bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study
Authors: Bowlus Christopher L. , Eksteen Bertus , Cheung Angela C. , Thorburn Douglas , Moylan Cynthia A. , Pockros Paul J. , Forman Lisa M. , Dorenbaum Alejandro , Hirschfield Gideon M. , Kennedy Ciara , Jaecklin Thomas , McKibben Andrew , Chien Elaine , Baek Marshall , Vig Pamela , Levy Cynthia
Published: May 2023

Background:

Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC.

Methods:

This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed.

Results:

Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (−14.84 µmol/L; 95% CI, −27.25 to −2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (−22.3 µmol/L, 95% CI, −40.38 to −4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline.

Conclusions:

Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.
Proportional Internal Work—a New Parameter of Exercise Testing in Study of Health in Pomerania (SHIP)
Authors: Ittermann Till , Ewert Ralf , Habedank Dirk , Kaczmarek Sabine , Felix Stephan B. , Dörr Marcus , Stubbe Beate , Bahls Martin
Published: May 2023

Purpose:

Cardiopulmonary exercise testing usually requires a maximal exhaustive effort by the patient and is time consuming. The purpose of this study was to assess whether the cost to initiate exercise termed “proportional internal work” (PIW) was related to cardiovascular disease (CVD) risk factors, ventilatory parameters, and mortality.

Methods:

We used data from population-based Study of Health in Pomerania. A total of 2829 (49.5% female) study participants with a median age of 52 (42-62) yr were included. Standardized questionnaires were used to assess CV risk factors. The cardiopulmonary exercise testing was performed using a modified Jones protocol. Regression models adjusted for sex and age were used to relate PIW with CVD risk factors and ventilatory parameters. The PIW was calculated by the following formula: (Oxygen uptake at rest – Oxygen uptake without load)/V˙o2peak) × 100. Cox regression analysis was used to relate PIW and all-cause mortality.

Results:

We identified a nonlinear association between PIW and percent predicted V˙o2peak. Women had a 2.96 (95% CI, 2.61-3.32) greater PIW than men. With each year of age and every point in body mass index, the PWI increased by 0.04 (95% CI, 0.03-0.05) and 0.16 (95% CI, 0.12-0.20), respectively. After adjustment for age, sex, smoking, and body mass index, a 1-point greater PIW was associated with a 5% higher risk to die (HR = 1.05; 95% CI, 1.01-1.07).

Conclusions:

The PIW is a new cardiopulmonary exercise testing parameter related to CVD risk and all-cause mortality. Future studies should assess the prognostic relevance of PIW for CVD prevention.
A new frontier for fat: dietary palmitic acid induces innate immune memory
Authors: Seufert Amy L. , Napier Brooke A.
Published: May 2023

Dietary saturated fats have recently been appreciated for their ability to modify innate immune cell function, including monocytes, macrophages, and neutrophils. Many dietary saturated fatty acids (SFAs) embark on a unique pathway through the lymphatics following digestion, and this makes them intriguing candidates for inflammatory regulation during homeostasis and disease. Specifically, palmitic acid (PA) and diets enriched in PA have recently been implicated in driving innate immune memory in mice. PA has been shown to induce long-lasting hyper-inflammatory capacity against secondary microbial stimuli in vitro and in vivo, and PA-enriched diets alter the developmental trajectory of stem cell progenitors in the bone marrow. Perhaps the most relevant finding is the ability of exogenous PA to enhance clearance of fungal and bacterial burdens in mice; however, the same PA treatment enhances endotoxemia severity and mortality. Westernized countries are becoming increasingly dependent on SFA-enriched diets, and a deeper understanding of SFA regulation of innate immune memory is imperative in this pandemic era.
Work as a Frontline Volunteer During the COVID-19 Outbreak in Hubei, China: A Qualitative Inquiry of Male Nurses
Authors: CHEN Liuliu , CHEN Xiangying , DENG Zhijian , ZHAO Junyan , YANG Liu , ZHANG Jianghui , PENG Jianying , SUN Lili , QIU Yeyin , DENG Renli , ZHANG Hongtao
Published: May 2023

Background

During the coronavirus (COVID-19) outbreak in 2019, an increased large number of male nurses volunteered for frontline assignment. Their excellent performance suggests that male nurses have several advantages over female nurses. However, research into the activities of Chinese male nurses engaged in frontline work during the COVID-19 pandemic remains limited.

Purpose

This study was designed to summarize the reflections of male nurses on their experiences while volunteering for frontline COVID-19 duty in Hubei, China.

Methods

An interpretative qualitative descriptive study was conducted from May to July 2020 on male nurses who had volunteered for frontline COVID-19 duty in Hubei. Twelve male nurses were selected using a purposive sampling method. Data were collected using semistructured interviews, transcribed verbatim, and analyzed using thematic analysis.

Results

Four main themes and 11 subthemes were identified, including (a) changing the way of thinking at work (four subthemes), (b) clarity regarding career development (three subthemes), (c) change in life philosophy (two subthemes), and (d) personal growth (two subthemes).

Conclusions

The experience of volunteering during the COVID-19 public health emergency influenced the male nurses positively in terms of improved organizational, management, and decision-making skills as well as improved performance. The beneficial attributes of male nurses should be taken into consideration when developing management policies related to nursing personnel.
American Medical Society of Sports Medicine Position Statement: Mononucleosis and Athletic Participation
Authors: Putukian Margot , McGrew Christopher A. , Benjamin Holly J. , Hammell Mary Kitazono , Hwang Calvin E. , Ray Jeremiah W. , Statuta Siobhan M. , Sylvester Jillian , Wilson Kristina
Published: May 2023

Infectious mononucleosis (IM) is a common illness in children and young adults caused primarily by the Epstein–Barr Virus (EBV). Transmission occurs primarily through sharing oral secretions, thus IM is known as the “kissing disease.” Common clinical manifestations include fever, pharyngitis, posterior cervical lymphadenopathy, and splenomegaly. Atypical lymphocytosis and transaminase elevations are common, and the diagnosis of IM is confirmed with laboratory findings of a positive heterophile antibody (“Monospot”), polymerase chain reaction, or antibodies specific to EBV. Individuals with acute IM may be quite symptomatic and not feel well enough to participate in sports. Splenic enlargement is common, with rupture a relatively rare occurrence, typically occurring within a month of symptom onset, but this risk complicates sports participation, and is often the reason for restricting activity. The management of IM is primarily supportive, with no role for antivirals or corticosteroids. The variability of clinical presentation and the risk of splenic rupture in patients with IM present clinicians with challenging return to play/return to sport (RTS) decisions. This position statement updates the Evidence-Based Subject Review on Mononucleosis by the American Medical Society for Sports Medicine published in 2008 and reviews the epidemiology, clinical manifestations, laboratory assessment, and management including RTS for the athlete with IM. This statement also addresses complications, imaging, special considerations, diversity and equity considerations, and areas for future clinical research. Understanding the evidence regarding IM and sport is essential when communicating with athletes and their families and incorporating shared decision-making in the RTS decision.
Secondary renal amyloidosis due to primary Sjogren’s syndrome: a case report
Authors: Mohammed Shorsh A. , Karim Dana O. , Fakhralddin Saman S. , Bapir Rawa , Hadi Tahani Shakr , Hussein Dlsoz M. , Hiwa Dilan S. , Hamasalih Hussein M. , Hasan Sabah J. , Kakamad Fahmi H.
Published: May 2023

Introduction and importance:

Amyloidosis is a rare disorder characterized by the deposition of abnormal proteins in extracellular tissues, resulting in the dysfunction of vital organs and, eventually, death. The occurrence of amyloidosis due to primary Sjogren’s syndrome (pSS) is a rare finding. This study describes a rare case of pSS complicated by amyloid-associated amyloidosis.

Case presentation:

A 35-year-old male was diagnosed with nephrotic syndrome and secondary amyloidosis caused by pSS. He had microscopic hematuria, a creatinine level of 6.59 mg/dl, and an elevated erythrocyte sedimentation rate of 107 mm/hrs. Furthermore, investigations of antinuclear antibodies, antimitochondrial antibodies, SSA, SSA native, and Ro-52 recombinant as well as rheumatoid factor showed positive results. After establishing the diagnosis of pSS through clinical, physical, and laboratory assessments, a renal biopsy was performed, which revealed the occurrence of secondary amyloidosis.

Clinical discussion:

The risk of developing secondary amyloidosis depends on the extent of elevated serum amyloid levels as well as persistent subclinical inflammation. The definitive diagnosis of amyloidosis requires histological confirmation of amyloid fibril deposition in tissue.

Conclusion:

Secondary renal amyloidosis is an unusual condition in patients with pSS. Still, it should be regarded in the differential diagnosis of patients with proteinuria and/or renal failure, and a renal biopsy should be performed.
Li-Fraumeni syndrome in the setting of re-occurring malignancies after 27 years of remission: a case report
Authors: Mousa Ahmed H. , Ibrahim Abdullatif S. , Alsayed Abdelrahman Waleed , Albukhari Zain Z. , Mogharbel Ajfan , Alshanberi Asim M. , Albar Nezar Y.
Published: May 2023

Introduction and importance:

Multiple primary tumors are defined as multiple simultaneous (within 6 months) or heterogeneous tumors.

Case presentation:

Here, the authors present the case of a 58-year-old Saudi female patient with Li-Fraumeni syndrome who has multiple primary tumors.

Clinical discussion:

The surgical cytoreduction or ‘debulking’ technique is the main treatment option started in individuals with High Grade Serous Ovarian CanceR. This surgical strategy aims to completely remove all disseminated tumor masses that are present in the patient’s peritoneal cavity on a macroscopic level.

Conclusion:

In conclusion, in our case, she has developed her ovarian cancer 27 years after her breast cancer got treated. This was already stage IIIB to stage IV. If it was not for her incidental discovery of her urinary bladder cancer, which is most likely is a long-term sequel of using cyclophosphamide 27 years ago.

Multiple primary tumors are defined as multiple simultaneous (within 6 months) or heterogeneous tumors. Here, the authors present the case of a 58-year-old Saudi female patient with Li-Fraumeni syndrome who has multiple primary tumors. In conclusion, in our case, she has developed her ovarian cancer 27 years after her breast cancer got treated. This was already stage IIIB to stage IV. If it was not for her incidental discovery of her urinary bladder cancer, which is most likely is a long-term sequel of using cyclophosphamide 27 years ago.
Effectiveness of mixture of aspirin and ethanol regimen in the management of geographic tongue: a prospective study
Authors: Sohal Karpal S. , Owibingire Sira S. , Moshy Jeremiah R. , Odhiambo Walter A. , Lubasha Boniphace
Published: May 2023

Background:

Geographic tongue is usually an asymptomatic inflammatory disorder of the tongue; however, symptomatic cases do occur and require treatment. Several management strategies have been reported yet they are neither specific nor curative.

Objective:

The objective was to evaluate the effectiveness of an aspirin-ethanol mixture in the management of geographic tongue.

Methods:

In this prospective study, an analysis of medical reports of symptomatic cases of geographic tongue managed using an aspirin-ethanol mixture was done. The treatment regimen involved dissolving 3 mg of aspirin (acetylsalicylic acid) into 1 ml of 70% v/v ethanol. Then a sterile gauze is soaked in the prepared mixture and is topically used to clean the tongue with gentle pressure for 2–3 min.

Results:

The records of 23 patients were analyzed. There were more females (19, 82.6%), and the age range of patients was 15–43 years (mean age of 23.4 years). The symptoms that the patient described included: oral discomfort, burning sensations of the tongue, pain, and loss of taste. Only 21 (91.3%) patients were asymptomatic at 3 months of follow-up.

Conclusions:

Short-term topical application of the aspirin-ethanol mixture was shown to be effective in treating symptomatic geographic tongue.
Delayed diagnosis of duodenal duplication cyst in a child with recurrent pancreatitis operated by Whipple procedure: a case report
Authors: Shubietah Abdalhakim R. M. , Deek Soud M. S. , Zakaria Zaid , Saleh Fares , Abdulkareemsrour Abdulmotti , Naser Mohamad , Dibas Yazan M.S. , Jabri Mohammed S.M. , AbuMohsen Haytham M. A.
Published: May 2023

Introduction:

Children with acute pancreatitis may experience abdominal pain; the causes of which include anatomical abnormalities and medications. The rare anatomical etiology of duodenal duplication cyst is typically asymptomatic and discovered incidentally. The authors present a unique case of a Whipple-operated duodenal duplication cyst.

Case presentation:

The authors present the case of a 12-year-old Arab male who was admitted to our hospital with worsening, severe epigastric pain, stabbing in nature, and radiating to the back, suggestive of acute pancreatitis. Serum lipase levels were significantly elevated. The patient received appropriate care. His medical history is notable for multiple bouts of pancreatitis in the last 18 months. Previous investigations at other hospitals were mostly unrevealing. A more extensive workup was performed, revealing a duodenal cystic structure. This led to the diagnosis of a duodenal duplication cyst. The Whipple procedure was decided upon due to his recurrent pancreatitis, which caused fibrotic adhesions and anatomic region distortion. The patient underwent surgery and recovered uneventfully.

Discussion:

Acute pancreatitis in children is frequent and can be caused by unrecognized duodenal duplication cysts. When symptomatic, the majority present with vague abdominal pain. Despite using ultrasound as an adjunctive for diagnosis, the cyst might not become apparent until the condition has progressed to an advanced stage. A delayed diagnosis may result in complications necessitating risky surgeries.

Conclusion:

Children with recurrent pancreatitis should be evaluated for a duodenal duplication cyst. Early use of computed tomography scans may be necessary to identify the cause and spare the patient from risky procedures like Whipple surgery.
Current status and future directions of amyotrophic lateral sclerosis research in Africa: a perspective
Authors: Aderinto Nicholas , Muili AbdulBasit Opeyemi , Afolayan Oluwatosin , Jolayemi Mubarak Mustapha
Published: May 2023

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a global burden. Despite significant strides in ALS research, challenges facing ALS research in Africa are substantial. This paper discusses the current status and future directions of ALS research in Africa. Challenges and opportunities for ALS research in the region are highlighted, including limited funding and resources, the need for collaboration, and capacity building. Emerging technologies in ALS research in Africa are described, including telemedicine, neuroimaging, and genetic studies. Priorities for future ALS research in Africa are identified, including epidemiological studies, developing culturally appropriate diagnostic and management tools, and clinical trials of emerging treatments. Addressing these priorities will be critical to advancing ALS research and improving patient outcomes in Africa.
Cutaneous metastases as a primary manifestation of invasive ductal carcinoma of the breast: a case report
Authors: Kara Tahhan Nour , Abou Azan Anas , Jomaa Al Ali Isam , Abdul Aziz Jeer , Sara Samer
Published: May 2023

Introduction:

Cutaneous metastases as the first sign of invasive ductal carcinoma are not common. The ambiguous presentation of asymptomatic lesions may result in various diagnoses including dermatologic causes. Early diagnosis is essential in such cases.

Case presentation:

A 43-year-old woman with no risk factors for developing breast cancer at a young age was diagnosed with invasive ductal carcinoma of the left breast after dermatologic complaints of diffuse lesions on the left-back and right subclavian region. The patient remained asymptomatic except for the recent cutaneous presentation, which did not arouse much suspicion.

Conclusion:

Cutaneous metastases of breast cancer remain uncommon, but at the same time represent a poor prognosis for the patient, and when they do occur, treatment options are limited. The delay in taking the proper diagnostic measures in such cases imposes a need to adopt a wider perspective when dealing with the possible occurrence of advanced disease. This also adds up to the importance of breast self-examination by women at a young age and full examination by physicians, especially when they encounter a misguiding presentation.
Feasibility of Bone Mineral Density and Bone Microarchitecture Assessment Using Deep Learning With a Convolutional Neural Network
Authors: Yoshida Kazuki , Tanabe Yuki , Nishiyama Hikaru , Matsuda Takuya , Toritani Hidetaka , Kitamura Takuya , Sakai Shinichiro , Watamori Kunihiko , Takao Masaki , Kimura Eizen , Kido Teruhito
Published: May 2023

Objectives

We evaluated the feasibility of using deep learning with a convolutional neural network for predicting bone mineral density (BMD) and bone microarchitecture from conventional computed tomography (CT) images acquired by multivendor scanners.

Methods

We enrolled 402 patients who underwent noncontrast CT examinations, including L1–L4 vertebrae, and dual-energy x-ray absorptiometry (DXA) examination. Among these, 280 patients (3360 sagittal vertebral images), 70 patients (280 sagittal vertebral images), and 52 patients (208 sagittal vertebral images) were assigned to the training data set for deep learning model development, the validation, and the test data set, respectively. Bone mineral density and the trabecular bone score (TBS), an index of bone microarchitecture, were assessed by DXA. BMDDL and TBSDL were predicted by deep learning with a convolutional neural network (ResNet50). Pearson correlation tests assessed the correlation between BMDDL and BMD, and TBSDL and TBS. The diagnostic performance of BMDDL for osteopenia/osteoporosis and that of TBSDL for bone microarchitecture impairment were evaluated using receiver operating characteristic curve analysis.

Results

BMDDL and BMD correlated strongly (r = 0.81, P < 0.01), whereas TBSDL and TBS correlated moderately (r = 0.54, P < 0.01). The sensitivity and specificity of BMDDL for identifying osteopenia or osteoporosis were 93% and 90%, and 100% and 94%, respectively. The sensitivity and specificity of TBSDL for identifying patients with bone microarchitecture impairment were 73% for all values.

Conclusions

The BMDDL and TBSDL derived from conventional CT images could identify patients who should undergo DXA, which could be a gatekeeper tool for detecting latent osteoporosis/osteopenia or bone microarchitecture impairment.
The mammalian skull: development, structure and function
Authors: Fostowicz-Frelik Łucja , Tseng Z. Jack
Published: May 2023

The mammalian skull is an informative and versatile study system critical to research efforts across the broad spectrum of molecular, cellular, organismal and evolutionary sciences. The amount of knowledge concerning mammalian skull continues to grow exponentially, fuelled by the advent of new research methods and new material. Computed microtomography, including X-ray imaging using synchrotron radiation, proved to be an important tool for the descriptive and quantitative analysis of cranial anatomy. A major conceptual change, namely combining genetics and development with evolution into ‘evo-devo’ studies, also contributed to our knowledge of the mammalian skull enormously. These advances, coupled with novel techniques now allow researchers to integrate the process of cranial development with data from the fossil record, which is also augmented by seminal discoveries from Africa, Asia and both Americas. However, for decades, there has been no comprehensive source covering fundamental aspects of this vibrant field of evolutionary biology. To address this gap, we offer in this theme issue a balanced mix of research papers and reviews from leading experts in the field and a younger generation of scientists from five continents.

This article is part of the theme issue ‘The mammalian skull: development, structure and function’.
Cis
-regulatory landscapes in the evolution and development of the mammalian skull
Authors: Kaucka Marketa
Published: May 2023

Extensive morphological variation found in mammals reflects the wide spectrum of their ecological adaptations. The highest morphological diversity is present in the craniofacial region, where geometry is mainly dictated by the bony skull. Mammalian craniofacial development represents complex multistep processes governed by numerous conserved genes that require precise spatio-temporal control. A central question in contemporary evolutionary biology is how a defined set of conserved genes can orchestrate formation of fundamentally different structures, and therefore how morphological variability arises. In principle, differential gene expression patterns during development are the source of morphological variation. With the emergence of multicellular organisms, precise regulation of gene expression in time and space is attributed to
cis
-regulatory elements. These elements contribute to higher-order chromatin structure and together with
trans
-acting factors control transcriptional landscapes that underlie intricate morphogenetic processes. Consequently, divergence in
cis
-regulation is believed to rewire existing gene regulatory networks and form the core of morphological evolution. This review outlines the fundamental principles of the genetic code and genomic regulation interplay during development. Recent work that deepened our comprehension of
cis
-regulatory element origin, divergence and function is presented here to illustrate the state-of-the-art research that uncovered the principles of morphological novelty.

This article is part of the theme issue ‘The mammalian skull: development, structure and function’.
Updated knowledge and a proposed nomenclature for nuclear receptors with two DNA Binding Domains (2DBD-NRs)
Authors: Wu Wenjie , LoVerde Philip T.
Published: May 2023

Nuclear receptors (NRs) are important transcriptional modulators in metazoans. Typical NRs possess a conserved DNA binding domain (DBD) and a ligand binding domain (LBD). Since we discovered a type of novel NRs each of them has two DBDs and single LBD (2DBD-NRs) more than decade ago, there has been very few studies about 2DBD-NRs. Recently, 2DBD-NRs have been only reported in Platyhelminths and Mollusca and are thought to be specific NRs to lophotrochozoan. In this study, we searched different databases and identified 2DBD-NRs in different animals from both protostomes and deuterostomes. Phylogenetic analysis shows that at least two ancient 2DBD-NR genes were present in the urbilaterian, a common ancestor of protostomes and deuterostomes. 2DBD-NRs underwent gene duplication and loss after the split of different animal phyla, most of them in a certain animal phylum as paralogues, rather than orthologues, of that in another animal phylum. Amino acid sequence analysis shows that the conserved motifs in typical NRs are also present in 2DBD-NRs and they are gene specific. From our phylogenetic analysis of 2DBD-NRs and following the rule of Nomenclature System for the Nuclear Receptors, a nomenclature for 2DBD-NRs is proposed.
Chronic exposure of mice to phthalates enhances TGF beta signaling and promotes uterine fibrosis
Authors: Shukla Ritwik , Mahmuda Arshee , Laws Mary J. , Flaws Jodi A. , Bagchi Milan K. , Wagoner Johnson Amy J. , Bagchi Indrani C.
Published: May 2023

Phthalates are synthetic chemicals widely used as plasticizers and stabilizers in various consumer products. Because of the extensive production and use of phthalates, humans are exposed to these chemicals daily. While most studies focus on a single phthalate, humans are exposed to a mixture of phthalates on a regular basis. The impact of continuous exposure to phthalate mixture on uterus is largely unknown. Thus, we conducted studies in which adult female mice were exposed for 6 months to 0.15 ppm and 1.5 ppm of a mixture of phthalates containing di(2-ethylhexyl) phthalate, di-iso-nonyl phthalate, benzyl butyl phthalate, di-n-butyl phthalate, diisobutyl phthalate, and diethyl phthalate via chow ad libitum. Our studies revealed that consumption of phthalate mixture at 0.15 ppm and 1.5 ppm for 6 months led to a significant increase in the thickness of the myometrial layer compared to control. Further investigation employing RNA-sequencing revealed an elevated transforming growth factor beta (TGF-β) signaling in the uteri of mice fed with phthalate mixture. TGF-β signaling is associated with the development of fibrosis, a consequence of excessive accumulation of extracellular matrix components, such as collagen fibers in a tissue. Consistent with this observation, we found a higher incidence of collagen deposition in uteri of mice exposed to phthalate mixture compared to unexposed controls. Second Harmonic Generation imaging showed disorganized collagen fibers and an increase in uterine stiffness upon exposure to phthalate mixture. Collectively, our results demonstrate that chronic exposure to phthalate mixture can have adverse effects on uterine homeostasis.
NAIP—NLRC4 Inflammasome Activation in Tuft Cells Activates a PGD2–ILC3 Signaling Circuit that Protects Against Enteric Infection
Authors: Churchill Madeline J. , Bauer Renate , Honodel Roslyn , Christopher Tighe , Smita Shuchi , Warner Lindsey , Mooney Bridget M. , Wojno Elia D. Tait , Rauch Isabella
Published: May 2023

Intestinal epithelial cells (IEC) use innate sensing pathways to distinguish pathogens from commensals. One such pathway, the NAIP—NLRC4 inflammasome, initiates extrusion of infected IEC and mediator release upon cytosolic bacterial sensing. Tuft cells are primarily known for their function in anti-parasite immunity. We previously reported that activation of the inflammasome in tuft cells leads to release of prostaglandin D2 (PGD2). We test the hypothesis that tuft cell specific release of PGD2after inflammasome activation initiates antibacterial responses. NAIP—NLRC4 inflammasome activation in tuft cells leads to a type 3 antimicrobial response with increased IL-22 and antimicrobial protein levels within the small intestine, which is dependent on PGD2signaling. A subset of ILC3 express the PGD2receptor CRTH2 and we show them as the source of the increased IL-22. Inflammasome activation in tuft cells also leads to better control ofSalmonellaTyphimurium. These data support that intestinal tuft cells can also induce antibacterial responses.

PGD2release after NAIP—NLRC4 inflammasome activation in tuft cells signals onto ILC3s and mediates host defense mechanisms againstSalmonellaTyphimurium within the small intestine. Tuft cells therefore not only promote immune reactions against parasites, but also bacteria.
Comparison of concentrations of lead (Pb) in meat from wild-shot common pheasants killed using shotgun pellets principally composed of lead, iron (Fe), bismuth (Bi) and zinc (Zn)
Authors: Green Rhys E. , Taggart Mark A. , Guiu Maider , Waller Hayley , Pap Sabolc , Sheldon Rob , Pain Deborah J.
Published: May 2023

The source of almost all of the lead (Pb) found in meat from carcasses of wild-shot small game animals is often thought to be small embedded fragments of the lead shotgun pellets usually used by hunters to kill them. Available circumstantial evidence supports this conjecture, but an unknown proportion of the lead in game meat might be biologically-incorporated and absorbed by the game animal from ingested shotgun pellets and other environmental sources, such as soil and residues from mining. A critical test comparing lead concentrations in meat from animals known to have been killed using different types of shotgun ammunition has not been performed until now. We compared lead concentrations in samples of edible meat from carcasses of 27 wild-shot common pheasants (Phasianus colchicus) from which only lead shotgun pellets were recovered post mortem with concentrations for 20 birds from which only iron pellets were recovered. Shotgun pellets were removed from the meat samples before analysis. The mean concentration of lead was about 30 times greater in the meat of pheasants shot with lead than those shot with iron and was similar to mean concentrations of lead reported previously from Europe-wide samples of meat from wild-shot small game animals, including pheasants, killed using unknown types of ammunition. These results support the hypothesis that changing the type of shotgun ammunition in use for hunting from lead to iron would greatly reduce the concentration of lead in meat from wild-shot small game.
MethPhaser: methylation-based haplotype phasing of human genomes
Authors: Fu Yilei , Aganezov Sergey , Mahmoud Medhat , Beaulaurier John , Juul Sissel , Treangen Todd J. , Sedlazeck Fritz J
Published: May 2023

The assignment of variants across haplotypes, phasing, is crucial for predicting the consequences, interaction, and inheritance of mutations and is a key step in improving our understanding of phenotype and disease. However, phasing is limited by read length and stretches of homozygosity along the genome. To overcome this limitation, we designed MethPhaser, the first method that utilizes methylation signals from Oxford Nanopore Technologies to extend SNV-based phasing. Across control samples, we extend the phase length N50 by almost 3-fold while minimally increasing the phasing error by ∼0.02%. Nevertheless, methylation signals have limitations, such as random signals on sex chromosomes or tissue purity. To assess the latter, we also applied MethPhaser on blood samples from 4 patients, still showing improvements over SNV-only phasing. MethPhaser further improves phasing acrossHLAand multiple other medically relevant genes, improving our understanding of how mutations interact across multiple phenotypes. MethPhaser is available athttps://github.com/treangenlab/methphaser.
Comparative analysis of gonadal hormone receptor expression in the house mouse, meadow vole, and prairie vole brain
Authors: Denney Katherine A. , Wu Melody V. , Sun Simón(e) D. , Moon Soyoun , Tollkuhn Jessica
Published: May 2023

The socially monogamous prairie vole (Microtus ochrogaster) and promiscuous meadow vole (Microtus pennsylvanicus) are closely related, but only prairie voles display long-lasting pair bonds, biparental care, and selective aggression towards unfamiliar individuals after pair bonding. These social behaviors in mammals are largely mediated by steroid hormone signaling in the social behavior network (SBN) of the brain. Hormone receptors are reproducible markers of sex differences that can provide more information than anatomy alone, and can even be at odds with anatomical dimorphisms. We reasoned that behaviors associated with social monogamy in prairie voles may emerge in part from unique expression patterns of steroid hormone receptors in this species, and that these expression patterns would be more similar across males and females in prairie than in meadow voles or the laboratory mouse. To obtain insight into steroid hormone signaling in the developing prairie vole brain, we assessed expression of estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), and androgen receptor (Ar) within the SBN, usingin situhybridization at postnatal day 14 in mice, meadow, and prairie voles. We found species-specific patterns of hormone receptor expression in the hippocampus and ventromedial hypothalamus, as well as species differences in the sex bias of these markers in the principal nucleus of the bed nucleus of the stria terminalis. These findings suggest the observed differences in gonadal hormone receptor expression may underlie species differences in the display of social behaviors.
Molecular Basis for Maternal Inheritance of Human Mitochondrial DNA
Authors: Lee William , Zamudio-Ochoa Angelica , Buchel Gina , Podlesniy Petar , Gutierrez Nuria Marti , Puigros Margalida , Calderon Anna , Tang Hsin-Yao , Li Li , Koski Amy , Trullas Ramon , Mitalipov Shoukhrat , Temiakov Dmitry
Published: May 2023

Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1, 2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3, 4. However, whether these mechanisms play a decisive role in paternal mtDNA elimination has been disputed5, 6. We found that mitochondria in human spermatozoa are devoid of mtDNA and lack mitochondrial transcription factor A (TFAM), the major nucleoid protein required to protect, maintain, and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial pre-sequence, ordinarily removed upon mitochondrial import. Phosphorylation of this pre-sequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM re-localization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mitochondrial DNA, thereby explaining maternal inheritance in this species.
RIP140 regulates HES1 oscillatory expression and mitogenic activity in colon cancer cells
Authors: Sfeir Nour , Kajdan Marilyn , Jalaguier Stéphan , Bonnet Sandrine , Teyssier Catherine , Pyrdziak Samuel , Yuan Rong , Bousquet Emilie , Maraver Antonio , Bernex Florence , Pirot Nelly , Boissiere Florence , Castet-Nicolas Audrey , Lapierre Marion , Cavaillès Vincent
Published: May 2023

Background

The transcription factor RIP140 (Receptor Interacting Protein of 140 kDa) regulates intestinal homeostasis and tumorigenesis through the Wnt signaling. In this study, we have investigated its effect on the Notch/HES1 signaling pathway.

Methods

The impact on HES1 expression and activity was evaluated in colorectal cancer (CRC) cell lines and in transgenic mice, invalidated or not for theRip140gene in the intestinal epithelium. A tumor microarray and transcriptomic data sets were used to investigate RIP140 and HES1 expression in relation with patient survival. Statistical comparisons were performed with Mann-Whitney or Kruskal-Wallis orChi2tests.

Results

In CRC cells, RIP140 positively regulatedHES1gene expression at the transcriptional level via an RBPJ/NICD-mediated mechanism. In support of thesein vitrodata, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, analyzed by immunohistochemistry, thus supporting the positive regulation ofHES1gene expression by RIP140.

Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition ofHES1gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140.

Conclusions

Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway with a dual effect onHES1gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.
A Hydroponic-Based Bioassay to FacilitatePlasmodiophora brassicaePhenotyping
Authors: Salih Rasha , Brochu Anne-Sophie , Labbé Caroline , Strelkov Stephen E. , Franke Coreen , Bélanger Richard , Pérez-López Edel
Published: May 2023

Clubroot, caused by the obligate parasitePlasmodiophora brassicae, is one of the most devastating diseases affecting the canola/oilseed rape (Brassica napus) industry worldwide. Currently, the planting of clubroot-resistant (CR) cultivars is the most effective strategy used to restrict the spread and the economic losses linked to the disease. However, virulentP. brassicaeisolates have been able to infect many of the currently available CR cultivars, and the options to manage the disease are becoming limited. Another challenge has been achieving consistency in evaluating host reactions toP. brassicaeinfection, with most bioassays conducted in soil and/or potting medium, which requires significant space and can be labour intensive. Visual scoring of clubroot symptom development can also be influenced by user bias. Here, we have developed a hydroponic bioassay using well-characterizedP. brassicaesingle-spore isolates representative of clubroot virulence in Canada, as well as field isolates from three Canadian provinces, in combination with canola inbred homozygous lines carrying resistance genetics representative of CR cultivars available to growers in Canada. To improve the efficiency and consistency of disease assessment, symptom severity scores were compared with clubroot evaluations based on the scanned root area. According to the results, this bioassay offers a reliable, less expensive, and reproducible option to evaluateP. brassicaevirulence, as well as a means to identify which canola resistance profile(s) may be effective against particular isolates. This bioassay will contribute to the breeding of new CR canola cultivars and the identification of virulence genes inP. brassicaethat could trigger resistance and have been very elusive to this day.
Resolving genotype-phenotype discrepancies of the Kidd blood group system using long-read nanopore sequencing
Authors: Gueuning M , Thun GA , Trost N , Schneider L , Sigurdardottir S , Engström C , Larbes N , Merki Y , Frey BM , Gassner C , Meyer S , Mattle-Greminger MP
Published: May 2023

Due to substantial improvement in read accuracy, third-generation long-read sequencing holds great potential in blood group diagnostics, particularly in cases where traditional genotyping or sequencing techniques, primarily targeting exons, fail to explain serological phenotypes. In this study, we employed Oxford Nanopore sequencing to resolve all genotype-phenotype discrepancies in the Kidd blood group system (JK, encoded bySLC14A1) observed over seven years of routine high-throughput donor genotyping using a mass spectrometry based platform at Blood Transfusion Service Zurich. Discrepant results from standard serological typing and donor genotyping were confirmed by commercial PCR-SSP kits. To resolve discrepancies, we amplified the entire coding region ofSLC14A1(∼24 kb, exons 3 to 10) in two overlapping long-range PCRs in all samples. Amplicons were barcoded and sequenced on a MinION flow cell. Sanger sequencing and bridge-PCRs were used to confirm findings. Among 11,972 donors with both serological and genotype data available for the Kidd system, we identified 10 cases with unexplained conflicting results. Five were linked to known weak and null alleles caused by variants not included in the routine donor genotyping. In two cases, we identified novel null alleles on theJK*01(Gly40Asp; c.119G>A) andJK*02(Gly242Glu; c.725G>A) haplotype, respectively. Remarkably, the remaining three cases were associated with a yet unknown deletion of ∼5 kb spanning exons 9-10 of theJK*01allele, which other molecular methods had failed to detect. Overall, nanopore sequencing demonstrated reliable and accurate performance for detecting both single-nucleotide and structural variants. It possesses the potential to become a robust tool in the molecular diagnostic portfolio, particularly for addressing challenging structural variants such as hybrid genes, deletions and duplications.
Evolutionary Genomics of Sister Species Differing in Effective Population Sizes and Recombination Rates
Authors: Ye Zhiqiang , Pfrender Michael E. , Lynch Michael
Published: May 2023

Studies of closely related species with known ecological differences provide exceptional opportunities for understanding the genetic mechanisms of evolution. Here, we compared population-genomics data betweenD. pulexandD. pulicaria, two reproductively compatible sister species experiencing ecological speciation, the first largely confined to intermittent ponds and the second to permanent lakes in the same geographic region.D. pulicariahas lower genome-wide nucleotide diversity, a smaller effective population size, higher incidence of private alleles, and substantially more linkage-disequilibrium thanD. pulex. Functional enrichment analysis revealed that positively selected genes inD. pulicariaare enriched in potentially aging-related categories such as cellular homeostasis, which may explain the extended lifespan inD. pulicaria. We also found that opsin-related genes, which may mediate photoperiodic responses, are under different selection pressures in these two species. Additionally, genes involved in mitochondrial functions, ribosomes, and responses to environmental stimuli are found to be under positive selection in both species. Our results provide insights into the physiological traits that differ within this regionally sympatric sister-species pair that occupies unique microhabitats.
Early cellular and molecular signatures correlate with severity of West Nile Virus infection
Authors: Lee Ho-Joon , Zhao Yujiao , Fleming Ira , Mehta Sameet , Wang Xiaomei , Wyk Brent Vander , Ronca Shannon E. , Kang Heather , Chou Chih-Hung , Fatou Benoit , Smolen Kinga K. , Levy Ofer , Clish Clary B. , Xavier Ramnik J. , Steen Hanno , Hafler David A. , Love J. Christopher , Shalek Alex K. , Guan Leying , Murray Kristy O. , Kleinstein Steven H. , Montgomery Ruth R.
Published: May 2023

Infection with West Nile Virus (WNV) can drive a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence at 3 months and 1 year employing multiplexed single cell protein and transcriptional profiling (CyTOF and Seq-Well) complemented with matched serum proteomics and metabolomics. At the acute time point, we detected both an elevated proportion of pro-inflammatory markers in innate immune cell types and reduced frequency of regulatory T cell activity in participants with severe infection compared to those with asymptomatic infection. Single-cell transcriptomics of paired samples revealed that asymptomatic donors had higher expression of genes associated with innate immune pathways, in particular anti-inflammatory CD16+monocytes at the acute time point. A multi-omics analysis identified factors--beyond those from individual analyses--that distinguished immune state trajectory between severity groups. Here we highlighted the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.
UV-induced feather color change reflects its porphyrin content
Authors: Hasegawa Masaru , Arai Emi , Ito Shosuke , Wakamatsu Kazumasa
Published: May 2023

Pigmentary coloration is widespread in animals. Its evolutionary and ecological features are often attributed to the property of predominant pigments; therefore, most research has focused on predominant pigments such as carotenoids in carotenoid-based coloration. However, coloration results from predominant pigments and many other minority pigments, and the importance of the latter is overlooked. Here, we focused on porphyrin, an “uncommon” pigment found in bird feathers, and investigate its importance in the context of feather color changes in the barn swallowHirundo rustica. We found that the “pheomelanin-based coloration” of the barn swallow faded after the irradiation of UV light, and this effect was particularly strong in the feathers of young swallows (nestlings and fledglings, here). We also found that it is not the predominant pigment, pheomelanin, but protoporphyrin IX pigment that showed the same pattern of depigmentation after the irradiation of UV light, particularly in the feathers of young swallows. In fact, the abovementioned age-dependent feather color change was statistically explained by the amount of porphyrin in the feathers. The current study demonstrates that a minority pigment, porphyrin, explains within-season dynamic color change, an ecological feature of feather coloration. The porphyrin-mediated rapid color change would benefit young birds, in which feather coloration affects the parental food allocation during a few weeks before independence, but not later. Future studies should not ignore these minor but essential pigments and their evolutionary and ecological functions.

Significance statement

Predominant pigments are assumed to determine animal coloration and its ecological features. It is then not surprising that the evolutionary and ecological features of animal coloration are often attributed to the chemical properties of predominant pigments. However, coloration results from predominant pigments and several other minority pigments. By irradiating UV light on reddish throat feathers of the barn swallowHirundo rustica, we examined within-season dynamic color change in relation to a minority pigment, porphyrin, which has not previously been examined but is a candidate pigment for feather color change, because porphyrin can be easily photodegraded. We found that not the predominant pigment, pheomelanin, but porphyrin pigments explained the feather color change. Minor pigments and their chemical properties should not be dismissed to understand the ecological and evolutionary functions of animal coloration.