bluuebunny/crossref_metadata_2025 huggingface dataset:
Lower Pole Breast Reconstruction Using Muscle-sparing Latissimus Dorsi Flap in Postburn Breast Deformity
Authors: Hussein Mohammed Ahmed , Abdelkader Rasha , El-Henawy Ayman Noaman , Makarem Kyrillos
Published: November 2021

Background:

Full-thickness burns of the anterior chest wall during childhood are a devastating problem that results in significant distortion of the developing breast. This deformed burnt breast represents a serious aesthetic problem, and can lead to functional impairment as well as severe emotional trauma for patients.

Methods:

Patients with postburn scarring affecting the lower pole of the breast were included. Only patients with small to medium-sized breasts were targeted. The lower breast pole was reconstructed using muscle-sparing latissimus dorsi flap. All patients had been subjectively assessed, including overall patient satisfaction regarding breast aesthetics, donor site morbidity, and functional deficits of latissimus dorsi muscle, 3 months postoperatively.

Results:

Six patients (seven breasts) were included in this study. Muscle-sparing latissimus dorsi flap was used to reconstruct lower breast pole in all patients. A horizontally-oriented skin paddle was used in five patients, whereas a vertically oriented skin paddle was used in one patient. Average patient satisfaction was 9.1 (SD 0.6) for the reconstructed lower breast pole. For the donor site, average overall satisfaction was 9.1 (SD 0.8). Latissimus dorsi muscle function was objectively confirmed in 90% of cases after 3 months postoperatively. Patients had an average score of 3.9 (SD 0.4) for the activity score as well.

Conclusions:

The muscle-sparing latissimus dorsi flap is a good reconstructive tool for lower breast pole in postburn breast reconstruction. It has a reliable versatile skin paddle that can resurface the whole lower breast pole, while avoiding many of the latissimus flap morbidities.
Breast Reconstruction during the COVID-19 Pandemic: A Systematic Review
Authors: Hemal Kshipra , Boyd Carter J. , Bekisz Jonathan M. , Salibian Ara A. , Choi Mihye , Karp Nolan S.
Published: November 2021

Introduction:

The COVID-19 pandemic posed unique challenges for breast reconstruction. Many professional organizations initially placed restrictions on breast reconstruction, leading surgeons to conceive innovative protocols for offering breast reconstruction. This study reviewed the current evidence on breast reconstruction during the COVID-19 pandemic to provide guidance for surgeons facing future crises.

Methods:

The MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews were searched for studies (1) describing implant and autologous breast reconstruction following mastectomy and (2) occurring during or pertaining to the COVID-19 pandemic.

Results:

Of the 1347 studies identified, 26 were included. Studies discussed type of reconstruction (18, 69%), complications (11, 42%), timing of reconstruction (10, 38%), protocols (10, 38%), COVID-19 screening (7, 27%), and length of hospital stay (7, 27%). The type of reconstruction varied depending on the stage of the pandemic: early on, autologous breast reconstruction was halted to preserve resources, but was later resumed. Within implant-based reconstruction, direct-to-implant was favored over serial tissue expansion. Several protocols were developed, with many emphasizing multidisciplinary collaborations for patient selection, use of specialized measures to reduce risk of COVID-19 transmission, and optimization of same-day discharge. Complication rates following breast reconstruction were similar to pre-pandemic rates.

Conclusions:

The COVID-19 pandemic has forever changed the landscape of breast reconstruction by raising important questions about delivery of care, cost, and resource utilization. The findings of this review may inform surgeons as they plan for similar future crises or strive for improved patient care and efficacy even during nonpandemic times.
Eyelid Crease Height Affects the Evaluation of Age-related Changes in the Eyelids
Authors: Akita Shinsuke , Maki Satoshi , Shiko Yuki , Kawasaki Yohei , Yamaji Yoshihisa , Tokumoto Hideki , Kosaka Kentaro , Ogata Hideyuki , Kubota Yoshitaka , Mitsukawa Nobuyuki
Published: November 2021

Background:

Although the functional and anatomical differences between the left and right eyelids are important in the evaluation of age-related changes in the eyelids, they have not been described clearly as indications for surgical treatments. This study aimed to investigate how laterality of the eyelids affects evaluation of age-related changes.

Methods:

Photographs of either one or both eyelids of 100 people were evaluated in four stages by 10 plastic surgeons. To investigate the consistency of the results between evaluations, surgeons evaluated the single-eyelid photographs (group U) or two-eyelid photographs (group B). It was investigated whether the difference in margin reflex distance 1, height of the upper eyelid crease, height of eyebrow, and levator contractile function were associated with mismatched evaluations.

Results:

The weighted kappa coefficient for groups B and U was 0.77 (substantial agreement). One-point difference in scores was observed in 23 cases. In the multiple logistic regression analysis, only the laterality the height of the eyelid crease was significantly different between patients whose evaluations were matched and those whose evaluations were mismatched (0.9 ± 0.1 mm versus 1.7 ± 0.2 mm; OR = 1.06, 95%CI: 1.01–1.10; P = 0.01).

Conclusions:

Besides the structure and function of each eyelid, the laterality of the height of the eyelid crease was important in the evaluation of the age-related changes in the eyelids. This factor may be important in evaluating the aesthetic and visual impressions of age-related changes in the eyelids.
Instructional Dermatology Surface Models
Authors: Ousley Lisa Ellen , Gentry Retha , Short Candice
Published: November 2021

The need for improving dermatology education is supported by the prevalence of skin cancer and by the high rates of skin disease. Instructional dermatology surface models were created by nurses in response to the rising incidence of skin cancer, the predominance of skin disease, and inadequate dermatology education. The aims of this nonexperimental descriptive research included (a) to establish the face validity and content validity of the models, (b) to assess the educational applicability for nursing and nondermatology students and clinicians, and (c) to further develop the models. A convenience sample of four physicians was recruited to evaluate the skin cancer models. A Likert scale was used to answer questions related to face and content validity and the applicability to dermatology education. The mean responses for the face and content validity and applicability to nondermatologist training were all ≤1.85, falling between the “strongly agree” and “agree” categories. The responses suggested good face and content validity of the skin cancer models. The models were created to promote effective learning and innovative nursing dermatology education.
Acne Management in Transgender Men and Boys
Authors: Somers Kathryn , Greenberg Katherine
Published: November 2021

Transgender men often seek hormonal therapy with testosterone and are thus prone to develop acne. Dermatology practitioners should be knowledgeable in the treatment of acne in transgender men. Isotretinoin and the iPledge system have particular hurdles in the transgender population that are discussed within.
Development of the Proposed 13 Entrustable Professional Activities for Physician Assistant Graduates
Authors: Acker Shekitta , Noelke Ashley , Huckabee Michael , Rieck Katie M.
Published: November 2021

Competency-based training has not consistently produced medical professionals who are ready to practice. To address this situation, entrustable professional activities (EPAs) have been introduced as a means to assess medical trainee readiness for their next phase of training or practice. Thirteen EPAs were developed by the Physician Assistant Education Association (PAEA) Presidents Commission in 2016 to indicate what activities they thought future physician assistant (PA) students should be expected to perform at the completion of their PA education. The 13 EPAs as proposed by the PAEA Presidents Commission were adopted by the Mayo Clinic PA program and further developed through multiple steps, including (1) Discovery and Alignment; (2) EPA Development; (3) Curriculum Development; (4) Assessment and Rubric Development, and (5) Implementation.
Dental Anesthesia for Medical Providers: A Novel Interprofessional Course
Authors: Howell Scott Emil Irving , Jafferbhoy Hennah , Trombly Colleen , Thompson Jesse , Knutson Linda
Published: November 2021

Purpose

To limit the use of opioids for nontraumatic dental conditions in emergency settings, the physician assistant (PA) and dental faculty at A.T. Still University designed a course that teaches PA students to administer dental anesthesia.

Methods

Dental faculty and teacher assistants taught PA students proper dental anesthesia. The course consisted of a recorded, prelaboratory lecture and in-person lab. During the laboratory, students rotated through 3 stations where they reviewed dental anatomy, practiced injections on dental anesthesia manikins, and simulated injections on student volunteers using the Safe-D-Needle. Students completed verbal and hands-on assessments.

Results

Ninety-seven percent of students passed the assessments on their first attempt. Course evaluations suggested the course had a positive effect on students' attitudes toward oral pain management.

Conclusion

This educational model allowed PAs to expand their emergency medicine toolbox. In the future, this model should be adapted to incorporate other healthcare professionals as well.
Examining the Hepatic Immune System in Children With Liver Disease With Fine Needle Aspiration
Authors: Yuksel Muhammed , Demirbaş Burak , Mizikoğlu Özlem , Tütüncü Yildiz , Kanmaz Turan , Oğuzkurt Levent , Arikan Cigdem
Published: November 2021

Objectives:

Liver biopsy is the standard in diagnosing liver diseases. Yet, it provides little space to perform comprehensive immune profiling of the liver. Hence, we explored whether fine needle aspirates (FNAs) could be used to elucidate the hepatic immunity in children.

Methods:

We enrolled 74 children undergoing diagnostic (n = 17) or protocol biopsy (n = 57) following liver transplantation (LT). Matched blood and FNAs were obtained. Additionally, explant liver tissue was collected from children (n = 14) undergoing LT. Immune cells were isolated from peripheral blood, FNAs and explanted livers. Immune‐phenotypical profiling was done by flow cytometry.

Results:

Biopsied patients (58% female) were at a median age of 46 months (interquartile range [IQR]: 12–118) and LT patients (71% female) were 48 months (IQR: 21–134, P = 0.78) old. CD69+, a hallmark of tissue‐resident immune cells was expressed in 1.3% of CD3+ T cells from blood being higher in FNA (20%) and tissue (49%, P < 0.001). CD4+ T‐cell frequencies in tissue (13%) and FNAs (20%) were lower compared to blood (35%, P < 0.001) whereas CD8+ T cells in tissue (33.5%) and FNA (32%) were higher than in blood (25%, P < 0.01). Mucosal associated invariant T cells were enriched in liver tissue (8.8%) and in the FNA (4.4%) compared to blood (1.7%, P < 0.001). Whereas the percentage of total Tregs (CD4+CD25+FOXP3+CD127low/−) decreased, the proportion of activated Tregs (CD4+CD45RA‐FOXP3high) increased in FNA and explant. Breg (CD19+CD20+CD24highCD38high) frequencies were similar in all groups.

Conclusion:

FNA is a practical method to sample the liver immune system collecting even small cell subsets such as regulatory T/B cells.
Neurobrucellosis
Authors: Bouferraa Youssef , Bou Zerdan Maroun , Hamouche Ramzi , Azar Eid , Afif Claude , Jabbour Rosette
Published: November 2021

Background:

Brucella are small, nonmotile, intracellular, and aerobic gram-negative bacteria. Of the 10 species that currently form the genus Brucella, 5 were shown to be pathogenic in humans.

Review Summary:

The epidemiology, clinical manifestations, diagnosis and imaging, and treatment of neurobrucellosis will be reviewed.

Brucellosis’s transmission to humans occurs by direct contact with contaminated animals. Older patients are at increased risk of nervous system involvement in brucellosis. Brucella spp. can lead to central nervous system involvement through direct damage via invasion of neural tissue or indirect damage caused by endotoxins or immune inflammatory reactions elicited by the presence of the bacteria in the body. Patients can have general nonspecific symptoms in addition to neurological and psychiatric symptoms. There are 4 diagnostic criteria for the diagnosis of neurobrucellosis, which include signs and symptoms suggestive of neurobrucellosis, a positive finding of Brucella spp. in the cerebrospinal fluid (CSF), and/or a positive titer of antibodies targeting brucella in the CSF, lymphocytosis with high protein levels and low glucose levels in CSF, and imaging findings (either cranial magnetic resonance imaging or computed tomography) peculiar to neurobrucellosis. For the treatment, a combined therapy is favored over monotherapy for the eradication of Brucella. Moreover, a multirouted therapy has been associated with increased treatment efficacy. The prognosis of neurobrucellosis is dependent on patients’ clinical presentation: brucellar meningitis is associated with a good prognosis, whereas diffuse central nervous system involvement is associated with the development of long-term sequelae.

Conclusions:

Neurobrucellosis affects patients globally and in endemic areas. Neurologists should familiarize themselves with its clinical presentation, diagnosis, and treatment to provide optimal care for their patients.
COVID-19 Associated Wake-Up Stroke Treated With DWI/FLAIR Mismatch Guided Intravenous Alteplase
Authors: Biag Earl , Solis Krystian , Abd Elazim Ahmed , Hussein Omar
Published: November 2021

Introduction:

Wake-up strokes are challenging to manage due to unknown time of onset. Recently, the wake-up trial demonstrated that recombinant tissue plasminogen activator (rtPA) could be administered based on the magnetic resonance imaging (MRI)- diffusion weighted imaging/fluid attenuated inversion recovery mismatch. Many still doubt the safety results due to the higher rate of hemorrhagic conversion reported. Although it was statistically insignificant, the study was terminated early. Furthermore, Corona virus disease-19 is associated with coagulopathy and a higher risk of hemorrhagic conversion.

Case Report:

A 46-year-old fully functioning male presented with a wake-up right hemiparesis, right facial droop, and expressive aphasia. His National Institute of Health Stroke Scale was 4 upon arrival. Last known well state was >4.5 hours. He tested positive for SARS-CoV-2 viral infection. He had left distal-M2 occlusion. He was deemed not a candidate for rtPA. Hyperacute-MRI protocol showed diffusion weighted imaging/fluid attenuated inversion recovery mismatch. The patient received rtPA at 6.5 hours from the last knwn well state. Follow-up MRI-susceptibility weighted imaging revealed fragmented clot. The stroke burden was less than that shown on the initial computed tomography-perfusion scans implying saved penumbra. There was no hemorrhagic conversion despite low fibrinogen levels.

Conclusion:

The hyperacute-MRI protocol for wake-up COVID-19 associated strokes might be a safe option.
COVID-19 Infection and Recurrent Stroke in Young Patients With Protein S Deficiency
Authors: Ali Leila , Jamoussi Hela , Kouki Nessrine , Fray Saloua , Echebbi Slim , Ben Ali Nadia , Fredj Mohamed
Published: November 2021

Introduction:

Protein S deficiency and coronavirus disease 2019 (COVID-19) are rare etiologies of ischemic stroke. We describe a case of an ischemic stroke revealing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a patient with a history of protein S deficiency and cerebral imaging suggestive of vasculitis.

Case Report:

A 52-year-old woman, with history of protein S deficiency, was admitted for right hemiparesis and aphasia that happened 6 hours before her consultation. Her National Institutes of Health Stroke Scale (NIHSS) was 11. She had hypoxia (SpO2 93%). COVID-19 polymerase chain reaction was positive. Cerebral computed tomography scan showed an ischemic stroke in the territory of the superficial left middle cerebral artery. The recommended time period for thrombolysis was exceeded and we did not dispose of sufficient resources to deliver thrombectomy. She was treated with aspirin, statins, antibiotic therapy, and oxygen. Considering the high risk of thromboembolic complications and the history of protein S deficiency, anticoagulation treatment with heparin followed by acenocoumarol was started. Evolution was marked by the appearance of 24 hours regressive, acute symptoms of confusion. Brain magnetic resonance imaging showed new ischemic strokes in both anterior cerebral arteries and on magnetic resonance angiography narrowing of the left internal carotid artery and both anterior cerebral arteries suggestive of vasculitis was seen. We maintained anticoagulation and prescribed methylprednisolone 500 mg daily for 3 days. Evolution was marked by improvement of clinical deficit and respiratory status.

Conclusions:

SARS-CoV-2 infection potentializes the prothrombotic effect and vascular inflammation by accentuating protein S deficit. The place of steroids seems justifiable in the presence of symptoms of vasculitis in brain imaging.
Neurological Symptoms and Diagnoses in Patients Hospitalized With COVID-19
Authors: Haki Cemile , Demirci Hakan , Ayar Yavuz , Demir Canan , Caliskan Gulbahar
Published: November 2021

Background:

Coronavirus disease 2019 (COVID-19) is a disease that affects many organs, especially the lung, and may lead to multiorgan failure. Studies describing neurological dysfunctions involving the central and peripheral nervous systems have emerged. In our study, we aimed to evaluate the neurological signs and symptoms in hospitalized patients with COVID-19.

Methods:

The data of 290 patients admitted to our center (ward and intensive care unit) who received a diagnosis of COVID-19 were analyzed retrospectively. Patients’ demographic, clinical and laboratory data, and their neurological diseases, symptoms, and complications were compared.

Results:

Male sex, heart disease, chronic obstructive pulmonary disease and having a history of neurological disease were associated with increased mortality in patients with COVID-19. Seizures and altered consciousness were also found to be more common in patients who died. In addition, lower platelet counts (P=0.001), higher C-reactive protein levels (P<0.001) and higher D-dimer levels (P=0.003) were associated with increased risk of mortality.

Conclusions:

We believe that close monitoring of any possible neurological manifestations is mandatory in hospitalized patients at the onset of COVID-19 and during disease progression. Clinical findings such as neurological symptoms and acute phase reactants are important in the follow-up and treatment of the disease.
Caste, sex, and parasitism influence brain plasticity in a social wasp
Authors: Gandia Kristine M. , Cappa Federico , Baracchi David , Hauber Mark. E. , Beani Laura , Uy Floria M. K.
Published: November 2021

Phenotypic plasticity is the capacity of a single genotype to exhibit different phenotypes, and can be an adaptive response to specific environmental and social conditions. Social insects are particularly well-suited to study plasticity, because the division of labor amongst females and the different life histories of males and females are associated with specific sensory needs. Here, we take advantage of the social waspPolistes dominulato explore if brain plasticity is influenced by caste and sex, and the exploitation by the parasiteXenos vesparum. Within sexes, males had proportionally larger optic lobes, while females, regardless of caste, had larger antennal lobes, which is consistent with sensory needs of sex-specific life histories. Within castes, reproductive females had larger calyces, as predicted by their sensory needs for extensive within-colony interactions and forming winter aggregations, than workers who spend more time foraging for nest material and prey. Surprisingly, parasites had different effects on female and male hosts. Female workers were castrated and behaviorally manipulated by female or male parasites, but only showed moderate differences in relative allocation of different brain tissue compared to non-parasitized workers. In contrast, the testes and behavior of parasitized males were essentially unaffected, but they had smaller brains and greater relative volume of most sensory brain regions than non-parasitized males. Our results are consistent with caste and sex mediating brain plasticity inP. dominulaand that the parasite’s manipulation can also drive differential allocation of brain regions depending on host sex.
Intratumoral Delivered Novel Circular mRNA Encoding Cytokines for Immune Modulation and Cancer Therapy
Authors: Yang Jiali , Zhu Jiafeng , Chen Yiyun , Du Yaran , Tan Yiling , Wu Linpeng , Sun Jiaojiao , Zhai Mengting , Wei Lixiang , Li Na , Huang Ke , Hou Qiangbo , Tong Zhenbo , Bechthold Andreas , Sun Zhenhua , Zuo Chijian
Published: November 2021

The application of mRNA as a novel kind of vaccine has been proved recently, due to the emergence use authorization (EUA) by FDA for the two COVID-19 mRNA vaccines developed by Moderna and BioNTech. Both of the two vaccines are based on canonical linear mRNA, and encapsulated by lipid nanoparticle (LNP). Circular mRNA, which is found to mediate potent and durable protein expression, is an emerging technology recently. Owing to its simplicity of manufacturing and superior performance of protein expression, circular mRNA is believed to be a disruptor for mRNA area. However, the application of circular mRNA is still at an initiation stage, proof of concept for its usage as future medicine or vaccine is necessary. In the current study, we established a novel kind of circular mRNA, termed C-RNA, based on Echovirus 29 (E29)-derived internal ribosome entry sites (IRES) and newly designed homology arms and RNA spacers. Our results demonstrated that this kind of circular mRNA is able to mediate strong and durable protein expression, compared to typical linear mRNA. Moreover, for the first time, our study demonstrated that direct intratumoral administration of C-RNA encoding a mixture of cytokines achieved successful modulation of intratumoral and systematic anti-tumor immune responses and finally leading to an enhancement of anti-PD-1 antibody-induced tumor repression in syngeneic mouse model. Additionally, after an optimization of the circular mRNA formulation, a significant improvement of C-RNA mediated protein expression was observed. With this optimized formulation, C-RNA induced enhanced anti-tumor effect via intratumoral administration and elicited significant activation of tumor-infiltrated total T cells and CD8+ T cells. Collectively, we established C-RNA, a novel circular mRNA platform, and demonstrated that it can be applied for direct intratumoral administration for cancer therapy.
Specific Sensitivity to Rare and Extreme Events: Quasi-Complete Black Swan Avoidance vs Partial Jackpot Seeking in Rat Decision-Making*
Authors: Degoulet Mickaël , Willem Louis-Matis , Baunez Christelle , Luchini Stéphane , Pintus Patrick A.
Published: November 2021

Most studies assessing animal decision-making under risk rely on probabilities that are typically larger than 10%. To study Decision-Making in uncertain conditions, we explore a novel experimental and modelling approach that aims at measuring the extent to which rats are sensitive - and how they respond - to outcomes that are both rare (probabilities smaller than 1%) and extreme in their consequences (deviations larger than 10 times the standard error). In a four-armed bandit task, stochastic gains (sugar pellets) and losses (time-out punishments) are such that extremely large - but rare - outcomes materialize or not depending on the chosen options. All rats feature both limited diversification, mixing two options out of four, and sensitivity to rare and extreme outcomes despite their infrequent occurrence, by combining options with avoidance of extreme losses (Black Swans) and exposure to extreme gains (Jackpots). Notably, this sensitivity turns out to be one-sided for the main phenotype in our sample: it features a quasi-complete avoidance of Black Swans, so as to escape extreme losses almost completely, which contrasts with an exposure to Jackpots that is partial only. The flip side of observed choices is that they entail smaller gains and larger losses in the frequent domain compared to alternatives. We have introduced sensitivity to Black Swans and Jackpots in a new class of augmented Reinforcement Learning models and we have estimated their parameters using observed choices and outcomes for each rat. Adding such specific sensitivity results in a good fit of the selected model - and simulated behaviors that are close - to behavioral observations, whereas a standard Q-Learning model without sensitivity is rejected for almost all rats. This model reproducing the main phenotype suggests that frequent outcomes are treated separately from rare and extreme ones through different weights in Decision-Making.
An epigenetic memory of inflammation controls context-dependent lineage plasticity in the pancreas
Authors: Falvo David J. , Grimont Adrien , Zumbo Paul , Yang Julie L. , Osterhoudt Alexa , Pan Grace , Rendeiro Andre F. , Wilkinson John E. , Dündar Friederike , Elemento Olivier , Yantiss Rhonda K. , Betel Doron , Koche Richard , Chandwani Rohit
Published: November 2021

Inflammation is essential to the disruption of tissue homeostasis, and, in the pancreas, can destabilize the identity of terminally differentiated acinar cells. Herein we employ lineage-traced mouse models to delineate the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and unveil the presence of an epigenetic memory of inflammation in the pancreatic acinar cell compartment. We observe that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular baseline after several months, representing an incomplete cell fate decision. In vivo, this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis with an oncogenic Kras mutation. We demonstrate that both persistent chromatin and transcriptional changes constituting memory are recalled with oncogenic stress. Together, our findings define the dynamics and recall of an epigenetic memory of inflammation that impacts cell fate decisions in a context-dependent manner.
Elexacaftor/Tezacaftor/Ivacaftor alters branching morphogenesis of the mouse embryonic lung
Authors: Lhuillier Mickaël , Aoust Laura , Dreano Elise , Franco-Montoya Marie-Laure , Landry-Truchon Kim , Houde Nicolas , Chhun Stéphanie , Hinzpeter Alexandre , Edelman Aleksander , Delacourt Christophe , Jeannotte Lucie , Sermet-Gaudelus Isabelle , Hadchouel Alice
Published: November 2021

Introduction

CFTR modulators triple combo-therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) has proven to clinically benefit homozygous and heterozygous F508del patients. As a result, an increasing number of pregnancies is expected. Studies of the potential impact of these modulators on the development of the foetus are mandatory.

Materials

We used the early mouse embryonic lung organ culture model to analyse ex vivo the lung branching process and the relative expression of Fgf10, Fgfr2IIIb, Shh, and Hhip development regulator genes in different conditions: standard culture medium, treatment with ETI or with Forskolin ± Inh172. Development of lung branching and distal bud caliber were evaluated in lung explants from heterozygous F508del Cftrtm1Eur/+ and control Cftrtm1Eur+/+ (WT) mouse embryos at E12.5 during pseudo-glandular stage.

Results

Exposure to ETI of the Cftrtm1Eur/+ and WT lung explants induced a significant decrease in lung branching after 48h culture and the percentage of terminal bud dilations was significantly increased. These results were recapitulated by cAMP-dependent CFTR continuous activation by Forskolin and reversed by addition of Inh172.

ETI induced a significant decrease in Fgf10, Fgfr2IIIb, Shh and Hhip expression in lung explants of both E12.5 Cftrtm1Eur/+ and WT embryos treated with ETI for 72h.

Conclusion

Our results provide evidence that the triple association Elexacaftor/Tezacaftor/Ivacaftor alters lung branching morphogenesis of WT and heterozygous F508del mouse embryos during the pseudo-glandular stage. Those results argue for a close monitoring of pregnancies in patients treated with these drugs.

Plain Language

Introduction

The triple combo-therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) improves homozygous and heterozygous F508del patients. As a result, an increasing number of pregnancies is expected. Studies of this treatment on the development of the foetus are lacking. We incubated lungs of murine foetus not carrying CFTR mutation or F508del heterozygous. We show that ETI induces significant defect of lung development and the formation of cysts. These results are at least partly due to CFTR activation. Those results argue for a close monitoring of pregnancies in patients treated with these drugs.
Wheat photosystem II heat tolerance responds dynamically to short and long-term warming
Authors: Posch Bradley C. , Hammer Julia , Atkin Owen K. , Bramley Helen , Ruan Yong-Ling , Trethowan Richard , Coast Onoriode
Published: November 2021

Heat-induced inhibition of photosynthesis is a key factor in declining wheat performance and yield. Variation in wheat heat tolerance can be characterised using the critical temperature (Tcrit) above which incipient damage to the photosynthetic machinery occurs. We investigated intraspecies variation and plasticity of wheat Tcrit under elevated temperature in field and controlled environment experiments. We also assessed whether intraspecies variation in wheat Tcrit mirrors patterns of global interspecies variation in heat tolerance reported for mostly wild, woody plants. In the field, wheat Tcrit varied through the course of a day, peaking at noon and lowest at sunrise, and increased as plants developed from heading to anthesis and grain filling. Under controlled temperature conditions, heat stress (36°C) was associated with a rapid rise in wheat Tcrit (i.e. within two hours of heat stress) that peaked after 3–4 days. These peaks in Tcrit indicate a physiological limitation to photosystem II heat tolerance. Analysis of a global dataset (comprising 183 Triticum and wild wheat (Aegilops) species) generated from the current study and a systematic literature review showed that wheat leaf Tcrit varied by up to 20°C (about two-thirds of reported global plant interspecies variation). However, unlike global patterns of interspecies Tcrit variation which has been linked to latitude of genotype origin, intraspecific variation in wheat Tcrit was unrelated to that. Yet, the observed genotypic variation and plasticity of wheat Tcrit suggests that this trait could be a useful tool for high-throughput phenotyping of wheat photosynthetic heat tolerance.
Quality-controlled R-loop meta-analysis reveals the characteristics of R-Loop consensus regions
Authors: Miller H. E. , Montemayor D. , Abdul J. , Vines A. , Levy S. , Hartono S. , Sharma K. , Frost B. , Chedin F. , Bishop A. J. R.
Published: November 2021

R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA during transcription. While the pathological consequences of R-loops have been well-studied to date, the locations, classes, and dynamics of physiological R-loops remain poorly understood. R-loop mapping studies provide insight into R-loop dynamics, but their findings are challenging to generalize. This is due to the narrow biological scope of individual studies, the limitations of each mapping modality, and, in some cases, poor data quality. In this study, we reprocessed 693 R-loop mapping datasets from a wide array of biological conditions and mapping modalities. From this data resource, we developed an accurate method for R-loop data quality control, and we reveal the extent of poor-quality data within previously published studies. We then identified a set of high-confidence R-loop mapping samples and used them to define consensus R-loop sites called “R-loop regions” (RL regions). In the process, we revealed the stark divergence between S9.6 and dRNH-based R-loop mapping methods and identified biologically meaningful subtypes of both constitutive and variable R-loops. Taken together, this work provides a much-needed method to assess R-loop data quality and reveals intriguing aspects of R-loop biology.
Isolation of gametes and zygotes from Setaria viridis
Authors: Toda Erika , Kiba Takatoshi , Kato Norio , Okamoto Takashi
Published: November 2021

Setaria viridis, the wild ancestor of foxtail millet (Setaria italica), is an effective model plant for larger C4 crops because it has several desirable traits, such as short generation time, prolific seed production and a small genome size. These advantages are well suited for investigating molecular mechanisms in angiosperms, especially C4 crop species. Here, we report a procedure for isolating gametes and zygotes from S. viridis flowers. To isolate egg cells, ovaries were harvested from unpollinated mature flowers and cut transversely, which allowed direct access to the embryo sac. Thereafter, an egg cell was released from the cut end of the basal portion of the dissected ovary. To isolate sperm cells, pollen grains released from anthers were immersed in a mannitol solution, resulting in pollen-grain bursting, which released sperm cells. Additionally, S. viridis zygotes were successfully isolated from freshly pollinated flowers. Isolated zygotes cultured in a liquid medium developed into globular-like embryos and cell masses. Thus, isolated S. viridis gametes, zygotes and embryos are attainable for detailed observations and investigations of fertilization and developmental events in angiosperms.
Exploration and analysis of R-loop mapping data with RLBase
Authors: Miller H. E. , Montemayor D. , Li J. , Levy S. , Pawar R. , Hartono S. , Sharma K. , Frost B. , Chedin F. , Bishop A. J. R.
Published: November 2021

R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA during nascent transcription. In 2012, Ginno et al. introduced the first R-loop mapping method, DNA:RNA immunoprecipitation (DRIP) sequencing. Since that time, dozens of studies have implemented R-loop mapping and new high-resolution techniques have been developed. The resulting datasets have tremendous potential to reveal the causes and consequences of R-loops genome-wide. However, poor quality and variability between mapping approaches pose serious barriers to the meta-analysis of these data. In our recent work, we reprocessed 693 R-loop mapping samples, devising new quality methods, defining a set of high-confidence mapping samples, and then deriving R-loop regions, consensus sites of R-loop formation. This analysis yielded the largest R-loop data resource to date along with novel computational approaches for R-loop mapping analysis. Now, we introduce RLBase, an innovative web server which builds upon those data and software by providing users with the capability to (1) explore hundreds of public R-loop mapping datasets, (2) explore consensus R-loop regions, (3) analyze user-supplied datasets to generate an HTML quality report, and (4) download all the processed data for the 693 samples we previously reprocessed and standardized. In addition to RLBase, we also describe the other software which, along with RLBase, provides a computational framework for R-loop bioinformatics. RLBase, and the rest of these software (termed “RLSuite”), are provided freely under an MIT license and made publicly available: https://gccri.bishop-lab.uthscsa.edu/rlsuite/. RLBase is directly accessible via the following URL: https://gccri.bishop-lab.uthscsa.edu/rlbase/.
Low selectivity index of ivermectin and macrocyclic lactones on SARS-CoV2 replication in vitro argues against their therapeutic use for COVID-19
Authors: Chable-Bessia Christine , Boullé Charlotte , Neyret Aymeric , Swain Jitandrya , Hénaut Mathilde , Merida Peggy , Gros Nathalie , Makinson Alain , Lyonnais Sébastien , Chesnais Cédric B. , Muriaux Delphine
Published: November 2021

There are very limited antiviral therapeutic options for coronavirus infections, therefore global drug re-purposing efforts are paramount to identify available compounds that could provide clinical benefits to patients with COVID-19. Ivermectin was first approved for human use as an endectocide in the 1980s. It remains one of the most important global health medicines in history and has recently been shown to exert in vitro activity against SARS-CoV-2. However, the macrocyclic lactone family of compounds has not previously been evaluated for activity against SARS-CoV-2. The present study aims at comparing their anti-viral activity in relevant pulmonary cell lines in vitro. Here, in vitro antiviral activity of the avermectins (ivermectin and selamectin) and milbemycins (moxidectin and milbemycin oxime) were assessed against a clinical isolate from a CHU Montpellier patient infected with SARS-CoV-2 in 2020. Ivermectin demonstrated anti-SARS-CoV-2 activity in vitro in human pulmonary cells in comparison to VeroE6 (with EC50 of 1-3 μM). Similarly, the other macrocyclic lactones moxidectin, milbemycin oxime and selamectin reduced SARS-CoV-2 replication in vitro (with EC50 of 2-5 μM). Immunofluorescence assays with ivermectin and moxidectin showed a reduction in the number of infected and polynuclear cells suggesting a drug action on viral cell fusion. However, cellular toxicity of the avermectins and milbemycins during infection showed a very low selectivity index <10 for all compounds. In conclusion, none of these agents appears suitable for human use for its anti-SARS-CoV-2 activity per se, due to low selectivity index. This is discussed in regards to recent clinical COVID studies on ivermectin.
The basic reproduction number of COVID-19 across Africa
Authors: Iyaniwura Sarafa A. , Rabiu Musa , David Jummy F. , Kong Jude D.
Published: November 2021

The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) took the world by surprise. Following the first outbreak of COVID-19 in December 2019, several models have been developed to study and understand its transmission dynamics. Although the spread of COVID-19 is being slowed down by vaccination and other interventions, there is still a need to have a clear understanding of the evolution of the pandemic across countries, states and communities. To this end, there is a need to have a clearer picture of the initial spread of the disease in different regions. In this project, we used a simple SEIR model and a Bayesian inference framework to estimate the basic reproduction number of COVID-19 across Africa. Our estimates vary between 1.98 (Sudan) and 9.66 (Mauritius), with a median of 3.67 (90% CrI: 3.31 - 4.12). The estimates provided in this paper will help to inform COVID-19 modeling in the respective countries/regions.
Generalized Radiograph Representation Learning via Cross-supervision between Images and Free-text Radiology Reports
Authors: Zhou Hong-Yu , Chen Xiaoyu , Zhang Yinghao , Luo Ruibang , Wang Liansheng , Yu Yizhou
Published: November 2021

Pre-training lays the foundation for recent successes in radiograph analysis supported by deep learning. It learns transferable image representations by conducting large-scale fully-supervised or self-supervised learning on a source domain. However, supervised pre-training requires a complex and labor intensive two-stage human-assisted annotation process while self-supervised learning cannot compete with the supervised paradigm. To tackle these issues, we propose a cross-supervised methodology named REviewing FreE-text Reports for Supervision (REFERS), which acquires free supervision signals from original radiology reports accompanying the radiographs. The proposed approach employs a vision transformer and is designed to learn joint representations from multiple views within every patient study. REFERS outperforms its transfer learning and self-supervised learning counterparts on 4 well-known X-ray datasets under extremely limited supervision. Moreover, REFERS even surpasses methods based on a source domain of radiographs with human-assisted structured labels. Thus REFERS has the potential to replace canonical pre-training methodologies.
Fungal biodiversity in Arctic paleoecosystems assessed by metabarcoding of lake sedimentary ancient DNA
Authors: Seeber PA , von Hippel B , Kauserud H , Löber U , Stoof-Leichsenring KR , Herzschuh U , Epp LS
Published: November 2021

Fungi are crucial organisms in most ecosystems as they exert ecological key functions and are closely associated with land plants. Fungal community changes may therefore help reveal biodiversity changes in past ecosystems. Lake sediments contain DNA of organisms in the catchment area, which allows reconstructing past biodiversity by using metabarcoding of ancient sedimentary DNA. We developed a novel PCR primer combination for fungal metabarcoding targeting a short amplicon to account for length bias of amplification due to ancient DNA degradation. In-silico PCRs showed higher diversity using this primer combination than using previously established fungal metabarcoding primers. We analyzed existing data from sediment cores from four artic and one boreal lake in Siberia. These cores had been stored for 2–22 years and examined degradation effects of ancient DNA and storage time-related bias in fungal communities. Amplicon size differed between fungal divisions, however, we observed no significant effect of sample age on amplicon length and GC content, suggesting robust results. We also found no indication of post-coring fungal growth during storage distorting ancient fungal communities. Terrestrial soil fungi, including mycorrhizal fungi and saprotrophs, were predominant in all lakes, which supports the use of lake sedimentary ancient DNA for reconstructing terrestrial communities.
Riding into the future on a fly: toward a better understanding of phoresy and avian lice evolution (Phthiraptera) by screening bird carcasses for phoretic lice on hippoboscid flies (Diptera)
Authors: Lee Leshon , Tan David J.X. , Oboňa Jozef , Gustafsson Daniel R. , Yuchen Ang , Meier Rudolf
Published: November 2021

Many phoretic relationships between insects are understudied because of taxonomic impediments. We here illustrate for avian lice riding on hippoboscid flies how new natural history data on phoretic relationships can be acquired quickly with NGS barcoding. Most avian lice are host-specific, but some can arrive on new hosts by riding hippoboscid flies that feed on bird blood. Our summary of the literature yielded 254 published records which we here show to belong to two large and 13 small interaction networks for birds, flies, and lice. In order to generate new records, we then developed a new protocol based on screening bird carcasses sourced by citizen scientists. The inspection of 131 carcasses from Singapore lead to the first record of aGuimaraesiellalouse species riding onOrnithoica momiyamaiflies collected from a pitta carcass. Phoresy may explain why this louse species is now known from three phylogenetically disparate hosts (Pitta moluccensis,Ficedula zanthopygia;Pardaliparus elegans). A second new case of phoresy enhances a large interaction network dominated byOrnithophila metallica, a cosmopolitan and polyphagous hippoboscid fly species. Overall, we argue that many other two- and three-way phoretic relationships between arthropods (e.g., mites, pseudoscorpiones, beetles, flies) can be resolved using cost-effective large-scale NGS barcoding, which can be used to pre-sort specimens for taxonomic revision and thus partially overcome some taxonomic impediments.
Montage electron tomography of vitrified specimens
Authors: Peck Ariana , Carter Stephen D. , Mai Huanghao , Chen Songye , Burt Alister , Jensen Grant J.
Published: November 2021

Cryo-electron tomography provides detailed views of macromolecules in situ. However, imaging a large field of view to provide more cellular context requires reducing magnification during data collection, which in turn restricts the resolution. To circumvent this trade-off between field of view and resolution, we have developed a montage data collection scheme that uniformly distributes the dose throughout the specimen. In this approach, sets of slightly overlapping circular tiles are collected at high magnification and stitched to form a composite projection image at each tilt angle. These montage tilt-series are then reconstructed into massive tomograms with a small pixel size but a large field of view. For proof-of-principle, we applied this method to the thin edge of HeLa cells. Thon rings to better than 15 Å were observed in the montaged tilt-series, and diverse cellular features were evident in the resulting tomograms. These results indicate that the additional dose required by this technique is not prohibitive to performing structural analysis to intermediate resolution across a large field of view. We anticipate that montage tomography will prove particularly useful for lamellae, increase the likelihood of imaging rare cellular events, and facilitate visual proteomics.
Feedback information sharing in the human brain reflects bistable perception in the absence of report
Authors: Canales-Johnson Andres , Beerendonk Lola , Chennu Srivas , Davidson Matthew J. , Ince Robin A.A. , van Gaal Simon
Published: November 2021

In the search for the neural basis of conscious experience, perception and the cognitive processes associated with reporting perception are typically confounded as neural activity is recorded while participants explicitly report what they experience. Here we present a novel way to disentangle perception from report using eye-movement analysis techniques based on convolutional neural networks and neurodynamical analyses based on information theory. We use a bistable visual stimulus that instantiates two well-known properties of conscious perception: integration and differentiation. At any given moment, observers either perceive the stimulus as one integrated unitary object or as two differentiated objects that are clearly distinct from each other. Using electroen-cephalography, we show that measures of integration and differentiation based on information theory closely follow participants’ perceptual experience of those contents when switches were reported. We observed increased information integration between anterior to posterior electrodes (front to back) prior to a switch to the integrated percept, and higher information differentiation of anterior signals leading up to reporting the differentiated percept. Crucially, information integration was closely linked to perception and even observed in a no-report condition when perceptual transitions were inferred from eye movements alone. In contrast, the link between neural differentiation and perception was observed solely in the active report condition. Our results, therefore, suggest that perception and the processes associated with report require distinct amounts of anterior-posterior network communication and anterior information differentiation. While front-to-back directed information is associated with changes in the content of perception when viewing bistable visual stimuli, regardless of report, frontal information differentiation was absent in the no-report condition and therefore is not directly linked to perceptionper se.