics covered include the importance of study design, the nature of the comparator, and the prespecified statistical analysis plan. The column also discusses what is considered a positive versus a supportive study and the differences between phase 2 and phase 3 studies and the rationale for including both in the development process. While this information is particularly germane to intranasal esketamine, it also serves as a more general example of the drug development and approval process.
Gravettian hand stencils as sign language formatives
Authors: Etxepare Ricardo , Irurtzun Aritz
Published: March 2021

Several Upper Palaeolithic archaeological sites from the Gravettian period display hand stencils with missing fingers. On the basis of the stencils that Leroi-Gourhan identified in the cave of Gargas (France) in the late 1960s, we explore the hypothesis that those stencils represent hand signs with deliberate folding of fingers, intentionally projected as a negative figure onto the wall. Through a study of the biomechanics of handshapes, we analyse the articulatory effort required for producing the handshapes under the stencils in the Gargas cave, and show that only handshapes that are articulable in the air can be found among the existing stencils. In other words, handshape configurations that would have required using the cave wall as a support for the fingers are not attested. We argue that the stencils correspond to the type of handshape that one ordinarily finds in sign language phonology. More concretely, we claim that they correspond to signs of an ‘alternate’ or ‘non-primary’ sign language, like those still employed by a number of bimodal (speaking and signing) human groups in hunter–gatherer populations, like the Australian first nations or the Plains Indians. In those groups, signing is used for hunting and for a rich array of ritual purposes, including mourning and traditional story-telling. We discuss further evidence, based on typological generalizations about the phonology of non-primary sign languages and comparative ethnographic work, that points to such a parallelism. This evidence includes the fact that for some of those groups, stencil and petroglyph art has independently been linked to their sign language expressions.

This article is part of the theme issue ‘Reconstructing prehistoric languages’.
Genome analyses of 174 strains of Mycobacterium tuberculosis provide insight into the evolution of drug resistance and reveal potential drug targets
Authors: Verma Helianthous , Nagar Shekhar , Vohra Shivani , Pandey Shubhanshu , Lal Devi , Negi Ram Krishan , Lal Rup , Rawat Charu Dogra
Published: March 2021

Mycobacterium tuberculosis

is a known human pathogen that causes the airborne infectious disease tuberculosis (TB). Every year TB infects millions of people worldwide. The emergence of multi-drug resistant (MDR), extensively drug resistant (XDR) and totally drug resistant (TDR)

M. tuberculosis

strains against the first- and second-line anti-TB drugs has created an urgent need for the development and implementation of new drug strategies. In this study, the complete genomes of 174 strains of

M. tuberculosis

are analysed to understand the evolution of molecular drug target (MDT) genes. Phylogenomic placements of

M. tuberculosis

strains depicted close association and temporal clustering. Selection pressure analysis by deducing the ratio of non-synonymous to synonymous substitution rates (dN/dS) in 51 MDT genes of the 174

M

.

tuberculosis

strains led to categorizing these genes into diversifying (D, dN/dS>0.70), moderately diversifying (MD, dN/dS=0.35–0.70) and stabilized (S, dN/dS<0.35) genes. The genes rpsL, gidB, pncA and ahpC were identified as diversifying, and Rv0488, kasA, ndh, ethR, ethA, embR and ddn were identified as stabilized genes. Furthermore, sequence similarity networks were drawn that supported these divisions. In the multiple sequence alignments of diversifying and stabilized proteins, previously reported resistance mutations were checked to predict sensitive and resistant strains of

M. tuberculosis

. Finally, to delineate the potential of stabilized or least diversified genes/proteins as anti-TB drug targets, protein–protein interactions of MDT proteins with human proteins were analysed. We predict that kasA (dN/dS=0.29), a stabilized gene that encodes the most host-interacting protein, KasA, should serve as a potential drug target for the treatment of TB.
Vascular Inflammation in Lungs of Patients with Fatal Coronavirus Disease 2019 (COVID-19) Infection: Possible role for the NLRP3 inflammasome
Authors: Paul Oindrila , Tao Jian Qin , Litzky Leslie , Feldman Michael , Montone Kathleen , Rajapakse Chamith , Bermudez Christian , Chatterjee Shampa
Published: March 2021

Hyperinflammation is a key event that occurs with SARS-CoV-2 infection. In the lung, hyperinflammation leads to structural damage to tissue. To date, numerous lung histological studies have shown extensive alveolar damage, but there is scarce documentation of vascular inflammation in postmortem lung tissue. Here we document histopathological features and monitor the NLRP3 inflammasome in fatal cases of disease caused by SARS Cov2 (COVID-19). We posit that inflammasome formation along the vessel wall is a characteristic of lung inflammation that accompanies COVID-19 and that it is a probable candidate that drives amplification of inflammation post infection.
The presence of SARS-CoV-2 RNA in different freshwater environments in urban settings determined by RT-qPCR: implications for water safety
Authors: Mahlknecht Jürgen , Alonso-Padilla Diego , Ramos Edrick , Reyes Luisa Ma. , Álvarez Mario Moises
Published: March 2021

This study is the first focused on the presence of SARS-CoV-2 in different freshwater environments in an urban setting. Groundwater and surface water reservoirs for drinking water as well as water from receiving rivers of the Monterrey Metropolitan Area were sampled repeatedly during a SARS-CoV-2 peak phase between October 2020 and January 2021, and viral RNA was measured by quantitative reverse transcription polymerase chain reaction. Forty-four percent of the groundwater samples had detectable viral loads between 2.6 and 38.3 copies/ml. A significant correlation between viral load and sucralose concentration in groundwater reaffirmed the hypothesis of leaching and infiltrating effluent from surface and/or failing sewage pipes and emphasized the importance of water disinfection. Twelve percent of the surface water dam samples tested positive for viral RNA, with values varying between 3.3 and 3.8 copies/ml. Finally, 13% of the river samples were positive for viral RNA, with concentrations ranging from 2.5 to 7.0 copies/ml. Untreated wastewater samples taken in the same period showed viral loads of up to 3535 copies/ml, demonstrating a dilution effect and/or wastewater facilities efficiency of three orders of magnitude. Variations in the viral loads in the groundwater and surface water over time and at the submetropolitan level generally reflected the reported trends in infection cases for Monterrey. The viral loads in the freshwater environments of Monterrey represent a low risk for recreational activities according to a preliminary risk assessment model. However, this result should not be taken lightly due to uncertainty regarding data and model constraints and the possibility of situations where the infection risk may increase considerably.
Lives Saved from Age-Prioritized Covid-19 Vaccination
Authors: Goldstein Joshua R. , Cassidy Thomas , Mahmud Ayesha S.
Published: March 2021

BACKGROUND

The criteria used to allocate scarce COVID-19 vaccines are hotly contested. While some are pushing just to get vaccines into arms as quickly as possible, others advocate prioritization in terms of risk.

OBJECTIVE

Our aim is to use demographic models to show the enormous potential of vaccine risk-prioritization in saving lives.

METHODS

We develop a simple mathematical model that accounts for the age distribution of the population and of COVID-19 mortality. This model considers only the direct live-savings for those who receive the vaccine, and does not account for possible indirect effects of vaccination. We apply this model to the United States, Japan, and Bangladesh.

RESULTS

In the United States, we find age-prioritization would reduce deaths during a vaccine campaign by about 93 percent relative to no vaccine and 85 percent relative to age-neutral vaccine distribution. In countries with younger age structures, such as Bangladesh, the benefits of age-prioritization are even greater.

CONTRIBUTION

For policy makers, our findings give additional support to risk-prioritized allocation of COVID-19 vaccines. For demographers, our results show how the age-structures of the population and of disease mortality combine into an expression of risk concentration that shows the benefits of prioritized allocation. This measure can also be used to study the effects of prioritizing other dimensions of risk such as underlying health conditions.
Gambling on an empty stomach: Hunger modulates preferences for learned but not described risks
Authors: van Swieten Maaike M.H. , Bogacz Rafal , Manohar Sanjay G.
Published: March 2021

We assess risks differently when they are explicitly described, compared to when we learn directly from experience, suggesting dissociable decision-making systems. Our needs, such as hunger, could globally affect our risk preferences, but do they affect described and learned risks equally? On one hand, explicit decision-making is often considered flexible and contextsensitive, and might therefore be modulated by metabolic needs. On the other hand, implicit preferences learned through reinforcement might be more strongly coupled to biological drives. To answer this, we asked participants to choose between two options with different risks, where the probabilities of monetary outcomes were either described or learned. In agreement with previous studies, rewarding contexts induced risk-aversion when risks were explicitly described, but risk-seeking when they were learned through experience. Crucially, hunger attenuated these contextual biases, but only for learned risks. The results suggest that our metabolic state determines risk-taking biases when we lack explicit descriptions.
Human gaze is systematically offset from the center of cone topography
Authors: Reiniger Jenny L. , Domdei Niklas , Holz Frank G. , Harmening Wolf M.
Published: March 2021

The small physical depression of the human retina, the fovea, is the retinal locus of prime visual resolution, achieved by a peaking topography of the light sensitive cone photoreceptor outer segments1–3and a post-receptor wiring scheme preserving high-density sampling4,5. Humans dynamically direct their gaze such that the retinal images of objects of interest fall onto the foveola, the central one-degree diameter of the fovea6–8, but it is yet unclear if a relationship between the individual photoreceptor topography at this location and visual fixation behavior exists9,10. By employing adaptive optics in vivo imaging and micro-stimulation11–13, we created topographical maps of the complete foveolar cone mosaics in both eyes of 20 healthy participants while simultaneously recording the retinal location of a fixated visual object in a psychophysical experiment with cellular resolution. We found that the locus of fixation was systematically shifted away from the topographical centers towards a naso-superior quadrant on the retina, about 5 minutes of arc of visual angle on average, with a mirror symmetrical trend between fellow eyes. In cyclopean view, the topographical centers were superior to the fixated target, corresponding to areas in the visual field usually more distant14,15and thus containing higher spatial frequencies. Given the large variability in foveal topography between individuals, and the surprising precision with which fixation is repeatedly directed to just a small bouquet of cones in the foveola, these findings demonstrate a finely tuned, functionally relevant link between the development of the cellular mosaic of photoreceptors and visual behavior.
Molecular features of RNA silencing against phloem-restricted polerovirus TuYV enable amplification of silencing signal from host transcripts
Authors: Clavel Marion , Lechner Esther , Incarbone Marco , Vincent Timothée , Cognat Valerie , Smirnova Ekaterina , Lecorbeiller Maxime , Brault Véronique , Ziegler-Graff Véronique , Genschik Pascal
Published: March 2021

In plants and some animal lineages, RNA silencing is an efficient and adaptable defense mechanism against viruses. To counter it, viruses encode suppressor proteins that interfere with RNA silencing. Phloem-restricted viruses are spreading at an alarming rate and cause substantial reduction of crop yield, but how they interact with their hosts at the molecular level is still insufficiently understood. Here, we investigate the antiviral response against phloem-restricted turnip yellows virus (TuYV) in the model plantArabidopsis thaliana. Using a combination of genetics, deep sequencing, and mechanical vasculature enrichment, we show that the main axis of silencing active against TuYV involves 22-nt vsiRNA production by DCL2, and their preferential loading into AGO1. Unexpectedly, and despite the viral encoded VSR P0 previously shown to mediate degradation of AGO proteins, vascular AGO1 undergoes specific post-translational stabilization during TuYV infection. We also identify vascular novel secondary siRNA produced from conserved plant transcripts and initiated by DCL2-processed AGO1-loaded vsiRNA, supporting a viral strategy to modulate host response. Collectively, our work uncovers the complexity of antiviral RNA silencing against phloem-restricted TuYV and prompts a re-assessment of the role of its suppressor of silencing P0 during genuine infection.
UNC-45A is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System
Authors: Clemente Valentino , Hoshino Asumi , Meints Joyce , Shetty Mihir , Starr Tim , Lee Michael , Bazzaro Martina
Published: March 2021

UNC-45A is a cytoskeletal-associated protein with a dual and non-mutually exclusive role as a regulator of the acto-myosin system and as a Microtubule (MT)-destabilizing protein. UNC-45A is overexpressed in human cancers including in ovarian cancer patients resistant to the MT-stabilizing drug Paclitaxel. Mapping of UNC-45A in the mouse upper genital tract and central nervous system reveals its enrichment in highly proliferating and prone to remodeling cells and in microtubule-rich areas of in the ovaries and in neurons respectively. In both apparatuses UNC-45A is also abundantly expressed in the ciliated epithelium. Because regulators of acto-myosin contractility and MT stability are essential for the physiopathology of the female reproductive tract and of neuronal development our findings suggest that UNC-45A may have a role in ovarian cancer initiation and development and in neurodegeneration.
CSF1R inhibitor levels determine sex-specific phenotype of resilient microglia and neurofunctional rescue leading to extended survival in tauopathy mice
Authors: Johnson Noah R. , Yuan Peng , Castillo Erika , Lopez T. Peter , Yue Weizhou , Bond Annalise , Rivera Brianna M. , Sullivan Miranda C. , Hirouchi Masakazu , Giles Kurt , Aoyagi Atsushi , Condello Carlo
Published: March 2021

Microglia are central to pathogenesis in many neurological conditions. Drugs targeting colony- stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, CSF1R inhibitors were evaluated in tauopathy mice using multiple dosing schemes, drug analogs, and longitudinal measurements in the brain and plasma. A sex- independent reduction in pathogenic tau was seen in several models and non-microglial gene expression patterns reverted toward a normal wild type signature. Surprisingly, despite greater drug exposure in male mice, functional rescue and extended survival was only observed in female mice. A dose-dependent upregulation of immediate early genes and neurotransmitter dysregulation were observed in the brains of male mice only, indicating that excitotoxicity may have precluded functional benefits. Drug-resilient microglia in male mice exhibited morphological and gene expression patterns consistent with increased neuroinflammatory signaling, suggesting a mechanistic basis for sex-specific excitotoxicity. These data argue that complete microglial ablation is neither required nor desirable for neuroprotection and that therapeutics targeting microglia must consider sex-dependent effects on functional outcomes.
Factors informing healthcare workers’ willingness to work during the COVID-19 pandemic
Authors: Malesza Marta
Published: March 2021

Objective

The COVID-19 pandemic represents a substantial challenge to healthcare workers. Exploring the determinants of their willingness to work is crucial to ensuring hospital function during the outbreak. Hence, this study examines the factors affecting the motivation and hesitation of health workers in the face of the COVID-19 pandemic in Poland.

Study Design

An online, anonymous survey was carried out among Polish healthcare workers during the COVID-19 pandemic.

Method

The respondents were asked about their demographic characteristics, stress-related factors, and their self-reported motivation and hesitation to work. The responses were gathered during September-December 2020.

Results

912 valid responses were obtained. Of these, 22.8% (N = 208) respondents reported being strongly motivated to work while 37.8% (N = 345) expressed strong hesitation. The participants’ demographic characteristics and their responses to the stress-related questions were assigned to four categories depending on the odds ratios of motivation and hesitation. While some factors were linked to enhanced motivation and reduced hesitation, others solely affected either motivation or hesitation, and yet others had a positive impact on both.

Conclusion

Overall, the study indicates that in order to increase hospital workers’ motivation and decrease their hesitation, they must be made to feel protected by both their hospitals and local and national authorities.
Fusion of the N-terminal 119 amino acids with the RelA-CTD renders its growth inhibitory effects ppGpp-dependent
Authors: Tailor Krishma , Sagar Prarthi , Dave Keyur , Pohnerkar Jayashree
Published: March 2021

The guanosine nucleotide derivatives ppGpp and pppGpp, are central to the remarkable capacity of bacteria to adapt to fluctuating environment and metabolic perturbations. These alarmones are synthesized by two proteins, RelA and SpoT inE. coliand the activities of each of the two enzymes are highly regulated for homeostatic control of (p)ppGpp levels in the cell. Although the domain structure and function of RelA are well defined, the findings of this study unfold the regulatory aspect of RelA that is possibly relevantin vivo. We uncover here the importance of the N-terminal 1-119 amino acids of the enzymatically compromised (p)ppGpp hydrolytic domain (HD) of monofunctional RelA for the (p)ppGpp mediated regulation of RelA-CTD function. We find that even moderate level expression of RelA appreciably reduces growth when the basal levels of (p)ppGpp in the cells are higher than in the wild type, an effect independent of its ability to synthesize (p)ppGpp. This is evidenced by the growth inhibitory effects of oversynthesis of the RelA-CTD in therelA+strain but not inrelAnull mutant, suggesting the requirement of the functional RelA protein for basal level synthesis of (p)ppGpp, accordingly corroborated by the restoration of the growth inhibitory effects of the RelA-CTD expression in therelA1 spoT202mutant. The N-terminal 119 amino acids of RelA fused in-frame with the RelA-CTD, both from 406-744 amino acids (including TGS) and from 454-744 amino acids (sans TGS) caused growth inhibition only inspoT1andspoT202 relA1mutants, uncovering the hitherto unrealized (p)ppGpp-dependent regulation of RelA-CTD function. An incremental rise in the (p)ppGpp levels is proposed to progressively modulate the interaction of RelA-CTD with the ribosomes, with possible implications in the feedback regulation of the N-terminal (p)ppGpp synthesis function, a proposal that best explains the nonlinear relationship between (p)ppGpp synthesis and increased ratio of RelA:ribosomes, bothin vitroas well asin vivo.
Comparative repeat profiling of two closely related conifers (Larix decidua and Larix kaempferi) reveals high genome similarity with only few fast-evolving satellite DNAs
Authors: Heitkam Tony , Schulte Luise , Weber Beatrice , Liedtke Susan , Breitenbach Sarah , Kögler Anja , Morgenstern Kristin , Brückner Marie , Tröber Ute , Wolf Heino , Krabel Doris , Schmidt Thomas
Published: March 2021

In eukaryotic genomes, cycles of repeat expansion and removal lead to large-scale genomic changes and propel organisms forward in evolution. However, in conifers, active repeat removal is thought to be limited, leading to expansions of their genomes, mostly exceeding 10 gigabasepairs. As a result, conifer genomes are largely littered with fragmented and decayed repeats. Here, we aim to investigate how the repeat landscapes of two related conifers have diverged, given the conifers’ accumulative genome evolution mode. For this, we applied low coverage sequencing and read clustering to the genomes of European and Japanese larch,Larix decidua(Lamb.) Carrière andLarix kaempferi(Mill.), that arose from a common ancestor, but are now geographically isolated. We found that bothLarixspecies harbored largely similar repeat landscapes, especially regarding the transposable element content. To pin down possible genomic changes, we focused on the repeat class with the fastest sequence turnover: satellite DNAs (satDNAs). Using comparative bioinformatics, Southern, and fluorescentin situhybridization, we reveal the satDNAs’ organizational patterns, their abundances, and chromosomal locations. Four out of the five identified satDNAs are widespread in theLarixgenus, with two even present in the more distantly relatedPseudotsugaandAbiesgenera. Unexpectedly, the EulaSat3 family was restricted toL. deciduaand absent fromL. kaempferi, indicating its evolutionarily young age. Taken together, our results exemplify how the accumulative genome evolution of conifers may limit the overall divergence of repeats after speciation, producing only few repeat-induced genomic novelties.
Two interacting transcriptional coactivators cooperatively control plant immune responses
Authors: Chen Huan , Li Min , Qi Guang , Zhao Ming , Liu Longyu , Zhang Jingyi , Chen Gongyou , Wang Daowen , Liu Fengquan , Fu Zheng Qing
Published: March 2021

The phytohormone salicylic acid (SA) plays a pivotal role in plant defense against biotrophic and hemibiotrophic pathogens. Genetic studies have identified NPR1 and EDS1 as two central hubs in plant local and systemic immunity. However, it is unclear how NPR1 orchestrates gene regulation and whether EDS1 directly participates in transcriptional reprogramming. Here we show that NPR1 and EDS1 synergistically activatePathogenesis-Related(PR) genes and plant defenses by forming a protein complex and co-opting with Mediator. In particular, we discover that EDS1 functions as an autonomous transcriptional coactivator with intrinsic transactivation domains and physically interacts with the CDK8 subunit of Mediator. Upon SA induction, EDS1 is directly recruited by NPR1 onto thePR1promoter via physical NPR1-EDS1 interactions, thereby potentiatingPR1activation. We further demonstrate that EDS1 stabilizes NPR1 protein and NPR1 transcriptionally upregulatesEDS1in plant-pathogen interactions. Our results reveal an elegant interplay of key coactivators with Mediator and elucidate novel molecular mechanisms for activating transcription during immune responses.
Identifying Differential Methylation in Cancer Epigenetics via a Bayesian Functional Regression Model
Authors: Shokoohi Farhad , Stephens David A. , Greenwood Celia M.T.
Published: March 2021

DNA methylation plays an essential role in regulating gene activity, modulating disease risk, and determining treatment response. Researchers can obtain insight into methylation patterns at a single nucleotide level utilizing next-generation sequencing technologies. However, complex features inherent in the data obtained via these technologies pose challenges beyond the typical big data problems. Identifying differentially methylated cytosines (dmc) or regions is one of such challenges. Current methodologies for identifying dmcs fall short in handling low read-depth data and missing values, capturing functional data patterns, granting multiple covariates (categorical, continuous, or combination), and multiple group comparisons. We have developed an efficient method to identify dmcs based on a Bayesian functional regression approach, termedDMCFB, that tackles these shortcomings. Through simulation studies, we establish thatDMCFBoutperforms current methods and results in better smoothing, and efficient imputation. We apply the proposed method to analyze a dataset containing patients with acute promyelocytic leukemia and control samples. WithDMCFB, we discovered many new dmcs, and more importantly, exhibited enhanced consistency of differential methylation within islands and at their adjacent shores. Furthermore, we detected differential methylation at more of the binding sites of the fused gene involved in this cancer.
A novel method for generating 3D constructs with branched vascular networks using multi-materials bioprinting and direct surgical anastomosis
Authors: Liu Xin , Wang Xinhuan , Zhang Liming , Sun Lulu , Wang Heran , Zhao Hao , Zhang Zhengtao , Huang Yiming , Zhang Jingjinqiu , Song Biaobiao , Li Chun , Zhang Hui , Li Song , Wang Shu , Zheng Xiongfei , Gu Qi
Published: March 2021

Vessels pervade almost all body tissues, and significantly influence the pathophysiology of human body. Previous attempts to establish multi-scale vascular connection and function in 3D model tissues using bioprinting have had limited success due to the incoordination between cell-laden materials and stability of the perfusion channel. Here, we report a methodology to fabricate centimetre-scale vascularized soft tissue with high viability and accuracy using multi-materials bioprinting involving inks with low viscosity and a customized multistage-temperature-control printer. The tissue formed was perfused with branched vasculature with well-formed 3D capillary network and lumen, which would potentially supply the cellular components with sufficient nutrients in the matrix. Furthermore, the same methodology was applied for generating liver-like tissue with the objective to fabricate and mimic a mature and functional liver tissue, with increased functionality in terms of synthesis of liver specific proteins afterin vitroperfusion andin vivosubperitoneal transplantation in mice. Moreover, to establish immediate blood perfusion, an elastic layer was printed wrapping sacrificial ink to support the direct surgical anastomosis of the carotid artery to the jugular vein. Our findings highlight the support extended by vasculature network in soft hydrogels which helps to sustain the thick and dense cellularization in engineered tissues.
Neural Representation of the Relational Self from Infancy to Adulthood
Authors: Ulmer-Yaniv Adi , Waidergoren Shani , Shaked Ariel , Salomon Roy , Feldman Ruth
Published: March 2021

Investigations into the neural underpinnings of the “self” highlight its complexity and multi-dimensionality and emphasize that various aspects of the self are sustained by different neural systems. Here, we focused on the Relational Self, a dimension denoting the self-within-attachment-relationships that taps the continuity of attachment across individual development and affiliative bonds. Mothers and children were followed across two decades and videotaped in naturalistic interactions at three ages: infancy (3-6 months), childhood (9-12 years), and young adulthood (18-24 years). During fMRI scanning, young adults were exposed to videos of their own mother-child interactions from the three ages versus matched unfamiliar interactions. Relational Self-stimuli elicited greater activations across preregistered nodes of the human caregiving network, including thalamus-to-brainstem, amygdala, hippocampus, ACC, insula, and temporal cortex. Critically, Relational Self-stimuli were age-invariant in most regions of interest despite large variability of stimuli across multiple self-related features, such as similarity, temporal distance, affect, or mentalization, and Bayesian analysis indicated strong evidence for lack of age-related differences. PPI analysis demonstrated that Relational Self-stimuli elicited tighter connectivity between the ACC and insula. Greater child social engagement during interaction with mother correlated with higher ACC and insula response to Relational Self-stimuli. Findings highlight an important novel dimension in the neural representation of the self, suggest that the Relational Self may be sustained by a paralimbic interface integrating exteroceptive and interoceptive self-related signals, and demonstrate overlap in the attachment network of parents and children, lending support to perspectives on the continuity of attachment and self across the individual’s developmental history.

Significance Statement

Describing the neural underpinnings of the “self” is inherently complex due to the multi-dimensionality of the construct. Following mothers and children from infancy to adulthood, we focused on the Relational Self, a dimension denoting the self-within-attachment-relationships, and exposed young adults to own versus unfamiliar mother-child interactions across their relational history. Relational Self stimuli triggered greater activations in the human caregiving network, including thalamus-to-brainstem, amygdala, hippocampus, ACC, insula, and temporal cortex, were age-invariant, and elicited tighter connectivity between ACC and insula, creating a paralimbic interface of interoception-exteroception sustaining the Relational Self. Findings highlight a novel dimension in the neural representation of the self and lend support to perspectives emphasizing the cross-generational transmission of attachment and its continuity across the individual’s developmental history.