bluuebunny/crossref_metadata_2025 huggingface dataset:
Histo-morphological Characterization of the Tongue and Oropharyngeal Cavity of the Shining Sunbird (Cinnyris habessinicus)
Authors: El-Mansi Ahmed A , Al-Kahtani Mohamed A , Alshahrani Hend , Ibrahim Esam H , Al-Doaiss Amin , Abd-Elhafeez Hanan H , Soliman Soha A , Taha Ramadan , ElBealy Eman
Published: September 2023

Sunbirds, as specialized nectarivores, have developed multiple lingual and oropharyngeal peculiarities imposed by this dietary specialization that particularly extract floral nectar. We have described the functional morphology of the tongues and palates of the shining sunbird, Cinnyris habessinicus, using gross anatomical, histological, and scanning electron microscopic methods. The tongue was bifurcated with fringed lamella and extended posteriorly, forming a broad trough at the lingual body and terminating in two fleshy, alae linguae. The lingual apex and body are nonpapillate and nonglandular, and its root had a muscular pad followed by a conspicuous laryngeal mound bordered by three prominent rows of conical papillae. The lingual root had clusters of mucoid glands with rich acidic mucins, and the laryngeal region had complex papillary distribution at the back margins. Both the lingual body and root had well-developed skeletal elements, musculature, and connective tissues. Furthermore, the palate was membranous and made up of four main ridges with a central choanal slit guarded by choanal papillae. Overall, the presented results showed structural and anatomical features that are the results of the nectarivory dietary niche.
Changes in Rat Adrenal Cortex and Pineal Gland in Inverted Light–Dark Cycle: A Biochemical, Histological, and Immunohistochemical Study
Authors: Shawky Heba A , Abdel Hafez Sara Mohamed Naguib , Hasan Nabil Abdel Kader , Elbassuoni Eman , Abdelbaky Fatma Alzhraa Fouad , AboBakr Abdel Hamid Sayed
Published: September 2023

Poor sleep standards are common in everyday life; it is frequently linked to a rise in stress levels. The adrenal gland interacts physiologically with the pineal gland in the stress response. Pineal gland is a small endocrine organ that modulates sleep patterns. This work aimed to evaluate the inverted light–dark cycle rhythm on the histological changes within the adrenal cortex and pineal gland in adult male albino rats. Twenty adult male albino rats were equally divided into two groups: For the first control group, animals were kept on daylight–darkness for 12–12 h. The second group was kept under an inverted 12- to 12-h light–darkness cycle for 4 weeks. Adrenal sections were subjected to biochemical, histological, and immunohistochemical study. Inverted light–dark cycle group recorded a significant elevation of plasma corticosterone, tissue malondialdehyde, tumor necrosis factor-α, and interleukin-1β (IL-1β) associated with a significant reduction of catalase and superoxide dismutase. Adrenal cortex showed biochemical and histological changes. Pineal glands also showed loss of lobular architecture. A significant upregulation in activated inducible nitric oxide synthase (iNOS) and B-cell lymphoma-associated X (Bax) immunohistochemical expression was recorded in adrenal cortex associating with downregulation in B-cell lymphoma 2 (Bcl-2). It could be concluded that subchronic inverted light–dark cycle exerted direct effects on adrenal cortex and the pineal glands.
Teaching Clinical Reasoning in the Preclinical Period
Authors: Mallory Renee , Maciuba Joseph M , Roy Michael , Durning Steven J
Published: September 2023

Introduction

Developing the clinical reasoning skills necessary to becoming an astute diagnostician is essential for medical students. While some medical schools offer longitudinal opportunities for students to practice clinical reasoning during the preclinical curriculum, there remains a paucity of literature fully describing what that curriculum looks like. As a result, medical educators struggle to know what an effective clinical reasoning curriculum should look like, how it should be delivered, how it should be assessed, or what faculty development is necessary to be successful. We present our Introduction to Clinical Reasoning course that is offered throughout the preclinical curriculum of the Uniformed Services University of the Health Sciences. The course introduces clinical reasoning through interactive lectures and 28 case-based small group activities over 15 months.

The curriculum is grounded in script theory with a focus on diagnostic reasoning. Specific emphasis is placed on building the student’s semantic competence, constructing problem lists, comparing and contrasting similar diagnoses, constructing a summary statement, and formulating a prioritized differential diagnosis the student can defend. Several complementary methods of assessment are utilized across the curriculum. These include assessments of participation, knowledge, and application. The course leverages clinical faculty, graduate medical education trainees, and senior medical students as small group facilitators. Feedback from students and faculty consistently identifies the course as a highly effective and engaging way to teach clinical reasoning.

Conclusion

Our Introduction to Clinical Reasoning course offers students repeated exposure to well-selected cases to promote their development of clinical reasoning. The course is an example of how clinical reasoning can be taught across the preclinical curriculum without extensive faculty training in medical education or clinical reasoning theory. The course can be adapted into different instructional formats to cover a variety of topics to provide the early learner with sequential exposure and practice in diagnostic reasoning.
Fallback onto kicked neutron stars and its effect on spin-kick alignment
Authors: Müller Bernhard
Published: September 2023

Fallback in core-collapse supernova explosions is potentially of significant importance for the birth spins of neutron stars and black holes. It has recently been pointed out that the angular momentum imparted onto a compact remnant by fallback material is subtly intertwined with its kick because fallback onto a moving neutron star or black hole will preferentially come for a conical region around its direction of travel. We show that contrary to earlier expectations such one-sided fallback accretion onto a neutron star will tend to produce spin-kick misalignment. Since the baroclinic driving term in the vorticity equation is perpendicular to the nearly radial pressure gradient, convective eddies in the progenitor as well as Rayleigh–Taylor plumes growing during the explosion primarily carry angular momentum perpendicular to the radial direction. Fallback material from the accretion volume of a moving neutron star therefore carries substantial angular momentum perpendicular to the kick velocity. We estimate the seed angular momentum fluctuations from convective motions in core-collapse supernova progenitors and argue that accreted fallback material will almost invariably be accreted with the maximum permissible specific angular momentum for reaching the Alfvén radius. This imposes a limit of ${\sim }10^{-2}\, \mathrm{M}_\odot$ of fallback accretion for fast-spinning young neutron stars with periods of ${\sim }20\, \mathrm{ms}$ and less for longer birth spin periods.
Past the outer rim, into the unknown: structures beyond the Kuiper Cliff
Authors: de la Fuente Marcos C , de la Fuente Marcos R
Published: September 2023

Although the present-day orbital distribution of minor bodies that go around the Sun between the orbit of Neptune and the Kuiper Cliff is well understood, past ∼50 au from the Sun, our vision gets blurred as objects become fainter and fainter and their orbital periods span several centuries. Deep imaging using the largest telescopes can overcome the first issue but the problems derived from the second one are better addressed using data analysis techniques. Here, we make use of the heliocentric range and range-rate of the known Kuiper belt objects and their uncertainties to identify structures in orbital parameter space beyond the Kuiper Cliff. The distribution in heliocentric range there closely resembles that of the outer main asteroid belt with a gap at ∼70 au that may signal the existence of a dynamical analogue of the Jupiter family comets. Outliers in the distribution of mutual nodal distances suggest that a massive perturber is present beyond the heliopause.
A Proofreading Mutation with an Allosteric Effect Allows a Cluster of SARS-CoV-2 Viruses to Rapidly Evolve
Authors: Mack Andrew H , Menzies Georgina , Southgate Alex , Jones D Dafydd , Connor Thomas R
Published: September 2023

The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 virus is error prone, with errors being corrected by the exonuclease (NSP14) proofreading mechanism. However, the mutagenesis and subsequent evolutionary trajectory of the virus is mediated by the delicate interplay of replicase fidelity and environmental pressures. Here, we have shown that a single, distal mutation (F60S) in NSP14 can have a profound impact upon proofreading with an increased accumulation of mutations and elevated evolutionary rate being observed. Understanding the implications of these changes is crucial, as these underlying mutational processes may have important implications for understanding the population-wide evolution of the virus. This study underscores the urgent need for continued research into the replicative mechanisms of this virus to combat its continued impact on global health, through the re-emergence of immuno-evasive variants.
Detecting Episodic Evolution through Bayesian Inference of Molecular Clock Models
Authors: Tay John H , Baele Guy , Duchene Sebastian
Published: September 2023

Molecular evolutionary rate variation is a key aspect of the evolution of many organisms that can be modeled using molecular clock models. For example, fixed local clocks revealed the role of episodic evolution in the emergence of SARS-CoV-2 variants of concern. Like all statistical models, however, the reliability of such inferences is contingent on an assessment of statistical evidence. We present a novel Bayesian phylogenetic approach for detecting episodic evolution. It consists of computing Bayes factors, as the ratio of posterior and prior odds of evolutionary rate increases, effectively quantifying support for the effect size. We conducted an extensive simulation study to illustrate the power of this method and benchmarked it to formal model comparison of a range of molecular clock models using (log) marginal likelihood estimation, and to inference under a random local clock model. Quantifying support for the effect size has higher sensitivity than formal model testing and is straight-forward to compute, because it only needs samples from the posterior and prior distribution. However, formal model testing has the advantage of accommodating a wide range molecular clock models. We also assessed the ability of an automated approach, known as the random local clock, where branches under episodic evolution may be detected without their a priori definition. In an empirical analysis of a data set of SARS-CoV-2 genomes, we find “very strong” evidence for episodic evolution. Our results provide guidelines and practical methods for Bayesian detection of episodic evolution, as well as avenues for further research into this phenomenon.
Inflammation alters iron distribution in bone and spleen in mice
Authors: Chang JuOae , Debreli Coskun Melis , Kim Jonghan
Published: September 2023

Anemia of inflammation (or inflammation-associated anemia) decreases the quality of life in billions of patients suffering from various inflammatory diseases, such as infection, autoimmune diseases, and cancer, associated with a prolonged state of immune activation. While proper utilization of iron, a nutrient metal essential for erythropoiesis, is important for the prevention of anemia, the alteration of body iron homeostasis upon inflammation, which can contribute to the development of anemia, is not completely understood. Thus, we sought to examine temporal and spatial changes in the distribution of iron and iron-associated molecules during inflammation in mice. To induce inflammation, C57BL/6J mice were injected with turpentine oil weekly for 3 weeks, which resulted in anemia, decreased protein expression of ferroportin, a cellular iron exporter, in the spleen, duodenum, and liver, and increased iron stores in the duodenum and spleen. Tracer kinetic studies after oral administration of 59Fe revealed that more iron was found in the spleen and less in the femur bone in turpentine oil-injected mice compared to the saline-injected mice, indicating tissue-specific abnormalities in iron distribution during inflammation. However, there was no difference in the utilization of iron for red blood cell production after turpentine oil injection; instead, serum hemopexin level and lactate dehydrogenase activity were increased, suggesting increased red blood cell destruction upon inflammation. Our findings provide an improved understanding of temporal and spatial changes in the distribution and utilization of iron during inflammation.
Evolution of Cd2+ and Cu+ binding inHelix pomatiametallothioneins
Authors: Valsecchi Renato , Baumann Christian , Lila Ardit , Zerbe Oliver
Published: September 2023

Metallothioneins (MTs) are small proteins present in all kingdoms of life. Their high cysteine content enables them to bind metal ions, such as Zn2+, Cd2+, and Cu+, providing means for detoxification and metal homeostasis. Three MT isoforms with distinct metal binding preferences are present in the Roman Snail Helix pomatia. Here, we use nuclear magnetic resonance (NMR) to follow the evolution of Cd2+ and Cu+ binding from the reconstructed ancestral Stylommatophora MT to the three H. pomatia MT (HpMT) isoforms. Information obtained from [15N,1H]-HSQC spectra and T2 relaxation times are combined to describe the conformational stability of the MT-metal complexes. A well-behaved MT-metal complex adopts a unique structure and does not undergo additional conformational exchange. The ancestor to all three HpMTs forms conformationally stable Cd2+ complexes and closely resembles the Cd2+-specific HpCdMT isoform, suggesting a role in Cd2+ detoxification for the ancestral protein. All Cu+-MT complexes, including the Cu+-specific HpCuMT isoform, undergo a considerable amount of conformational exchange. The unspecific HpCd/CuMT and the Cu+-specific HpCuMT isoforms form Cu+ complexes with comparable characteristics. It is possible to follow how Cd2+ and Cu+ binding changed throughout evolution. Interestingly, Cu+ binding improved independently in the lineages leading to the unspecific and the Cu+-specific HpMT isoforms. C-terminal domains are generally less capable of coordinating the non-cognate metal ion than N-terminal domains, indicating a higher level of specialization of the C-domain. Our findings provide new insights into snail MT evolution, helping to understand the interplay between biological function and structural features toward a comprehensive understanding of metal preference.
Optimizing preclinical pediatric low-grade glioma models for meaningful clinical translation
Authors: Milde Till , Fangusaro Jason , Fisher Michael J , Hawkins Cynthia , Rodriguez Fausto J , Tabori Uri , Witt Olaf , Zhu Yuan , Gutmann David H
Published: September 2023

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in young children. While they are typically associated with good overall survival, children with these central nervous system tumors often experience chronic tumor- and therapy-related morbidities. Moreover, individuals with unresectable tumors frequently have multiple recurrences and persistent neurological symptoms. Deep molecular analyses of pLGGs reveal that they are caused by genetic alterations that converge on a single mitogenic pathway (MEK/ERK), but their growth is heavily influenced by nonneoplastic cells (neurons, T cells, microglia) in their local microenvironment. The interplay between neoplastic cell MEK/ERK pathway activation and stromal cell support necessitates the use of predictive preclinical models to identify the most promising drug candidates for clinical evaluation. As part of a series of white papers focused on pLGGs, we discuss the current status of preclinical pLGG modeling, with the goal of improving clinical translation for children with these common brain tumors.
Taxane-Based Chemotherapy Is Effective in Metastatic Appendiceal Adenocarcinoma
Authors: Dansby Julia , More Aditya , Zeineddine Mohammad , Yousef Abdelrahman , Bent Alisha , Dayyani Farshid , Wolff Robert , Overman Michael , Shen John Paul
Published: September 2023

Appendiceal cancer is a rare, orphan disease with no therapies currently approved by the FDA for its treatment. Given the limited data regarding drug efficacy, these tumors have historically been treated with chemotherapy designed for colon cancer. However, an overwhelming body of molecular data has demonstrated that appendiceal adenocarcinoma is a distinct entity with key molecular differences from colon cancer, notably rare APC mutation. Recognizing that APC loss-of-function is thought to contribute to taxane resistance and that taxanes are effective in the treatment of other gastrointestinal tumors, including gastric, esophageal, and small bowel adenocarcinoma, we completed a single-center retrospective study to assess efficacy. In a cohort of 13 patients with metastatic appendiceal adenocarcinoma, treated with taxane chemotherapy the median overall survival was 8.8 months. Of 10 evaluable patients, we observed 3 responses, 4 patients with stable disease, and 3 with progression (30% response rate, 70% disease control rate). The results of this study showing activity of taxane-based chemotherapy in appendiceal adenocarcinoma support further clinical investigation of taxane therapy in this orphan disease.
Informality, Consumption Taxes, and Redistribution
Authors: Bachas Pierre , Gadenne Lucie , Jensen Anders
Published: September 2023

Can taxes on consumption redistribute in developing countries? Contrary to consensus, we show that taxing consumption is progressive once we account for informal consumption. Using household expenditure surveys in 32 countries, we proxy for informal consumption using the type of store where purchases occur. We establish that the budget share spent in informal stores steeply declines with income, so that richer households pay a substantially larger share of their income in taxes. Our findings imply that the widespread policy of exempting food from taxation is hard to justify on equity grounds in low-income countries.
A Global, Regional, and National Burden and Quality of Care Index for Schizophrenia: Global Burden of Disease Systematic Analysis 1990–2019
Authors: Same Kaveh , Shobeiri Parnian , Rashidi Mohammad-Mahdi , Ghasemi Erfan , Saeedi Moghaddam Sahar , Mohammadi Esmaeil , Masinaei Masoud , Salehi Niloufar , Mohammadi Fateh Sahar , Farzad Maroufi Seyed , Abdolhamidi Elham , Moghimi Mana , Abbasi-Kangevari Zeinab , Rezaei Negar , Larijani Bagher
Published: September 2023

Background and Hypothesis

Schizophrenia is a mental disorder usually presented in adulthood that affects roughly 0.3 percent of the population. The disease contributes to more than 13 million years lived with disability the global burden of disease. The current study aimed to provide new insights into the quality of care in Schizophrenia via the implementation of the newly introduced quality of care index (QCI) into the existing data.

Study Design

The data from the global burden of disease database was used for schizophrenia. Two secondary indices were calculated from the available indices and used in a principal component analysis to develop a proxy of QCI for each country. The QCI was then compared between different sociodemographic index (SDI) and ages. To assess the disparity in QCI between the sexes, the gender disparity ratio (GDR) was also calculated and analyzed in different ages and SDIs.

Study Results

The global QCI proxy score has improved between 1990 and 2019 by roughly 13.5%. Concerning the gender disparity, along with a rise in overall GDR the number of countries having a GDR score of around one has decreased which indicates an increase in gender disparity regarding quality of care of schizophrenia. Bhutan and Singapore had 2 of the highest QCIs in 2019 while also showing GDR scores close to one.

Conclusions

While the overall conditions in the quality of care have improved, significant disparities and differences still exist between different countries, genders, and ages in the quality of care regarding schizophrenia.
What Kurt Schneider Really Said and What the DSM Has Made of it in Its Different Editions: A Plea to Redefine Hallucinations in Schizophrenia
Authors: Moritz Steffen , Gawęda Łukasz , Carpenter William T , Aleksandrowicz Adrianna , Borgmann Lisa , Gallinat Jürgen , Fuchs Thomas
Published: September 2023

Kurt Schneider has played a leading role in shaping our current view of schizophrenia, placing certain manifestations of delusions and hallucinations at the center of the disorder, especially ideas of persecution and voice-hearing. The first part of this review summarizes Schneider’s original ideas and then traces how the different editions of the DSM merged aspects of Kraepelin’s, Bleuler’s, and Schneider’s historical concepts. Special attention is given to the transition from the DSM-IV to the DSM-5, which eliminated much of Schneider’s original concept. In the second part of the article, we contrast the current definition of hallucination in the DSM-5 with that of Schneider. We present empirically derived arguments that favor a redefinition of hallucinations, much in accordance with Schneider’s original ideas. We plea for a two-dimensional model of hallucinations that represents the degree of insight and perceptuality, ranging from thoughts with full “mineness” via perception-laden thoughts and intrusions (including “as if” experiences”) to hallucinations. While we concur with the DSM-5 that cognitions that are indistinguishable from perceptions should be labeled as hallucinations, we suggest expanding the definition to internally generated sensory phenomena, including those with only partial resemblance to external perceptions, that the individual considers real and that may lie at the heart of a subsequent delusional superstructure.
Relationships between root exudation and root morphological and architectural traits vary with growing season
Authors: Gao Yuqiu , Wang Huimin , Yang Fengting , Dai Xiaoqin , Meng Shengwang , Hu Mingyuan , Kou Liang , Fu Xiaoli
Published: September 2023

Plants allocate a substantial amount of C belowground for root exudates and for the construction and adjustment of root morphological and architectural traits. What relationships exist between root exudates and other root traits and these relationships change with growing season, however, remain unclear. We quantified the root exudation rate and root morphological traits, including total root length (RL), total root surface area (RS), root diameter (RD), specific root length (SRL), specific root area (SRA) and root tissue density (RTD), and architectural traits, such as branching intensity (BI), and investigated their associations during the rapidly growing season (April and August) and the slowly growing season (December) of three common native tree species, Liquidambar formosana, Michelia maudiae and Schima superba, in subtropical China. We found that the linkages of RD, SRL, SRA, RTD and BI did not change with the growing season, reflecting their highly conservative relationships. The root exudation rate varied significantly with growing season (P < 0.05) and produced various associations with other root traits at different growing seasons. During the rapidly growing season (i.e., April), the exudation rate was the highest and was positively correlated with RL. The exudation rate was the lowest during the slowly growing season (i.e., December) and was negatively associated with RL, RS and RTD. Our findings demonstrate the seasonality of the linkages of root exudation rate with other root traits, which highlights the highly plastic and complex associations of belowground root traits. These findings help to deepen our understanding of plant nutrient acquisition strategies.
Employment Effects of Incentivized Gradual Retirement Plans
Authors: Rutten Albert , Knoef Marike , van Vuuren Daniël
Published: September 2023

We investigate the effect of Incentivized Gradual Retirement plans (GRPs) on employment. GRPs encourage later retirement of older workers by offering a reduction in working hours with only a limited decrease in net earnings and pension accrual. A second policy aim is that municipalities use this freed up capacity to hire more young employees. We exploit variation in the availability of GRPs between Dutch municipalities to identify its employment effects. We find that GRPs increase labor supply for older civil servants by almost 7 full-time weeks on a yearly basis. We do not find an increase in the hiring of young workers.
PYR‐41, an inhibitor of ubiquitin‐activating enzyme E1, attenuates 2,4‐dinitrochlorobenzene‐induced atopic dermatitis‐like skin lesions in mice
Authors: Yang Lian , Zhang Qing , Yang Yili , Wang Qun
Published: September 2023

PYR‐41 is an irreversible and cell permeable inhibitor of ubiquitin‐activating enzyme E1, and has been reported to inhibit the degradation of IκB protein. Previous studies have shown that PYR‐41 has effects on anti‐inflammatory, but whether it has therapeutic effects on allergic dermatitis is unclear. The aim of this research was to explore the therapeutic effects of PYR‐41 on atopic dermatitis. The effects of PYR‐41 on the activation of NF‐κB signaling pathway and the expression of inflammatory genes in HaCat cells were tested by western blot and qPCR. A mouse model was built, and the AD‐like skin lesions were induced by 2,4‐dinitrochlorobenzene (DNCB). Then, the treatment effects of PYR‐41 were examined by skin severity score, ear swelling, ELISA, and qPCR. The results showed that PYR‐41 can significantly reduce the K63‐linked ubiquitination level of nuclear factor‐κB essential modulator (NEMO) and tumor necrosis factor receptor associated factor 6 (TRAF6), inhibit the proteasomal degradation of IκBα, thereby activate TNF‐α‐induced NF‐κB signaling pathway in HaCat cells. In addition, DNCB‐treated mice have significant reduction in symptoms after treated by PYR‐41, including reduced ear thickening and reduced skin damage. Serum tests showed that PYR‐41 significantly reduced the expression of IgE, IFN‐γ, and TNF‐α. In conclusion, the current results suggest that PYR‐41 has potential to reduce the symptoms of atopic dermatitis.
Growth differentiation factor myostatin regulates epithelial‐mesenchymal transition genes and enhances invasion by increasing serine protease inhibitors E1 and E2 in human trophoblast cells
Authors: AbdelHafez Faten F. , Klausen Christian , Zhu Hua , Yi Yuyin , Leung Peter C. K.
Published: September 2023

Placental insufficiency disorders, including preeclampsia and intrauterine growth restriction, are major obstetric complications that can have devastating effects on both the mother and the fetus. These syndromes have underlying poor placental trophoblast cell invasion into uterine tissues. Placental invasion is controlled by many hormones and growth factors. Myostatin (MSTN) is a transforming growth factor‐β superfamily member recognized for its important role in muscle growth control. MSTN has also been shown to be secreted and functioning in the placenta, and its serum and/or placental levels were found to be upregulated in preeclampsia and intrauterine growth restriction. Considering that the mechanistic role of MSTN in placentation remains poorly understood, we hypothesized that MSTN uses ALK4/5‐SMAD2/3/4 signaling to increase human trophoblast invasion through a group of epithelial–mesenchymal transition genes including SERPINE2, PAI‐1, and SOX4. mRNA sequencing of control and MSTN‐treated primary human trophoblast cells (n = 5) yielded a total of 610 differentially expressed genes (false discovery rate <0.05) of which 380 genes were upregulated and 230 were downregulated. These differentially expressed genes were highly enriched in epithelial–mesenchymal transition genes, and a subset including SERPINE2, PAI‐1, and SOX4 was investigated for its role in MSTN‐induced trophoblast cell invasion. We found that MSTN induced upregulation of SERPINE2 via ALK4/5‐SMAD2/3/4 signaling; however, SMAD2 was not involved in MSTN‐induced PAI‐1 upregulation. SOX4 was involved in MSTN‐induced upregulation of SERPINE2, but not PAI‐1. Collectively, this study discovers novel molecular mechanisms of MSTN‐induced human trophoblast cell invasion and provides insight into the functional consequences of its dysregulation in placental insufficiency disorders.
PDK4 facilitates fibroblast functions and diabetic wound healing through regulation of HIF‐1α protein stability and gene expression
Authors: Ma Zhouji , Mo Ran , Yang Ping , Ding Youjun , Zhang Hao , Dong Zheng , Chen Yutong , Tan Qian
Published: September 2023

Fibroblast activation disorder is one of the main pathogenic characteristics of diabetic wounds. Orchestrated fibroblast functions and myofibroblast differentiation are crucial for wound contracture and extracellular matrix (ECM) formation. Pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme regulating energy metabolism, has been implicated in modulating fibroblast function, but its specific role in diabetic wounds remains poorly understood. In this study, we investigated the impact of PDK4 on diabetic wounds and its underlying mechanisms. To assess the effect of PDK4 on human dermal fibroblasts (HDFs), we conducted CCK‐8, EdU proliferation assay, wound healing assay, transwell assay, flow cytometry, and western blot analyses. Metabolic shifts were analyzed using the Seahorse XF analyzer, while changes in metabolite expression were measured through LC–MS. Local recombinant PDK4 administration was implemented to evaluate its influence on wound healing in diabetic mice. Finally, we found that sufficient PDK4 expression is essential for a normal wound‐healing process, while PDK4 is low expressed in diabetic wound tissues and fibroblasts. PDK4 promotes proliferation, migration, and myofibroblast differentiation of HDFs and accelerates wound healing in diabetic mice. Mechanistically, PDK4‐induced metabolic reprogramming increases the level of succinate that inhibits PHD2 enzyme activity, thus leading to the stability of the HIF‐1α protein, during which process the elevated HIF‐1α mRNA by PDK4 is also indispensable. In conclusion, PDK4 promotes fibroblast functions through regulation of HIF‐1α protein stability and gene expression. Local recombinant PDK4 administration accelerates wound healing in diabetic mice.
Surgical Treatment of Cervical Kyphosis and Atlantoaxial Dislocation in a Child With Loeys–Dietz Syndrome
Authors: Zhang Qiu-Qi , Zhang Yue-Hui , Liang Zhi-Hui , Song Jia , Shao Jiang
Published: September 2023

We report the case of a 3-year-old child with Loeys–Dietz syndrome, a rare genetic connective tissue disorder. The young girl had concurrent cervical kyphosis, atlantoaxial dislocation (AAD), and spinal cord compression. Posterior occipitocervical fusion was performed. Postoperative examination and clinical manifestations confirmed that all pedicle screws were satisfactorily placed, cervical kyphosis and AAD were corrected, and spinal cord compression was relieved. At the 1-year postoperative follow-up, the patient had recovered well, indicating that our operation was successful. To the best of our knowledge, this is the first reported surgical case of cervical kyphosis and AAD caused by Loeys–Dietz syndrome.
The Model for End-stage Liver Disease 3.0 is not superior to the Model for End-stage Liver Disease-Na in predicting survival: A retrospective cohort study
Authors: Duan Fangfang , Liu Chen , Zhai Hang , Quan Min , Cheng Jun , Yang Song
Published: September 2023

Background:

The Model for End-stage Liver Disease (MELD) 3.0 yields high prognostic performance for patients with end-stage liver disease (ESLD). However, its prognostic performance for patients with alcohol-related liver disease (ARLD) has limited results. The aim of this study was to perform such an evaluation among Chinese patients.

Methods:

Patients hospitalized with ARLD in one institution between 2015 and 2018 were retrospectively included and followed up for 12 months. The original MELD, MELD-Na, MELD 3.0, and modified Maddrey discriminant function (MDF) scores were calculated for each patient at baseline. Their prognostic performances for 1-year survival were assessed. Time-dependent receiver operating characteristic curves were constructed, and AUCs were calculated for each scoring system.

Results:

Among the 576 patients included in our analysis, 209 patients had alcoholic hepatitis (AH). By the 1-year follow-up, 14.8% (84/567) of all the patients and 23.4% (49/209) of those with AH had died. Overall, patients who had died had higher MELD, MELD-Na, MELD 3.0, and MDF scores (all p < 0.001) than those who had not. The same was true in the AH subgroup (MELD: p < 0.001, MELD-Na: p < 0.001, MELD 3.0: p = 0.007, MDF: p = 0.017). The AUC of the MELD 3.0 for prediction of 1-year survival among patients with ARLD was 0.682, lower than that of the original MELD (0.728, p < 0.001) and MELD-Na (0.735, p < 0.001). Moreover, in the AH subgroup, the AUC for the prediction of 1-year survival was lower than that in the MELD-Na subgroup (0.634 vs. 0.708, p < 0.001).

Conclusions:

The MELD 3.0 was not superior to the original MELD or the MELD-Na in predicting the mortality of patients with ARLD.
Association of Continuous Glucose Monitor Receipt and Diabetes Care Provider Type
Authors: Gaulke Amanda P. , Giordano Jennifer , Grossman Daniel S.
Published: September 2023

Objective:

To compare the prevalence of West Virginia Medicaid (WVM) beneficiaries with type 1 diabetes (T1D) with a WVM administrative claim for continuous glucose monitoring (CGM) supplies by whether they received medical care from a board-certified endocrinologist.

Methods:

A total of 1494 WVM beneficiaries aged 20–64 with T1D were retrospectively followed from May 2018 to April 2020. The sample consisted of 2 groups: those receiving medical care from board-certified endocrinologists and those receiving medical care from other providers. CGM prevalence is compared before and after WVM started providing insurance coverage for beneficiaries with T1D to use CGM systems in May 2019 using linear regression with and without adjustments for patient characteristics.

Results:

Thirty-five percent of beneficiaries received care from a board-certified endocrinologist at any point during the sample period. Post–May 2019, the prevalence of WVM administrative claims for CGM supplies was significantly higher among beneficiaries receiving care from an endocrinologist compared with other providers.

Conclusions:

Receiving diabetes care from a board-certified endocrinologist is positively associated with having administrative claims for CGM supplies.
The Head Control Scale: Responsiveness and Concurrent Validity With the Alberta Infant Motor Scale
Authors: Thomas Jodi , Rosen Elaine , Dumas Helene
Published: September 2023

Purpose:

The purpose of this study was to investigate the Head Control Scale's (HCS's) responsiveness and concurrent validity with the Alberta Infant Motor Scale (AIMS).

Methods:

The HCS and the AIMS were administered to 50 infants and young children. Thirty children were reevaluated at hospital discharge or at 18 months of age.

Results:

A statistically significant positive change was noted in mean score from the initial HCS assessment to the second assessment for total score and all position scores. Concurrent validity between HCS and AIMS total scores was excellent.

Conclusion:

Responsiveness to changes in head control and concurrent validity with the AIMS were established, supporting HCS use in clinical practice.
Risk Factors for Missed Appointments at a Multisite Academic Urban Urogynecology Practice
Authors: Miranne Jeannine M. , Courtepatte Alexa , Schatzman-Bone Stephanie , Minassian Vatche A.
Published: September 2023

Importance

Missed appointments lead to decreased clinical productivity and poor health outcomes.

Objectives

The objectives of this study were to describe sociodemographic and clinical characteristics of patients who miss urogynecology appointments and identify risk factors for missed appointments.

Study Design

We conducted an institutional review board–approved case-control study of women 18 years or older scheduled for a urogynecology appointment at 1 of 4 sites associated with an urban academic tertiary care center over 4 months. Patients were included in the missed appointment group if they canceled their appointments the same day or did not show up for them. For comparison, we included a control group consisting of patients immediately preceding or following the ones who missed their appointments with the same visit type. Logistic regression was used to identify risk factors for missed appointments.

Results

Four hundred twenty-six women were included: 213 in the missed appointment group and 213 in the control group. Women who missed appointments were younger (60 years [interquartile range (IQR), 47–72 years] vs 69 years [IQR, 59–78 years], P < 0.0001). More women in the missed appointment group were Hispanic (24.4% vs 13.1%) and non-Hispanic Black (7.5% vs 3.8%, P = 0.009), had Medicaid (17.4% vs 6.57%, P = 0.0006), missed previous appointments (24.9% vs 11.7% P = 0.0005), waited longer for appointments (39 days [IQR, 23.5–55.5 days] vs 30.5 days [IQR, 12.8–47.0 days], P = 0.002), and made appointments for urinary incontinence (44.1% vs 26.8%, P = 0.0002). On multivariate logistic regression, women with Medicaid had significantly higher odds of missing appointments (adjusted OR, 2.11 [1.04–4.48], P = 0.044).

Conclusions

Women with Medicaid were more likely to miss urogynecology appointments. Further research is needed to address barriers this group faces when accessing care.
Clavibacter lycopersici sp. nov.: a peach-colored actinobacterium isolated from symptomless tomato plant
Authors: Osdaghi Ebrahim , Taghavi S. Mohsen , Hamidizade Mozhde , Fazliarab Amal , Hajian Maleki Habibeh , Li Xiang , Jacques Marie-Agnes , Portier Perrine
Published: September 2023

In 2015, Gram-positive peach-coloured actinobacterial strains were isolated from symptomless tomato phyllosphere in Iran. Biochemical and physiological characteristics, as well as 16S rRNA phylogeny showed that the strains belong to

Clavibacter

sp., while they were non-pathogenic on the host of isolation, and morphologically distinct from the tomato pathogen

C. michiganensis

and other plant-associated bacteria. Multilocus sequence analysis of five housekeeping genes showed that the two peach-coloured strains CFBP 8615T (Tom532T) and CFBP 8616 (Tom495) were phylogenetically distinct from all validly described

Clavibacter

species. Whole genome sequence-based indices, i.e. average nucleotide identity (orthoANI) and digital DNA-DNA hybridization (dDDH), showed that the two peach-colored strains share nearly 100 % orthoANI value with one another, while they differ from all validly described

Clavibacter

species with the orthoANI/dDDH values <93 % and <50 %, respectively. Thus, based on both phenotypic features and orthoANI/dDDH indices the peach-coloured strains could belong to a new species within

Clavibacter

. In this study, we provide a formal species description for the peach-coloured tomato-associated

Clavibacter

strains. Clavibacter lycopersici sp. nov. is proposed for the new species with Tom532T = CFBP 8615T = ICMP 22100T as type strain.
Single-cell mitochondrial variant enrichment resolved clonal tracking and spatial architecture in human embryonic hematopoiesis
Authors: Xue Yan , Chao Yiming , Lin Xinyi , Huang Yuanhua , Ho Joshua WK , Sugimura Ryohichi
Published: September 2023

The ability to perform lineage tracing at the single-cell level is critical to reconstructing dynamic transitions during cell differentiation. However, prospective tracing approaches inevitably encounter outstanding challenges including barcoding precision, barcode diversity, and detection efficiency, which can skew inferred lineage relationships. Human pluripotent stem cells (hPSC) even face risks of DNA-damage-induced toxicity-related cell death. We explored the use of naturally occurring somatic mutations in mitochondrial transcripts detected in single-cell RNA-seq as genetic lineage barcodes in HPSC. In this study, we used an enrichment of scRNA-seq mitochondrial reads and a robust computational method to identify clonally relevant mitochondrial variants as endogenous genetic barcodes for clonal tracking of early embryonic hematopoiesis from hPSC. We modeled the development of embryonic tissues from hPSCs and delineated the ontogeny of hematopoietic cells by mitochondrial variant lineage tracing. We identified multiple waves of erythropoiesis in time-series scRNA-seq data. We further applied mitochondrial variant lineage tracing to spatial transcriptomics and identified the clonal development of both erythro-myeloid progenitors and their niche cells. Our study highlights the power of mitochondrial variants as an endogenous marker for clonal tracking in modeling human development from stem cells.
Tunable PhenoCycler Imaging of the Murine Pre-Clinical Tumour Microenvironments
Authors: Abraham Madelyn J. , Goncalves Christophe , McCallum Paige , Gupta Vrinda , Preston Samuel E. J. , Huang Fan , Chou Hsiang , Gagnon Natascha , Johnson Nathalie A. , Miller Wilson H. , Mann Koren K. , del Rincon Sonia V.
Published: September 2023

The tumour microenvironment (TME) consists of tumour-supportive immune cells, endothelial cells, and fibroblasts. PhenoCycler, a high-plex single cell imaging platform, is used to characterize the complexity of the TME. Here, we used PhenoCycler to spatially resolve the TME of 8 routinely employed pre-clinical models of lymphoma, breast cancer, and melanoma. Our data reveal distinct TMEs in the different cancer models that were imaged, and show that cell-cell contacts differ depending on the tumour type examined. For instance, we found that the immune infiltration in a murine model of melanoma is altered in cellular organization in melanomas that become resistant to αPD-1 therapy, with depletions in a number of cell-cell interactions. Furthermore, we provide detailed pipelines for the conjugation of antibodies that are optimized for PhenoCycler staining of murine FFPE tissues specifically, alongside open-source data analysis procedures. Overall, this is a valuable resource study seamlessly adaptable to any field of research involving murine models.
Electrophysiological Mechanisms in the Anterior Insula Cortex during Reward Expectancy
Authors: Yang Linglin , Lehongre Katia , Ye Hongyi , Yu Xinfeng , Navarro Vincent , Cheng Sen , Lin Zheng , Axmacher Nikolai , Wang Shuang , Zhang Hui
Published: September 2023

Reward expectancy contributes to behavioral performance by coordinating the allocation of cognitive resources, which incorporates the involvement of the anterior insular cortex (AIC). To investigate the electrophysiological mechanisms underlying reward expectancy in the AIC, we collected intracranial electroencephalography (iEEG) data from epilepsy patients implanted for clinical purposes. During the recording, they navigated a virtual T-maze where they encountered rewards at three predetermined locations. We focused on the time window proximal to entering the reward zone, which was defined as the expectancy stage. During this stage, a strong phase-amplitude coupling (PAC) effect was found between local theta oscillation and gamma activity within the AIC. Interestingly, the PAC effect exhibited a specific temporal structure in which the peak gamma power was progressively coupled to an earlier theta phase before each onset of the same reward. Meanwhile, the reward-specific brain patterns were pre-activated during the expectancy stage of rewards. This pre-activation was tended to take place simultaneously with the occurrence of peak gamma activities across individual trials. Furthermore, the pre-activation of reward-specific patterns also progressively shifted forward on theta phases as more trials were conducted. These phenomena of phase shift were reminiscent of the phase precession effect in which single neurons fire at progressively earlier phases of low-frequency oscillations, and thus were called phase-precession-like effects (PPLEs). Additionally, subjects exhibiting PPLEs in the AIC presented less variability and a more notable improvement in response latency across trials. These results revealed possible electrophysiological mechanisms of the AIC underlying reward expectancy.
Protein Kinase A Inhibition Epigenetically SilencesRen1
Authors: Smith Jason P. , Paxton Robert , Medrano Silvia , Sheffield Nathan C. , Sequeira-Lopez Maria Luisa S. , Gomez R. Ariel
Published: September 2023

Rationale

Renin-expressing cells are myoendocrine cells crucial for survival which detect changes in blood pressure and release renin to maintain homeostasis. One of the pathways responsible for renin expression includes cAMP as a crucial factor. cAMP binds to subunits of protein kinase A (PKA), ultimately recruiting both CBP and p300. Binding to the cAMP-responsive element in the renin enhancer region thus amplifies renin transcription.

Objective

To evaluate transcriptomic and epigenomic changes occurring at the renin locus via cAMP pathway inhibition.

Methods and Results

We treated As4.1 cells (a tumoral cell line that constitutively expresses renin) with the PKA inhibitor H89 (treated) or DMSO (control). We then performed independent ATAC-seq, scRNA-seq, and ChIP-seq for H3K27Ac and P300 binding on biological replicates of treated and control As4.1 cells.Ren1expression is significantly reduced following PKA inhibition with a corresponding loss in H3K27Ac and P300 binding at the locus. A restricted set of nine genes with overlapping dynamically accessible regions, differential gene expression, and H3K27Ac and P300 binding were identified with roles among three primary renin regulatory paradigms.

Conclusions

The data suggests that cAMP pathway inhibition controls renin expression through a reduction not in accessibility alone, but via a switch from an active to poised state of epigenetic control, a shift towards a less differentiated cellular identity, and the disruption of not only cAMP, but baroreceptor and Notch mediated renin regulatory pathways.
Reducing individual differences in task fMRI with OGRE (One-step General Registration and Extraction) preprocessing
Authors: McAvoy Mark P. , Liu Lei , Zhou Ruiwen , Philip Benjamin A.
Published: September 2023

Volumetric analysis methods continue to enjoy great popularity in the analysis of task-related functional MRI (fMRI) data. Among these methods, the software package FSL (FMRIB, Oxford, UK) is omnipresent throughout the field. However, it remains unknown what advantages might be gained by integrating FSL with alternative preprocessing tools. Here we developed the One-step General Registration and Extraction (OGRE) pipeline to apply FreeSurfer brain extraction for simultaneous registration and motion correction (“one-step resampling”), for FSL volumetric analysis of fMRI data. We compared three preprocessing approaches (OGRE, FSL, and fMRIPrep) in a dataset wherein adult human volunteers (N=39) performed a precision drawing task during fMRI scanning. The three approaches produced grossly similar results, but OGRE’s preprocessing led to lower inter-individual variability across the brain and greater detected activation in primary motor cortex contralateral to movement. This demonstrates that FreeSurfer tools and one-step resampling can improve FSL’s volumetric analysis of fMRI data. The OGRE pipeline provides an off-the-shelf method to apply FreeSurfer-based brain extraction and one-step resampling of motion correction and registration for FSL analysis of task fMRI data.