bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased risk of osteoporosis and femoral neck fractures in patients with familial Mediterranean fever—a large retrospective cohort study
Authors: Patt Yonatan Shneor , Ben-Shabat Niv , Fisher Lior , Sharif Kassem , Arow Mohamad , Lassman Simon , Watad Abdulla , Skuja Vita , Shtewe Anan H , McGonagle Dennis , Amital Howard
Published: September 2023

Objectives

The direct impact of inflammatory conditions and their therapy with corticosteroids contribute to an increased risk of osteoporosis with associated fractures. Familial Mediterranean fever (FMF) is an autoinflammatory disorder not commonly treated with corticosteroids. Evidence regarding FMF association with osteoporosis and femur fractures is anecdotal. We aimed to evaluate the incidence and risk of osteoporosis and femoral neck fracture in FMF patients compared with the general population.

Methods

A retrospective cohort study using the electronic database of Clalit Health Services of all FMF patients first diagnosed between 2000 and 2016 and controls was conducted including age- and sex-matched controls in a 1:1 ratio. Follow-up continued until the first diagnosis of osteoporosis or fracture. Risk for these conditions was compared using univariate and multivariate Cox regression models.

Results

A total of 9769 FMF patients were followed for a median period of 12.5 years. Of these, 304 FMF patients were diagnosed with osteoporosis compared with 191 controls, resulting in an incidence rate (per 10 000 persons-years) of 28.8 and 17.8, respectively, and a crude hazard ratio of 1.62 (95% CI 1.35, 1.93; P < 0.001). Patients were diagnosed with osteoporosis at a considerably younger age than controls [60.1 (s.d. 12.4) vs 62.5 (s.d. 11.0) years; P = 0.028]. A total of 56 FMF patients were diagnosed with femoral neck fracture compared with 35 controls, resulting in an incidence rate of 5.3 and 3.3, respectively, and a crude HR of 1.60 (95% CI 1.05, 2.44; P < 0.05).

Conclusion

FMF patients are at increased risk for osteoporosis and consequently femur fracture. Our findings emphasize the importance of considering bone health in the management of FMF patients.
Efficacy of water application of a humic substance, butyric acid, vitamins C, D, and E and/or electrolytes on performance and mortality in health-challenged nursery pigs¹
Authors: Edmonds Michael S , Weber Thomas E
Published: September 2023

Health challenges continue to be rampant in nursery pigs which has led to increased industry-wide mortality trends. Therefore, the objective of these three studies was to evaluate a water supplement (HV; HydraVantage, Kent Nutrition Group, Muscatine, IA) which is a proprietary blend of a humic substance, butyric acid, and vitamins C, D, and E, as well as an electrolyte blend on nursery pig performance and mortality. Experiment 1 consisted of 196 crossbred weanling pigs (7 pigs per pen with 14 pens per treatment) which were randomly allotted by BW to two treatments consisting of control (water for 33 d) or HV at 15 g/L of stock solution and proportioned through a medicator (1:128) for 11 d followed by water for 22 d. There were no performance differences. However, mortality was reduced (P < 0.01) from 6.12% for the control to 0.00% for HV. In experiment 2, there were 488 weanling pigs (6 to 10 pigs/pen with 14 pens per treatment) which were randomly allotted by BW to four treatments in a 34-d trial. Treatment 1 was control (water), and treatments 2 and 4 were HV at 15 g/L of stock solution for 11 and 34 d, respectively. Treatment 3 utilized HV at 15 g/L stock solution during days 0 to 11 with 7.5 g HV/L stock solution utilized during days 11 to 21 followed by water. No performance differences were observed among the four treatments. Mortality was 10.89%, 4.82%, 5.54%, and 7.26% for treatments 1 to 4, respectively, with treatment 1 having a higher mortality (P < 0.05) compared to treatments 2 to 4. In experiment 3, a 2 × 2 factorial study was conducted (7 pigs per pen with 14 pens per treatment) in which the treatments were: 1) water; 2) HV at 15 g/L stock solution for 34 d; 3) electrolytes at 241 g/L stock solution for 34 d; and 4) HV at 15 g/L of stock solution and electrolytes at 226 g/L of stock for 34 d. Overall pen gain tended to be improved (P = 0.09) with supplemental HV. Moreover, mortality was reduced (P = 0.06) by 36% (16.86% mortality for treatments 1 and 3 vs. 10.73% mortality for treatments 2 and 4). Supplemental electrolytes had no effect on mortality. These data suggest that HV has a positive effect by reducing mortality in nursery pigs undergoing health challenges.
Integrative revision of species limits in the genus Schiffornis (Aves: Tityridae) reveals cryptic diversity in the Neotropics
Authors: Lima Rafael Dantas , Bocalini Fernanda , Silveira Luís Fábio
Published: September 2023

Accurate species delimitation is essential for many biological subdisciplines. Nonetheless, current species diversity remains incompletely documented even in well-studied groups such as birds. Here, we take an integrative approach to examine species limits in the genus Schiffornis, a widespread group of dull-plumaged, whistle-voiced suboscine passerines of Neotropical humid-forest understory, currently considered to comprise seven species. We measured geographic variation in song, morphology, and mitochondrial and genome-wide nuclear markers to resolve the taxonomy of the genus. We show that Schiffornis comprises 13 separately evolving population lineages, of which most qualify as species taxa under all species definitions. These include a cryptic new species, several species splits, and the resurrection of a morphologically undifferentiated, but vocally and genetically distinct, taxon that was synonymized nearly a century ago in the Schiffornis turdina complex. We also found several hitherto unnoticed contact zones between diverging lineages and a leapfrog pattern of geographic song variation in the S. turdina complex, and we highlight potential avenues of further research of this genus.
Limited Audiological Assessment Results in Children With Otitis Media With Effusion
Authors: Merchant Gabrielle R. , Al-Salim Sarah , Skretta Delaney , Tempero Richard M.
Published: September 2023

Objectives:

Clinical practice guidelines predicate the need for evaluation of hearing in children with otitis media with effusion (OME). The objective of this work was to characterize the completeness of hearing assessment results in children with OME.

Design:

Forty participants with OME completed two full audiological assessments, one in a clinical setting and a second in a research setting. An additional 14 participants without OME completed a single audiological assessment in the research setting as a control group. The success of various behavioral and objective audiometric tests in each setting was quantified and evaluated.

Results:

Findings indicate that ear-specific behavioral audiometric information is substantially limited in children with OME, particularly in clinical settings. In contrast, objective testing including tympanometry and otoacoustic emission testing was largely successful.

Conclusions:

Ear-specific behavioral audiometric information is limited in children with OME and, consequently, consideration of these data for use as part of clinical decision making is also limited. Objective tests were more successful but are not direct measures of hearing.
Discoidin Domain Receptor Tyrosine Kinase 1 (DDR1) Is a Novel Therapeutic Target in Liposarcoma: A Tissue Microarray Study
Authors: Dean Dylan C. , Feng Wenlong , Walker Robert L. , Thanindratarn Pichaya , Temple H. Thomas , Trent Jonathan C. , Rosenberg Andrew E. , Hornicek Francis J. , Duan Zhenfeng
Published: September 2023

Background

Liposarcoma is the most commonly diagnosed subtype of soft tissue sarcoma. As these tumors often arise near vital organs and neurovascular structures, complete resection can be challenging; consequently, recurrence rates are high. Additionally, available chemotherapeutic agents have shown limited benefit and substantial toxicities. There is, therefore, a clear and unmet need for novel therapeutics for liposarcoma. Discoidin domain receptor tyrosine kinase 1 (DDR1) is involved in adhesion, proliferation, differentiation, migration, and metastasis in several cancers. However, the expression and clinical importance of DDR1 in liposarcoma are unknown.

Questions/purposes

The purposes of this study were to assess (1) the expression, (2) the association between DDR1 and survival, and (3) the functional roles of DDR1 in liposarcoma.

Methods

The correlation between DDR1 expression in tumor tissues and clinicopathological features and survival was assessed via immunohistochemical staining of a liposarcoma tissue microarray. It contained 53 samples from 42 patients with liposarcoma and 11 patients with lipoma. The association between DDR1 and survival in liposarcoma was analyzed by Kaplan-Meier plots and log-rank tests. The DDR1 knockout liposarcoma cell lines were generated by CRISPR-Cas9 technology. The DDR1-specific and highly selective DDR1 inhibitor 7RH was applied to determine the impact of DDR1 expression on liposarcoma cell growth and proliferation. In addition, the effect of DDR1 inhibition on liposarcoma growth was further accessed in a three-dimensional cell culture model to mimic DDR1 effects in vivo.

Results

The results demonstrate elevated expression of DDR1 in all liposarcoma subtypes relative to benign lipomas. Specifically, high DDR1 expression was seen in 55% (23 of 42) of liposarcomas and no benign lipomas. However, DDR1 expression was not found to be associated with poor survival in patients with liposarcoma. DDR1 knockout or treatment of 7RH showed decreased liposarcoma cell growth and proliferation.

Conclusion

DDR1 is aberrantly expressed in liposarcoma, and it contributes to several markers of oncogenesis in these tumors.

Clinical Relevance

This work supports DDR1 as a promising therapeutic target in liposarcoma.
A Simple, Cost-effective Microsuction Device
Authors: Alfaqeeh Faisal A. , Alhusain Abdullah M. , Andejani Doaa
Published: September 2023

In our proposed device, we converted a large suction tube into a small tube with reduced suction velocity. This can aid in microsurgical procedures in which meticulous suctioning while minimizing trauma to the surrounding structures is essential. This device can relieve the surgeon from having to be cautious about injuring any anastomoses or neurovascular structures while suctioning.
A Longitudinal Study of Group A Streptococcal Colonization and Pharyngitis in US Children
Authors: Frenck Robert W. , Laudat France , Liang John , Giordano-Schmidt Donna , Jansen Kathrin U. , Gruber William , Anderson Annaliesa S. , Scully Ingrid L.
Published: September 2023

Background:

Group A streptococci (GAS) are a major cause of pharyngitis in children. Recently, there were severe GAS outbreaks. The aims of this study were to assess pharyngeal colonization prevalence in healthy children, to assess different diagnostic definitions for GAS pharyngitis and to estimate incidence rates for these infections.

Methods:

A 2-year longitudinal study was conducted in healthy children in the United States. Pharyngeal swabs were cultured every 3 months for GAS colonization. Serum antistreptolysin O, antideoxyribonuclease B (DNaseB) and antistreptococcal C5a peptidase (SCP) antibody titers were assessed at baseline. When participants developed a sore throat, pharyngeal swabs were collected for rapid antigen detection test (RADT) and culture, and antibody titers were determined in serum samples. A range of case definitions were used for GAS pharyngitis.

Results:

A total of 422 children 3–12 years old were enrolled (140, 141 and 141 were 3–5, 6–9 and 10–12 years of age, respectively). The overall prevalence of GAS colonization during the study was 48%. Baseline antistreptolysin O, anti-DNaseB and anti-SCP antibody titers were higher for children older than 5 years. The incidence of GAS pharyngitis per 100 person-years was 15.9 for RADT/culture-proven and 4.6 for serologically confirmed pharyngitis.

Conclusions:

GAS throat colonization and pharyngitis were frequent in children 3–12 years old. The case definition employed impacted the measured incidence of GAS pharyngitis, with higher rates detected using RADT/culture-based definitions. These data suggest that case definition is important and that young children are exposed to GAS, which may inform plans for vaccine development and implementation.
Attitudes and Beliefs of Wildland Firefighters Toward Occupational Health Services
Authors: Klossner Tess M. , Drescher Matthew J. , Games Kenneth E.
Published: September 2023

Context

Wildland firefighters (WLFFs) are at an increased risk of health conditions, injuries, and illnesses related to sustained levels of intense physical activity. The purpose of this study was to identify and explore the current attitudes and beliefs of WLFFs regarding health services. Methods: We used consensual qualitative research design for this study. Participants engaged in an online, semistructured interview. Results: We identified four domains: (1) risk mitigation strategies, (2) culture of fire services, (3) access to health care services, and 4) identification of health care gap. Conclusions: Access to occupational health services for WLFFs is readily available in the form of emergency medical care. However, a lack of regular access to physical medicine and the continuation of care beyond acute treatment was apparent.
Incidence of Cochlear Implant Electrode Contacts in the Functional Acoustic Hearing Region and the Influence on Speech Recognition with Electric–Acoustic Stimulation
Authors: Nix Evan P. , Thompson Nicholas J. , Brown Kevin D. , Dedmon Matthew M. , Selleck A. Morgan , Overton Andrea B. , Canfarotta Michael W. , Dillon Margaret T.
Published: September 2023

Objectives

To investigate the incidence of electrode contacts within the functional acoustic hearing region in cochlear implant (CI) recipients and to assess its influence on speech recognition for electric–acoustic stimulation (EAS) users.

Study Design

Retrospective review.

Setting

Tertiary referral center.

Patients

One hundred five CI recipients with functional acoustic hearing preservation (≤80 dB HL at 250 Hz)

Interventions

Cochlear implantation with a 24-, 28-, or 31.5-mm lateral wall electrode array.

Main Outcome Measures

Angular insertion depth (AID) of individual contacts was determined from imaging. Unaided acoustic thresholds and AID were used to calculate the proximity of contacts to the functional acoustic hearing region. The association between proximity values and speech recognition in quiet and noise for EAS users at 6 months postactivation was reviewed.

Results

Sixty percent of cases had one or more contacts within the functional acoustic hearing region. Proximity was not significantly associated with speech recognition in quiet. Better performance in noise was observed for cases with close correspondence between the most apical contact and the upper edge of residual hearing, with poorer results for increasing proximity values in either the basal or apical direction (r
14 = 0.48, p = 0.043; r
18 = −0.41, p = 0.045, respectively).

Conclusion

There was a high incidence of electrode contacts within the functional acoustic hearing region, which is not accounted for with default mapping procedures. The variability in outcomes across EAS users with default maps may be due in part to electric-on-acoustic interference, electric frequency-to-place mismatch, and/or failure to stimulate regions intermediate between the most apical electrode contact and the functional acoustic hearing region.
Evaluation of Parental Perspectives and Concerns about Pediatric Cochlear Implantation: A Social Media Analysis
Authors: Huang Emily Y. , Hairston Tai K. , Walsh Jonathan , Ballard Megan E. , Boss Emily F. , Jenks Carolyn M.
Published: September 2023

Objective

Parents often experience uncertainty during decision-making for their child’s cochlear implantation (CI) surgery, and online forums provide insight on parental opinions that might not be expressed in clinic. This study aims to evaluate parental perspectives and concerns about pediatric CI using social media analysis.

Study Design

Qualitative study.

Setting

Three online forums involving parental posts about pediatric CI.

Intervention/Methods

Forums were queried using keywords (e.g., “cochlear implant”) to gather all U.S. parent-initiated posts about pediatric CI from 2006 to 2021. Thematic content analysis was performed to classify posts by overarching domain, themes, and subthemes. Posts were reviewed for thematic synthesis and double coded. Descriptive statistics were calculated for each theme by unique users.

Results

A total of 79 posts by 41 unique users were analyzed. Themes relating to decision for CI included facilitators, inhibitors, resources, and feelings. Parents posted about lack of benefit from hearing aids promoting decision for CI and high cost as an inhibitor. Some expressed concern about making a major decision for a minor. Parents often mentioned their child’s healthcare providers and social media as resources.

Conclusion

Through social media posts, parental priorities and concerns for decision-making of CI surgery were identified. Findings may guide discussions between physicians and parents and facilitate shared decision-making about CI.
Improving Documentation of Pain Reassessment after Pain Management Interventions in the NICU
Authors: Israel Smitha , Perazzo Sofia , Lee Morgan , Samson Rachel , Safari-Ferra Parissa , Badh Ranjodh , Abera Solomon , Soghier Lamia
Published: September 2023

Background:

Neonates exposed to painful procedures require pain assessment and reassessment using nonverbal scales. Nurses perform initial assessments routinely, but reassessment is variable. The goal was to increase pain reassessments in neonates with a previous score of 4 or higher within 60 minutes from 50% to 75% within 12 months.

Methods:

After identifying key drivers, we tested several interventions using the IHI’s Model for Improvement. The outcome measure was the rate of reassessments within 1 hour after scoring ≥4 on the Neonatal Pain Agitation and Sedation Scale (N-PASS). Duration of time between scoring and intervention was documented. Interventions included electronic health record (EHR) changes, direct communication with bedside nurses through text messages and emails, in-person education, and a yearly competency module. The process measure was the number of messages/emails to staff. Sedation scores were the balancing measure.

Results:

Baseline compliance was 50% with significant variability. A centerline shift occurred after the first intervention. After the first four interventions in the following 3 months, a 29% total increase occurred. Overall time-lapse between reassessments decreased from 102 to 90 minutes. Overall sedation scores decreased from -2.5 during the baseline to -1.7 during the sustain period. The goal of 75% pain reassessments was achieved and sustained for two years.

Conclusions:

Automated tools such as the trigger report provided data that increased noncompliance visibility. Real-time and personalized reminders and education improved awareness and set the tone for culture change. Electronic health record reminders for reassessments and standardized annual education helped in sustaining change.
Firearm Safety Screening in the Pediatric Hospital Setting: A Quality Improvement Initiative
Authors: Oddo Elizabeth R. , Kumar Neha , Andrews Annie L. , Kwon Stephanie
Published: September 2023

Background:

Firearm injuries are a leading cause of morbidity and mortality for US youth. Secure storage is protective against firearm injuries in children. Despite this evidence and national recommendations, rates of firearm safety screening among pediatric providers are low, particularly in the inpatient setting. Therefore, we aimed to increase the frequency of firearm safety screening among patients admitted to the Pediatric Hospital Medicine service.

Methods:

This project occurred in a tertiary pediatric hospital with a medium-sized pediatric residency program. The initial intervention was a firearm safety screening tool embedded into the electronic health record history and physical note template. Subsequent interventions included nursing education, monthly reminder emails, and gun violence discussions during intern orientation. Patients who screened positive were provided with educational materials and a free gun lock. Data collection occurred by chart review to determine the frequency of screening documentation in the H&P. A survey was also conducted among pediatric residents to identify persistent barriers to screening.

Results:

The percentage of inpatient firearm safety screening increased from 0.01% to 39% over 25 months, with a centerline shift noted after 2 months. Residents cited a lack of time with the patient and a belief that it was not the appropriate time to screen as persistent barriers to screening.

Conclusions:

This study identified an effective approach to improving firearm safety screening in an academic pediatric hospital. Hospitalization represents a unique opportunity for firearm safety screening and counseling, and inpatient providers should feel empowered to intervene in this setting.
Microevolution of clade II isolates ofCandida aurishighlights multifaceted intra-clade heterogeneity in acquiring resistance towards amphotericin B
Authors: Chauhan Anshu , Kumar Praveen , Kumar Mohit , Narayanan Aswathy , Yadav Kusum , Ali Basharat , Saini Amandeep , Singh Ashutosh , Banerjee Atanu , Rudramurthy Shivaprakash M. , Chakrabarti Arunaloke , Mondal Alok K. , Gaur Naseem A. , Sanyal Kaustuv , Prasad Rajendra
Published: September 2023

Candida aurisexhibits high-level resistance to amphotericin B (AmB). Mechanisms such as ergosterol biosynthesis malfunction, oxidative damage mismanagement, and increased drug efflux contribute to AmB resistance inC. auris. In this study, we experimentally evolved two East Asian drug-susceptible clade II isolates ofC. auris(P2428 and CBS10913T) isolated from different geographical locations to develop resistance against AmB. We analysed alterations in karyotype, genome sequence, and gene expression profiles to uncover the mechanisms driving AmB resistance. The independently evolved clade II adaptors displayed up to 4-16-fold higher MIC50, as compared to the parental cells.AOX2(alternative oxidase) and the cell wall integrity pathway have been identified as critical in the development of AmB resistance. However, we noted certain intra-clade heterogeneity in the associated mechanisms. While in P2428 adaptors (P-lines), the ergosterol and sphingolipid pathways appear to play a crucial role, this was not the case for CBS10913Tadaptors (A-lines), which acquired resistance independent of lipid-associated changes. The transcriptomic, WGS, and phenotypic analyses also confirm that the evolved AmB-resistant isolates follow distinct trajectories for adaptation, Furthermore, unlike the fluconazole-resistant isolates, as reported previously, changes in ploidy do not seem to contribute to the differential mechanisms of AmB resistance. Overall, this study not only provides insights into the mechanisms and pathways involved in AmB resistance but also highlights intra-clade-heterogeneity that exists within clade II ofC. auris.

Importance

Candida aurisdemonstrates significant resistance to amphotericin B (AmB) that stems from factors like alteration of ergosterol biosynthesis, perturbation of the oxidative damage response, etc. A comprehensive understanding of underlying mechanisms can be studied in a holistic manner by subjecting resistant as well as susceptible clinical isolates to a comparative genome-level analysis. An alternate and more dynamic approach is to expose susceptible isolates to a certain concentration of drug which is not lethal but can trigger the resistance mechanisms. In the present study, we evolvedC. auristowards AmB and observed novel and differential mechanisms of resistance development, in two different isolates despite belonging to the same clade. This study provides insights into the intra-clade heterogeneous behavior ofC. auristowards AmB.
Reduction in myocardial fibrosis in MDX mice on oral consumption ofAureobasidium Pullulansproduced Neu REFIX Beta-glucans; holds potential as an adjuvant in managing post-transplantation organ fibrosis
Authors: Preethy Senthilkumar , Yamamoto Naoki , Cherian Kottoorathu Mammen , Premsekar Rajasekaran , Levy Gary A , Senthilkumar Rajappa , Abraham Samuel JK
Published: September 2023

Organ fibrosis is one of the major causes of morbidity and mortality globally. Though fibrosis in genetic diseases such as Duchenne muscular dystrophy (DMD) may be attributed to the genetic defect, chronic microinflammation remains a key mechanism underlying such fibrosis, which also precedes both other organ fibrosis and post-organ transplant fibrosis. Having proven the anti-inflammatory, anti-fibrotic effects of Beta-1,3-1,6-glucan (Neu-REFIX) produced by N-163 strain ofAureobasidium Pullulansin earlier clinical and pre-clinical studies, we performed the current study to evaluate its effects on myocardial fibrosis. N-163 beta-glucan was administered to 45 mice in three groups, each fifteen animals, Gr. 1, normal mice, Gr.2, mdx mice as vehicle, Gr.3, mdx mice which were administered Neu REFIX beta-glucan orally. Evaluation of Collagen Type I (Col-I) in myocardium was performed by immunohistochemistry. Percentage of myocardium Col-I positive area of 6.42 ± 2.67 significantly decreased in the Neu-REFIX group (4.32 ± 1.78) (p-value < 0.01). As myocardial fibrosis has been shown to be reduced following treatment with N-163 beta glucan in a genetic, muscle structure anomaly disease such as DMD, in addition to adding value to DMD patients, in whom myocardial failure occurs in the advanced stages leading to pre-mature death, Neu-REFIX beta-glucan adjuvant treatment in the setting of solid organ transplantation may be of value to reduce the incidence of fibrosis which is a known feature of chronic allograft rejection leading to graft loss.
Distinct transcriptional profiles of maternal and fetal placental macrophages at term are associated with gravidity
Authors: Ozarslan Nida , Robinson Joshua F. , Buarpung Sirirak , Kim M. Yvonne , Ansbro Megan R. , Akram Jason , Montoya Dennis J. , Kamya Moses R. , Kakuru Abel , Dorsey Grant , Rosenthal Philip J. , Cheng Genhong , Feeney Margaret E. , Fisher Susan J. , Gaw Stephanie L.
Published: September 2023

Maternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Little is known regarding the molecular phenotypes and roles of these distinct monocyte/macrophage populations. Here, we used RNA sequencing to investigate the transcriptional profiles of MIMs and HBCs in six normal term pregnancies. Our analyses revealed distinct transcriptomes of MIMs and HBCs. Genes involved in differentiation and cell organization pathways were more highly expressed in MIMs vs. HBCs. In contrast, HBCs had higher expression of genes involved in inflammatory responses and cell surface receptor signaling. Maternal gravidity influenced monocyte programming, as expression of pro-inflammatory molecules was significantly higher in MIMs from multigravidas compared to primigravidas. In HBCs, multigravidas displayed enrichment of gene pathways involved in cell-cell signaling and differentiation. In summary, our results demonstrated that MIMs and HBCs have highly divergent transcriptional signatures, reflecting their distinct origins, locations, functions, and roles in inflammatory responses. Our data further suggested that maternal gravidity influences the gene signatures of MIMs and HBCs, potentially modulating the interplay between tolerance and trained immunity. The phenomenon of reproductive immune memory may play a novel role in the differential susceptibility of primigravidas to pregnancy complications.
Mixed Multi-Level Visual, Reward, and Motor Signals in Dorsomedial Frontal Cortex Area F7 during Active Naturalistic Video Exploration
Authors: Aboharb Farid , Serene Stephen , Sliwa Julia , Freiwald Winrich
Published: September 2023

In the primate brain the frontal lobes support complex functions, including social cognition. Understanding the functional organization of these regions requires an approach for rich functional characterization. Here we used a novel paradigm, the visual exploration of dynamic social and non-social video scenes, to characterize diverse functions in area F7 of dorsomedial premotor cortex in the macaque monkey (Macaca mulatta) previously suggested to be involved in the representation of social interactions. We found that neural populations within this area carry information about both visual events in the videos, like head turning, and higher-level social categories, like grooming. In addition to signaling visual events, the population also encoded the delivery of juice reward. Our novel free viewing paradigm and naturalistic stimuli elicited active visual exploration, and we found that a large fraction of F7 neurons responded to the subject’s own saccadic eye movements. Information from these three different domains were not separated across distinct neural sub-populations, but distributed, such that many neurons carried sensory, reward, and motor information in a mixed format. Thus we uncover a hitherto unappreciated diversity of functions in region F7 within dorsomedial frontal cortex.
Larval brooding damselfishes and shifting body proportions: does pelagic larval swimming constrain reef fish morphology?
Authors: Lyons J.P. , Kavanagh K.D.
Published: September 2023

The vast majority of reef fishes, including damselfishes, have a pelagic larval stage that ends when any surviving larvae swim to a reef to settle. An extremely rare alternative lifestyle is ‘larval brooding’, where both parents protect larvae on the reef for months until they disperse nearby. The monophyletic clade of larval brooders includes two generaAcanthochromisandAltrichthys. In examination of the skeletons of these damselfishes, we found that all species of damselfish that brood larvae on the reef have a uniquely increased precaudal vertebral count, while all typical damselfishes have an invariable vertebral count with a greater proportion of caudal vertebrae. To explore the significance of the vertebral differences, we measured body proportions of larval brooders vs relatives with the typical pelagic larval stage. We found increased body cavity area and reduced muscle area in the larval brooderAcanthochromis polyacanthus. Furthermore, populations ofAcanthochromisthroughout its range have evolved significantly different proportions. In a comparison of known larval swimming ability among reef fishes, the larval brooders performed most poorly. We propose that when larval brooding evolved, relaxed selection on larval swimming performance allowed a shift in body proportions to favor a larger body cavity and altered axial patterning. Enlarged body cavity gives a fitness advantage as females could hold more of the large eggs and increase clutch size.
Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2 responding CD4+T cells
Authors: Sandoval Simone , Malany Keegan , Thongphanh Krista , Martinez Clarisa A. , Goodson Michael L. , Souza Felipe Da Costa , Lin Lo-Wei , Pennington Jamie , Lein Pamela J. , Kerkvliet Nancy I. , Ehrlich Allison K.
Published: September 2023

Neuropilin-1 (Nrp1), a transmembrane protein expressed on CD4+T cells, is mostly studied in the context of regulatory T cell (Treg) function. More recently, there is increasing evidence that Nrp1 is also highly expressed on activated effector T cells and that increases in these Nrp1-expressing CD4+T cells correspond with immunopathology across several T cell-dependent disease models. Thus, Nrp1 may be implicated in the identification and function of immunopathologic T cells. Nrp1 downregulation in CD4+T cells is one of the strongest transcriptional changes in response to immunoregulatory compounds that act though the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. To better understand the link between AhR and Nrp1 expression on CD4+T cells, Nrp1 expression was assessedin vivoandin vitrofollowing AhR ligand treatment. In the current study, we identified that the percentage of Nrp1 expressing CD4+T cells increases over the course of activation and proliferationin vivo. The actively dividing Nrp1+Foxp3-cells express the classic effector phenotype of CD44hiCD45RBlo, and the increase in Nrp1+Foxp3-cells is prevented by AhR activation. In contrast, Nrp1 expression is not modulated by AhR activation in non-proliferating CD4+T cells. The downregulation of Nrp1 on CD4+T cells was recapitulatedin vitroin cells isolated from C57BL/6 and NOD (non-obese diabetic) mice. CD4+Foxp3-cells expressing CD25, stimulated with IL-2, or differentiated into Th1 cells, were particularly sensitive to AhR-mediated inhibition of Nrp1 upregulation. IL-2 was necessary for AhR-dependent downregulation of Nrp1 expression bothin vitroandin vivo. Collectively, the data demonstrate that Nrp1 is a CD4+T cell activation marker and that regulation of Nrp1 could be a previously undescribed mechanism by which AhR ligands modulate effector CD4+T cell responses.
Neural circuit mechanisms underlying context-specific halting inDrosophila
Authors: Sapkal Neha , Mancini Nino , Kumar Divya Sthanu , Spiller Nico , Murakami Kazuma , Vitelli Gianna , Bargeron Benjamin , Maier Kate , Eichler Katharina , Jefferis Gregory S.X.E. , Shiu Philip K. , Sterne Gabriella R. , Bidaye Salil S.
Published: September 2023

Walking is a complex motor program involving coordinated and distributed activity across the brain and the spinal cord. Halting appropriately at the correct time is a critical but often overlooked component of walking control. While recent studies have delineated specific genetically defined neuronal populations in the mouse brainstem that drive different types of halting1–3, the underlying neural circuit mechanisms responsible for overruling the competing walking-state neural activity to generate context-appropriate halting, remain unclear. Here, we elucidate two fundamental mechanisms by whichDrosophilaimplement context-appropriate halting. The first mechanism (“walk-OFF” mechanism) relies on GABAergic neurons that inhibit specific descending walking commands in the brain, while the second mechanism (“brake” mechanism) relies on excitatory cholinergic neurons in the nerve-cord that lead to an active arrest of stepping movements. Using connectome-informed models4–6and functional studies, we show that two neuronal types that deploy the “walk-OFF” mechanism inhibit distinct populations of walking-promotion neurons, leading to differential halting of forward-walking or steering. The “brake” neurons on the other hand, override all walking commands by simultaneously inhibiting descending walking promoting pathways and increasing the resistance at the leg-joints leading to an arrest of leg movements in the stance phase of walking. We characterized two ethologically relevant behavioral contexts in which the distinct halting mechanisms were used by the animal in a mutually exclusive manner: the “walk-OFF” pathway was engaged for halting during feeding, and the “brake” pathway was engaged for halting during grooming. Furthermore, this knowledge of the neural targets and mechanisms for halting, allowed us to use connectomics to predict novel halting pathways that could be relevant in other behavioral contexts.
Unlocking Esophageal Carcinoma’s Secrets: An integrated Omics Approach Unveils DNA Methylation as a pivotal Early Detection Biomarker with Clinical Implications
Authors: Ali Akbar , Zhang Li , Liu Hong-Sheng
Published: September 2023

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Esophageal carcinoma (EC) ranks among the top six most prevalent malignancies worldwide with a recent surge in incidence. An innovative integrated omics technique is presented for discerning the two primary types of esophageal carcinoma (EC) AND Squamous cell carcinoma and adenocarcinoma. Utilizing The Cancer Genome Atlas (TCGA) data via Bioconductor, the research integrated DNA methylation and RNA expression analyses for esophageal cancer (ESCA). Key findings revealed DNA methylation’s pivotal role in ESCA progression and its potential as an early detection biomarker. Significant disparities in methylation patterns offered insights into the disease’s pathogenesis. A comparison with the TCGA Pan-Cancer dataset using Bioconductor tools enriched the understanding of ESCA genomics. Specifically, 131,220 hypomethylated probes were detected in tumors compared to 6,248 in healthy tissues. Additionally, 42,060 probe-gene pairs linked methylation variations to expression alterations, with 768 hypomethylated motifs identified. Thirteen of these motifs emerged as potential diagnostic markers. Transcription factor analyses spotlighted crucial regulators, including NFL3, ATF4, JUN, and CEBPG, revealing intricate regulatory networks in ESCA. Survival statistics further correlated clinical factors with patient longevity. This research recommends an innovative approach to identifying oesophageal abnormalities through DNA methylation and gene expression mechanisms. Research suggests DNA methylation may serve as an early detection biomarker, aiding in identifying esophagus cancer prior to more advanced stages.
Democratizing access to microfluidics: Rapid prototyping of open microchannels with low-cost LCD 3D printers
Authors: Leong Kelsey M. , Sun Aileen Y. , Quach Mindy L. , Lin Carrie H. , Craig Cosette A. , Guo Felix , Robinson Timothy R. , Chang Megan , Olanrewaju Ayokunle O.
Published: September 2023

Microfluidics offer user-friendly liquid handling for a range of biochemical applications. 3D printing microfluidics is rapid and cost-effective compared to conventional cleanroom fabrication. Typically, microfluidics are 3D printed using digital light projection (DLP) stereolithography (SLA), but many models in use are expensive (≥$10,000 USD), limiting widespread use. Recent liquid crystal display (LCD) technology advancements have provided inexpensive (<$500) SLA 3D printers with sufficient pixel resolution for microfluidic applications. However, there are only a few demonstrations of microfluidic fabrication, limited validation of print fidelity, and no direct comparisons between LCD and DLP printers. We compared a 40 µm pixel resolution DLP printer (∼$18,000 USD) with a 34.4 µm (<$380) LCD-SLA printer. Consistent with prior work, we observed linear trends between designed and measured channel widths ≥ 4 pixels on both printers, so we calculated accuracy above this size threshold. Using a standard IPA wash resin and optimized parameters for each printer, the average error between designed and measured widths was 2.11 ± 1.26% with the DLP printer and 15.4 ± 2.57% with the 34.4 µm LCD printer. The average coefficient of variation [CV] was ∼2% for both printers. Printing with optimized conditions for a low-cost water wash resin designed for LCD-SLA printers resulted in an average error of 2.53 ± 0.94% with the 34.4 µm LCD printer and 5.35 ± 4.49% with a 22 µm LCD printer. We characterized additional parameters including surface roughness, channel perpendicularity, and light intensity uniformity, and as an application of LCD-printed devices, we demonstrated consistent flow rates in capillaric circuits for self-regulated and self-powered delivery of multiple liquids. In conclusion, LCD printers are an inexpensive alternative for fabricating microfluidics, with minimal differences in fidelity and accuracy compared with a 20X more expensive DLP printer.
A Scalable Staining Strategy for Whole-Brain Connectomics
Authors: Lu Xiaotang , Wu Yuelong , Schalek Richard L. , Meirovitch Yaron , Berger Daniel R. , Lichtman Jeff W.
Published: September 2023

Mapping the complete synaptic connectivity of a mammalian brain would be transformative, revealing the pathways underlying perception, behavior, and memory. Serial section electron microscopy, via membrane staining using osmium tetroxide, is ideal for visualizing cells and synaptic connections but, in whole brain samples, faces significant challenges related to chemical treatment and volume changes. These issues can adversely affect both the ultrastructural quality and macroscopic tissue integrity. By leveraging time-lapse X-ray imaging and brain proxies, we have developed a 12-step protocol, ODeCO, that effectively infiltrates osmium throughout an entire mouse brain while preserving ultrastructure without any cracks or fragmentation, a necessary prerequisite for constructing the first comprehensive mouse brain connectome.
Sleep and circadian rhythm disruption by NPTX2 loss of function
Authors: Roh Seung-Eon , Xiao Meifang , Delgado Ana , Kwak Chuljung , Savonenko Alena , Bakker Arnold , Kwon Hyung-Bae , Worley Paul
Published: September 2023

Sleep and circadian rhythm disruption (SCRD) is commonly observed in aging, especially in individuals who experience progressive cognitive decline to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, precise molecular mechanisms underlying the association between SCRD and aging are not fully understood. Orexin A is a well-characterized “sleep neuropeptide” that is expressed in hypothalamic neurons and evokes wake behavior. The importance of Orexin is exemplified in narcolepsy where it is profoundly down-regulated. Interestingly, the synaptic immediate early gene NPTX2 is co-expressed in Orexin neurons and is similarly reduced in narcolepsy. NPTX2 is also down-regulated in CSF of some cognitively normal older individuals and predicts the time of transition from normal cognition to MCI. The association between Orexin and NPTX2 is further evinced here where we observe that Orexin A and NPTX2 are highly correlated in CSF of cognitively normal aged individuals and raises the question of whether SCRD that are typically attributed to Orexin A loss of function may be modified by concomitant NPTX2 down-regulation. Is NPTX2 an effector of sleep or simply a reporter of orexin-dependent SCRD? To address this question, we examined NPTX2 KO mice and found they retain Orexin expression in the brain and so provide an opportunity to examine the specific contribution of NPTX2 to SCRD. Our results reveal that NPTX2 KO mice exhibit a disrupted circadian onset time, coupled with increased activity during the sleep phase, suggesting difficulties in maintaining states. Sleep EEG indicates distinct temporal allocation shifts across vigilance states, characterized by reduced wake and increased NREM time. Evident sleep fragmentation manifests through alterations of event occurrences during Wake and NREM, notably during light transition periods, in conjunction with an increased frequency of sleep transitions in NPTX2 KO mice, particularly between Wake and NREM. EEG spectral analysis indicated significant shifts in power across various frequency bands in the wake, NREM, and REM states, suggestive of disrupted neuronal synchronicity. An intriguing observation is the diminished occurrence of sleep spindles, one of the earliest measures of human sleep disruption, in NPTX2 KO mice. These findings highlight the effector role of NPTX2 loss of function as an instigator of SCRD and a potential mediator of sleep disruption in aging.
Evolution of wheat blast resistance geneRmg8accompanied by differentiation of variants recognizing the powdery mildew fungus
Authors: Asuke Soichiro , Morita Kohei , Shimizu Motoki , Abe Fumitaka , Terauchi Ryohei , Nago Chika , Takahashi Yoshino , Shibata Mai , Yoshioka Motohiro , Iwakawa Mizuki , Kishi-Kaboshi Mitsuko , Su Zhuo , Nasuda Shuhei , Handa Hirokazu , Fujita Masaya , Tougou Makoto , Hatta Koichi , Mori Naoki , Matsuoka Yoshihiro , Kato Kenji , Tosa Yukio
Published: September 2023

Wheat blast, a devastating disease having spread recently from South America to Asia and Africa, is caused byPyricularia oryzaepathotypeTriticumwhich emerged in 1985.Rmg8andRmg7, genes for resistance to wheat blast found in common wheat and tetraploid wheat, respectively, recognize the same avirulence gene,AVR-Rmg8. Here, we show an evolutionary process in which resistance gene(s), which had obtained an ability to recognizeAVR-Rmg8before the differentiation ofTriticumandAegilops, has expanded its target pathogens. Molecular cloning revealed thatRmg7was one of alleles ofPm4(Pm4a), a gene for resistance to wheat powdery mildew on 2AL, whereasRmg8was its homoeolog on 2BL ineffective against wheat powdery mildew.Rmg8variants with the ability to recognizeAVR-Rmg8were distributed not only inTriticumspp. but also inAegilops speltoides,Ae. umbellulata,andAe. comosa. This result suggests that the origin of resistance gene(s) recognizingAVR-Rmg8dates back to the time before differentiation of A, B, S, U, and M genomes, that is, ∼5 million years before the emergence of its current target, the wheat blast fungus. Phylogenetic analyses suggested that, in the evolutionary process thereafter, some of their variants gained the ability to recognize the wheat powdery mildew fungus and evolved into genes for resistance to wheat powdery mildew.
The origin, divergence and inter-subspecies hybridization of house mice (Mus musculus)
Authors: Jing Meidong , Chen Yingjie , Yuan Wenbo , Song Ying , Bi Xiaoxin , Huang Ling
Published: September 2023

House mice (Mus musculus) are the ancestors of laboratory mouse strains and an excellent model for evolutionary biology. The origin, divergence and inter-subspecies hybridization of the three main subspecies (Mus musculus domesticus,M. m. musculus,M. m. castaneus) were not well-resolved. Population genomic analyses with 349 samples from Eurasia confirmed the Himalayas-India-Pakistan junctional region as the origin centre. The divergence ofM. m. domesticus,M. m. musculusandM. m. castaneusoccurred ∼333.6, 308.3 and 134.4 thousand years ago, respectively, which located in different interglacial stages in Pleistocene. Hybridization amongM. m. domesticus,M. m. musculus, andM. m. castaneusafter secondary contact during spread and gene flow between the ancestral population and different subspecies produced distinct genomic mixtures in populations from different regions of Eurasia. Long-distance introgression fromM. m. musculusintoM. m. castaneusand fromM. m. castaneusintoM. m. musculushappened in southern China and northern China, respectively. And extensive genomic introgression occurred on both autosomes and the X chromosomes. Genomic introgression in hybrids from East Asia and Europe revealed that the level of genomic differentiation, recombination rate and benefits for the survival and reproduction of hybrids determined the introgression capability of distinct genomic regions in inter-subspecies hybridization of house mice. Unidirectional introgression of the Y chromosome made all wild mice in East Asia hold themusculus-type Y chromosome. Our study provided comprehensive insights into the origin, divergence and inter-subspecies’ genomic introgression of house mice.