bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential metal sensing and metal‐dependent degradation of the broad spectrum root metal transporter IRT1
Authors: Spielmann Julien , Cointry Virginia , Devime Fabienne , Ravanel Stéphane , Neveu Julie , Vert Grégory
Published: October 2022

Iron is an essential micronutrient for plant growth and development. Under low iron conditions, Arabidopsis plants take up soil iron using the root iron transporter IRT1. In addition to iron, IRT1 also transports others divalent metals, including cadmium, which consequently accumulates into plant tissues and enters the food chain. IRT1 expression was shown to be regulated at the transcriptional and post‐translational levels by its essential metal substrates to maximize iron uptake while limiting the accumulation of zinc, manganese, or cobalt. Here, we characterized the regulation of IRT1 by cadmium. A short‐term exposure to cadmium decreased the cell surface levels of IRT1 through endocytosis and degradation, but with a lower efficiency than observed for other IRT1 metal substrates. We demonstrated that IRT1 endocytosis in response to cadmium is mediated through the direct binding of cadmium to histidine residues within the regulatory loop of IRT1. However, we revealed that the affinity of the metal sensing motif is much lower for cadmium compared to other metal substrates of IRT1. Finally, we proved that cadmium‐induced IRT1 degradation takes place through ubiquitin‐mediated endocytosis driven by the UBC35/36 E2 ubiquitin‐conjugating enzymes and the IDF1 E3 ubiquitin ligase. Altogether, this work sheds light on the mechanisms of cadmium‐mediated downregulation of IRT1 and provides an additional molecular basis for cadmium accumulation and toxicity in plants.
Absence of pathogenic viruses in COVID‐19 convalescent plasma
Authors: Kandathil Abraham J. , Benner Sarah E. , Bloch Evan M. , Shrestha Ruchee , Ajayi Olivia , Zhu Xianming , Caturegli Patrizio P. , Shoham Shmuel , Sullivan David , Gebo Kelly , Quinn Thomas C. , Casadevall Arturo , Hanley Daniel , Pekosz Andrew , Redd Andrew D. , Balagopal Ashwin , Tobian Aaron A. R.
Published: October 2022

Background

It is important to maintain the safety of blood products by avoiding the transfusion of units with known and novel viral pathogens. It is unknown whether COVID‐19 convalescent plasma (CCP) may contain pathogenic viruses (either newly acquired or reactivated) that are not routinely screened for by blood centers.

Methods

The DNA virome was characterized in potential CCP donors (n = 30) using viral genome specific PCR primers to identify DNA plasma virome members of the Herpesviridae [Epstein Barr Virus (EBV), cytomegalovirus (CMV), human herpesvirus 6A/B, human herpesvirus 7] and Anelloviridae [Torque teno viruses (TTV), Torque teno mini viruses (TTMV), and Torque teno midi viruses (TTMDV)] families. In addition, the RNA plasma virome was characterized using unbiased metagenomic sequencing. Sequencing was done on a HiSeq2500 using high output mode with a read length of 2X100 bp. The sequencing reads were taxonomically classified using Kraken2. CMV and EBV seroprevalence were evaluated using a chemiluminescent immunoassay.

Results

TTV and TTMDV were detected in 12 (40%) and 4 (13%) of the 30 study participants, respectively; TTMDV was always associated with infection with TTV. We did not observe TTMV DNAemia. Despite CMV and EBV seroprevalences of 33.3% and 93.3%, respectively, we did not detect Herpesviridae DNA among the study participants. Metagenomic sequencing did not reveal any human RNA viruses in CCP, including no evidence of circulating SARS‐CoV‐2.

Discussion

There was no evidence of pathogenic viruses, whether newly acquired or reactivated, in CCP despite the presence of non‐pathogenic Anelloviridae. These results confirm the growing safety data supporting CCP.
Long-term changes in the Earth's climate: Milankovitch cycles as an exercise in classical mechanics
Authors: Rainey R. C. T.
Published: October 2022

Long-term changes in the tilt of the Earth's axis, relative to the plane of its orbit, are of great significance to long-term climate change, because they control the size of the arctic and Antarctic circles. These “Milankovitch cycles” have hitherto been calculated by classical perturbation methods or by direct numerical integration of Newton's equations of motion. This paper presents an approximate calculation from simple considerations of angular momentum using similar methods to those used to study the precession of a spinning top. It is an instructive exercise in classical mechanics and gives a simple explanation of the phenomenon in terms of angular momentum. It is shown that the main component of “Milankovitch cycles” has a period of 41,000 yr and is due to one of the modes of precession of the Earth-Venus system. The other mode of this system produces a component of period 29,500 yr, and a third component of period 54,000 yr results from the influence of the precession of the orbits of Jupiter and Saturn. These results agree closely with several of the numerical simulations in the literature and strongly suggest that some other results in the literature are incorrect.
Detection probability and density estimation of fin whales by a Seaglider
Authors: Fregosi Selene , Harris Danielle V. , Matsumoto Haruyoshi , Mellinger David K. , Martin Stephen W. , Matsuyama Brian , Barlow Jay , Klinck Holger
Published: October 2022

A single-hydrophone ocean glider was deployed within a cabled hydrophone array to demonstrate a framework for estimating population density of fin whales (Balaenoptera physalus) from a passive acoustic glider. The array was used to estimate tracks of acoustically active whales. These tracks became detection trials to model the detection function for glider-recorded 360-s windows containing fin whale 20-Hz pulses using a generalized additive model. Detection probability was dependent on both horizontal distance and low-frequency glider flow noise. At the median 40-Hz spectral level of 97 dB re 1 μPa2/Hz, detection probability was near one at horizontal distance zero with an effective detection radius of 17.1 km [coefficient of variation (CV) = 0.13]. Using estimates of acoustic availability and acoustically active group size from tagged and tracked fin whales, respectively, density of fin whales was estimated as 1.8 whales per 1000 km2 (CV = 0.55). A plot sampling density estimate for the same area and time, estimated from array data alone, was 1.3 whales per 1000 km2 (CV = 0.51). While the presented density estimates are from a small demonstration experiment and should be used with caution, the framework presented here advances our understanding of the potential use of gliders for cetacean density estimation.
Detection of dynamic changes in interaural delay by older adults (L)
Authors: Saberi Kourosh , Farahbod Haleh , Turner Katie , Hickok Gregory
Published: October 2022

The ability of older adults (48 to 72) with relatively intact low-frequency hearing to detect the motion of an acoustic source was investigated using dynamically varying interaural delays. Thresholds were measured using a single-interval two-alternative forced-choice task in which listeners determined if the sound source was moving or stationary. Motion thresholds were significantly larger than stationary localization thresholds. No correlation was observed between age and motion-detection ability for the age range tested. An interesting finding was that there were similar thresholds for older and younger adults. Results suggest reliance on dominant low-frequency binaural timing cues unaffected by high-frequency hearing loss in older adults.
Health-Related Quality of Life Among Patients With Painful Chronic Ankle Instability
Authors: Kosik Kyle B. , Hoch Matthew C. , Slone Stacey , Bain Katherine A. , Gribble Phillip A.
Published: October 2022

More than half of individuals with chronic ankle instability (CAI) experience lingering pain from a previous injury. However, there is little empirical evidence investigating the role pain has on health-related quality of life (HRQL). The purpose of this cross-sectional study was to compare physical and psychological HRQL between CAI individuals with and without pain. Group comparisons demonstrated that CAI individuals with pain displayed a lower physical and mental HRQL than those without pain. In addition, CAI individuals with pain reported greater injury-related fear. These findings suggest that persistent pain compounds the negative effect that ankle joint instability has on physical and mental HRQL outcomes. Therefore, conservative therapies should consider multimodal approaches rather than focusing on joint stability alone.
CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection
Authors: Ponnalagu Devasena , Hamilton Shanna , Sanghvi Shridhar , Antelo Diego , Schwieterman Neill , Hansra Inderjot , Xu Xianyao , Gao Erhe , Edwards John C. , Bansal Shyam S. , Wold Loren E. , Terentyev Dmitry , Janssen Paul M. L. , Hund Thomas J. , Khan Mahmood , Kohut Andrew R. , Koch Walter J. , Singh Harpreet
Published: October 2022

Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate the outcome of IR injury will hold a key to efficient therapeutics. Here, we found chloride intracellular channel protein (CLIC4) presence in MAMs of cardiomyocytes and demonstrate its role in modulating ER and mitochondrial calcium homeostasis under physiological and pathological conditions. In a murine model, loss of CLIC4 increased myocardial infarction and substantially reduced cardiac function after IR injury. CLIC4 null cardiomyocytes showed increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation injury in comparison to wild-type cardiomyocytes. Overall, our results indicate that MAM-CLIC4 is a key mediator of cellular response to IR injury and therefore may have a potential implication on other pathophysiological processes.
Unexpected significance of a minor reaction pathway in daytime formation of biogenic highly oxygenated organic compounds
Authors: Shen Hongru , Vereecken Luc , Kang Sungah , Pullinen Iida , Fuchs Hendrik , Zhao Defeng , Mentel Thomas F.
Published: October 2022

Secondary organic aerosol (SOA), formed by oxidation of volatile organic compounds, substantially influence air quality and climate. Highly oxygenated organic molecules (HOMs), particularly those formed from biogenic monoterpenes, contribute a large fraction of SOA. During daytime, hydroxyl radicals initiate monoterpene oxidation, mainly by hydroxyl addition to monoterpene double bonds. Naturally, related HOM formation mechanisms should be induced by that reaction route, too. However, for α-pinene, the most abundant atmospheric monoterpene, we find a previously unidentified competitive pathway under atmospherically relevant conditions: HOM formation is predominately induced via hydrogen abstraction by hydroxyl radicals, a generally minor reaction pathway. We show by observations and theoretical calculations that hydrogen abstraction followed by formation and rearrangement of alkoxy radicals is a prerequisite for fast daytime HOM formation. Our analysis provides an accurate mechanism and yield, demonstrating that minor reaction pathways can become major, here for SOA formation and growth and related impacts on air quality and climate.
Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction
Authors: Kageyama Tatsuto , Shimizu Akihiro , Anakama Riki , Nakajima Rikuma , Suzuki Kohei , Okubo Yusuke , Fukuda Junji
Published: October 2022

During embryonic development, reciprocal interactions between epidermal and mesenchymal layers trigger hair follicle morphogenesis. This study revealed that microenvironmental reprogramming via control over these interactions enabled hair follicle induction in vitro. A key approach is to modulate spatial distributions of epithelial and mesenchymal cells in their spontaneous organization. The de novo hair follicles with typical morphological features emerged in aggregates of the two cell types, termed hair follicloids, and hair shafts sprouted with near 100% efficiency in vitro. The hair shaft length reached ~3 mm in culture. Typical trichogenic signaling pathways were up-regulated in hair follicloids. Owing to replication of hair follicle morphogenesis in vitro, melanosome production and transportation were also monitored in the hair bulb region. This in vitro hair follicle model might be valuable for better understanding hair follicle induction, evaluating hair growth and inhibition of hair growth by drugs, and modeling gray hairs in a well-defined environment.
A circulating subset of iNKT cells mediates antitumor and antiviral immunity
Authors: Cui Guangwei , Shimba Akihiro , Jin Jianshi , Ogawa Taisaku , Muramoto Yukiko , Miyachi Hitoshi , Abe Shinya , Asahi Takuma , Tani-ichi Shizue , Dijkstra Johannes M. , Iwamoto Yayoi , Kryukov Kirill , Zhu Yuanbo , Takami Daichi , Hara Takahiro , Kitano Satsuki , Xu Yan , Morita Hajime , Zhang Moyu , Zreka Lynn , Miyata Keishi , Kanaya Takashi , Okumura Shinya , Ito Takashi , Hatano Etsuro , Takahashi Yoshimasa , Watarai Hiroshi , Oike Yuichi , Imanishi Tadashi , Ohno Hiroshi , Ohteki Toshiaki , Minato Nagahiro , Kubo Masato , Holländer Georg A. , Ueno Hideki , Noda Takeshi , Shiroguchi Katsuyuki , Ikuta Koichi
Published: October 2022

Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244
−
CXCR6
−
), C1 (CD244
−
CXCR6
+
), or C2 (CD244
+
CXCR6
+
) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell–like features, whereas C1 iNKT cells showed more T cell–like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244
+
CXCR6
+
iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell–like properties distinct from conventional tissue-resident iNKT cells.
Digestible and metabolizable energy values of faba beans and field peas fed to growing pigs
Authors: Adekoya Abidemi Abosede , Adeola Olayiwola
Published: October 2022

The digestible energy (DE) and metabolizable energy (ME) in faba beans (FB) and field peas (FP) fed to growing pigs were estimated by the difference procedure in two experiments using the total collection method. Twenty-four barrows with mean initial body weight (BW) of 20.0 kg (SD = 1.13) and 20.4 kg (SD = 0.56) in the first (Exp. 1) and second experiments (Exp. 2), respectively, were assigned to three dietary treatments in a randomized complete block design with BW as a blocking factor. A reference diet was prepared using corn, soybean meal, and soybean oil as the energy-contributing ingredients. Organic FB and DS Admiral FP (FPD) in Exp. 1 and Hampton FP (FPH) and 4010 FP (FP4) in Exp. 2 were included at 30% in the reference diet. In Exp. 1, the determined DE and ME were 3772 and 3606 kcal·kg−1 dry matter (DM) in FB and 3683 and 3589 kcal·kg−1 DM in FPD, respectively. In Exp. 2, the respective DE and ME were 4164 and 4014 kcal·kg−1 DM in FPH and 3574 and 3467 kcal·kg−1 DM in FP4. In conclusion, the determined ME values for FB and FP were 77% to 90% of gross energy.
AAC Julius field pea
Authors: Bing Deng-Jin , Beauchesne Don , Miller Michelle , Cuthbert Richard , Mollison Brett , Naeem Hamid
Published: October 2022

AAC Julius is a semi-leafless, yellow cotyledonary field pea ( Pisum sativum L.) variety developed at Lacombe Research and Development Centre, Agriculture and Agri-Food Canada , Lacombe, AB, Canada. It has a maturity of 100 days, 1000-seed weight of 210 g, and a lodging score of 3.6 on the scale of 1–9. The seed crude protein content of AAC Julius is 24.8%. AAC Julius is resistant to powdery mildew (caused by Erysiphe pisi D.C.) and moderately susceptible to mycosphaerella blight (caused by Mycosphaerella pinodes) and Fusarium root rot (caused by Fusarium avenaceum (Fr.) Sacc. and F. solani).
COVID-19 in Carceral Systems: A Review
Authors: Puglisi Lisa B. , Brinkley-Rubinstein Lauren , Wang Emily A.
Published: October 2022

As with past pandemics of influenza, COVID-19 tore through US prisons and jails; however, the COVID-19 pandemic, uniquely, has led to more health research on carceral systems than has been seen to date. Herein, we review the data on its impact on incarcerated people, correctional officers, health systems, and surrounding communities. We searched medical, sociological, and criminology databases from March 2020 through February 2022 for studies examining the intersection of COVID-19, prisons and jails, and health outcomes, including COVID-19 incidence, prevalence, hospitalizations, and vaccination. Our scoping review identified 77 studies—the bulk of which focus on disease epidemiology in carceral systems, with a small minority that focuses on the efficacy or effectiveness of prevention and mitigation efforts, including testing, vaccination, and efforts to depopulate correctional facilities. We highlight areas for future research, including the experiences of incarcerated people and correctional staff, unanticipated health effects of prolonged quarantine, excess deaths due to delays in healthcare, and experimental studies on vaccine uptake and testing in correctional staff. These studies will enable a fuller understanding of COVID-19 and help stem future pandemics.
Linear Flow Analysis Inspired by Mathematical Methods from Quantum Mechanics
Authors: Magri Luca , Schmid Peter J. , Moeck Jonas P.
Published: October 2022

Since its birth in the 1920s, quantum mechanics has motivated and advanced the analysis of linear operators. In this effort, it significantly contributed to the development of sophisticated mathematical tools in spectral theory. Many of these tools have also found their way into classical fluid mechanics and enabled elegant and effective solution strategies as well as physical insights into complex fluid behaviors. This review provides supportive evidence for synergistically adopting mathematical techniques beyond the classical repertoire, both for fluid research and for the training of future fluid dynamicists. Deeper understanding, compelling solution methods, and alternative interpretations of practical problems can be gained by an awareness of mathematical techniques and approaches from quantum mechanics. Techniques such as spectral analysis, series expansions, considerations on symmetries, and integral transforms are discussed, and applications from acoustics and incompressible flows are presented with a quantum mechanical perspective.
Transition to Turbulence in Pipe Flow
Authors: Avila Marc , Barkley Dwight , Hof Björn
Published: October 2022

Since the seminal studies by Osborne Reynolds in the nineteenth century, pipe flow has served as a primary prototype for investigating the transition to turbulence in wall-bounded flows. Despite the apparent simplicity of this flow, various facets of this problem have occupied researchers for more than a century. Here we review insights from three distinct perspectives: ( a) stability and susceptibility of laminar flow, ( b) phase transition and spatiotemporal dynamics, and ( c) dynamical systems analysis of the Navier—Stokes equations. We show how these perspectives have led to a profound understanding of the onset of turbulence in pipe flow. Outstanding open points, applications to flows of complex fluids, and similarities with other wall-bounded flows are discussed.
Verb Classification Across Languages
Authors: Majewska Olga , Korhonen Anna
Published: October 2022

Recent developments in language modeling have enabled large text encoders to derive a wealth of linguistic information from raw text corpora without supervision. Their success across natural language processing (NLP) tasks has called into question the role of man-made computational resources, such as verb lexicons, in supporting modern NLP. Still, probing analyses have concurrently exposed the limitations of the knowledge possessed by the large neural architectures, revealing them to be clever task solvers rather than self-taught linguists. Can human-designed lexical resources still help fill their knowledge gaps? Focusing on verb classification, we discuss approaches to generating verb classes multilingually and weigh the relative benefits of undertaking expensive lexicographic work and outsourcing the task to untrained native speakers. Then, we consider the evidence for the utility of augmenting pretrained language models with external verb knowledge and ponder the ways in which human expertise can continue to benefit multilingual NLP.
Model-Based Clustering
Authors: Gormley Isobel Claire , Murphy Thomas Brendan , Raftery Adrian E.
Published: October 2022

Clustering is the task of automatically gathering observations into homogeneous groups, where the number of groups is unknown. Through its basis in a statistical modeling framework, model-based clustering provides a principled and reproducible approach to clustering. In contrast to heuristic approaches, model-based clustering allows for robust approaches to parameter estimation and objective inference on the number of clusters, while providing a clustering solution that accounts for uncertainty in cluster membership. The aim of this article is to provide a review of the theory underpinning model-based clustering, to outline associated inferential approaches, and to highlight recent methodological developments that facilitate the use of model-based clustering for a broad array of data types. Since its emergence six decades ago, the literature on model-based clustering has grown rapidly, and as such, this review provides only a selection of the bibliography in this dynamic and impactful field.
The Role of Praziquantel in the Prevention and Treatment of Fibrosis Associated with Schistosomiasis: A Review
Authors: Niu Xuehua , Hu Tao , Hong Ye , Li Xiaoyan , Shen Yuzhou
Published: October 2022

Schistosomiasis remains a major global public health concern. Currently, the control of this neglected tropical disease still depends on chemotherapy to reduce the prevalence and intensity of the parasite infection. It has been widely accepted that praziquantel is highly effective against all species of Schistosoma, and this agent is virtually the only drug of choice for the treatment of human schistosomiasis. Mass drug administration (MDA) with praziquantel has been shown to be effective in greatly reducing the prevalence and morbidity due to schistosomiasis worldwide. In addition to antischistosomal activity, a large number of experiential and clinical evidence has demonstrated the action of praziquantel against fibrosis caused by S. mansoni and S. japonicum infections through decreasing the expression of fibrotic biomarkers such as α-smooth muscle actin (α-SMA), collagen, matrix metalloproteinase (MMP), and tissue inhibitor of metalloproteinase (TIMP), and inhibiting the expression of proinflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β, as well as chemokines, and similar antifibrotic activity was observed in mouse models of fibrosis induced by carbon tetrachloride (CCl4) and concanavalin A (Con-A). In this review, we discuss the role of praziquantel in the prevention and treatment of fibrosis associated with schistosomiasis and the possible mechanisms. We call for randomized, controlled clinical trials to evaluate the efficacy and safety of praziquantel in the treatment of schistosomiasis-induced hepatic fibrosis, and further studies to investigate the potential of praziquantel against fibrosis associated with alcohol consumption, viruses, and toxins seem justified.
Comparison of the Therapeutic Effect of the Mini-Open Incision and Conventional Open Neurolysis of the Median Nerve for Carpal Tunnel Syndrome
Authors: Hu Feng , Lu Liang , Zeng Jianxue , Li Duoyu , Liu Bin
Published: October 2022

Objective. The aim of this study was to compare the therapeutic effects of the mini-open incision and conventional open surgery for carpal tunnel syndrome (CTS). Methods. The clinical data of 52 patients with CTS treated at the First Affiliated Hospital of the University of Science and Technology of China from October 2020 to February 2022 were retrospectively analyzed. The patients were divided into the conventional open surgery group (28 cases) and the mini-open incision group (24 cases) according to different surgical incisions applied. The incision length, operation time, time until postoperative return to work, and complications were observed in the two groups. The Visual Analog Scale (VAS) for pain at one day, one month, and three months after surgery and the Boston Carpal Tunnel Questionnaire scores before, at one month, and at three months after surgery were compared between the two groups. Results. The incision length, operation time, and time until return to work in the mini-open incision group were all shorter than those in the conventional open surgery group (2.58 ± 0.35 vs. 7.32 ± 0.61 cm, 18.67 ± 2.62 vs. 29.46 ± 3.42 min, and 5.33 ± 1.40 vs. 13.86 ± 2.70 d, respectively), and differences were statistically significant (

P

 < 0.05 in all). The VAS scores in the mini-open incision group were lower than those in the conventional open surgery group at one day and one month after surgery, while the difference in the VAS scores at three months after surgery was not statistically significant between the two groups. There was no statistically significant difference in neurological recovery between the two groups at postoperative follow-ups (

P

 > 0.05). The incidences of postoperative scar hyperplasia and scar pain were higher in the conventional open surgery group than those in the mini-open incision group, and differences were statistically significant (

P

 < 0.05 in both). Conclusion. Mini-open incision surgery for CTS was a safe and reliable procedure with a precise therapeutic effect, minimal surgical trauma, and high postoperative comfort for patients and could achieve enhanced recovery. Trial Registration. This trial is registered with ChiCTR2200064631.
A Case of Short Stature Caused by a Mutation in the ACAN Gene
Authors: Karatas Emine , Demir Mikail , Ozcelik Firat , Kara Leyla , Akyurek Esra , Berber Ugur , Hatipoglu Nihal , Ozkul Yusuf , Dundar Munis
Published: October 2022

Introduction: Aggrecanopathies are rare disorders associated with idiopathic short stature. They are caused by pathogenic changes in the ACAN gene located on chromosome 15q26. In this study, we present a case of short stature caused by mutations in the ACAN gene. Case Presentation: A 3-year-3-month-old male patient was referred to us because of his short stature. Physical examination revealed proportional short stature, frontal bossing, macrocephaly, midface hypoplasia, ptosis in the right eye, and wide toes. When the patient was 6 years and 3 months old, his bone age was compatible with 7 years of age. The patient underwent clinical exome sequencing and a heterozygous nonsense c.1243G>T, p.(Glu415*) pathogenic variant was detected in the ACAN gene. The same variant was found in his phenotypically similar father. Our patient is the second case with ptosis. Discussion: ACAN gene mutation should be considered in the differential diagnosis of patients with idiopathic short stature. The development and widespread use of next-generation sequencing technology has increased the diagnostic and treatment possibilities.
Endoscopic Accessibility of the Biliary System in the Postoperative Situs
Authors: Aulinger Benedikt , Schütte Kerstin , Schulz Christian
Published: October 2022

Background: Alterations in the anatomy of the upper gastrointestinal tract may pose a challenge to the endoscopist, especially if interventions to the biliary system are indicated in patients with altered continuity of the gastrointestinal tract, impeding to reach the papilla with conventional ERC techniques. The success of any endoscopic intervention in this setting depends on optimal knowledge on the postoperative anatomy in each individual patient. Summary: If conventional endoscopic retrograde cholangiopancreaticography is impossible, biliary tree access can be achieved by applying novel techniques including endosonography-directed approaches, overtube-assisted approaches or spiral enteroscopy to reach the papilla or biliodigestive anastomosis in case of long limbs, percutaneous or even hybrid approaches. This review gives an overview of the most common techniques. Key Message: The choice of endoscopic approach should be individual in each patient, taking indication and urgency, type of anatomic alteration, local expertise, patients’ characteristics and preferences as well as prognosis into account. Early interdisciplinary discussion is essential to choose the procedure with the optimal risk-benefit ratio in the individual patient.
UBC®Rapid Is Sensitive in Detecting High-Grade Bladder Urothelial Carcinoma and Carcinoma in situ in Asian Population
Authors: Zang Zhijiang , Kesavan Nisha Raishmi , Esuvaranathan Kesavan
Published: October 2022

Objectives: Bladder cancer is a common type of malignancy. UBC®Rapid is a novel immunoassay detecting urine cytokeratin 8/18 protein. Studies have shown good accuracy of UBC®Rapid in detecting bladder cancer. UBC®Rapid has however to date not been evaluated in Asian patients. We evaluated UBC®Rapid in detecting Asian bladder cancer, together with urine cytology. Methods: In total, 112 patients were recruited from National University Hospital Singapore and 103 patients were included in this study, comprising 49 patients with bladder urothelial carcinoma (UC), 21 patients with bladder benign lesions, and 33 patients with normal bladder. All the bladder cancer and benign lesions were confirmed by histology. Voided urine was collected for UBC®Rapid test. The results were compared with urine cytology. Results: The bladder UC group had remarkably higher UBC®Rapid value than the control groups. The sensitivity, specificity, positive, and negative predictive value of UBC®Rapid in detecting bladder UC were 53%, 85.5%, 76.5%, and 66.8%, respectively. Those of urine cytology were 40.8%, 96.3%, 90.9%, and 64.2%, respectively. Adding UBC®Rapid to urine cytology increased sensitivity to 57.1% but decreased specificity to 81.8%. UBC®Rapid was sensitive in detecting high-grade bladder UC (61.1%) and carcinoma in situ (CIS) (72.7%), as compared to urine cytology for bladder UC (55.6%) and CIS (54.5%), respectively. Conclusion: UBC®Rapid is sensitive in detecting high-grade bladder UC and CIS in Asian population. It may be useful as an adjunct test to achieve better detection of bladder cancer.
Interventional Radiology Options after Visceral Surgery
Authors: Deniz Sinan , Öcal Osman , Kühn Florian , Angele Martin Kurt , Werner Jens , Streitparth Florian
Published: October 2022

Background: Postoperative management of patients undergoing visceral surgery can present challenging clinical situations with significant morbidity and mortality. Interventional radiological techniques offer quick, safe, and effective minimally invasive treatment options in the postoperative management of visceral surgery. Summary: Most commonly done procedures include – but are not limited to – fluid or abscess drainage, biliary diversion, bleeding embolization, and re-canalization of a thrombosed vessel. While bleeding from side branches after hepatobiliary and pancreatic surgeries can be managed by coil embolization, the hepatic arterial injury should be managed by stent-graft placement. Hepatic venous complications can require a transhepatic or transjugular approach, whereas the transjugular intrahepatic portosystemic shunt approach has a higher clinical success rate in patients with portal vein thrombosis. Biliary leakages require multidisciplinary management, and interventional radiology can offer an efficient treatment, especially in patients with biliodigestive anastomosis. Key Messages: Interventional radiology provides a broad spectrum of procedures in the management of patients with recent visceral surgery.
Initiating Treatment with Low Fluorouracil Dose and Titrating According to Blood Levels in Patients Treated with a 46-Hour Continuous Infusion
Authors: Khatib Ahmad Waleed , Selub Samuel Maxwell , Uryvaey Anton , Baranseh Jalal , Shai Ayelet
Published: October 2022

Introduction: Fluorouracil (5-FU) pharmacokinetics are variable, leading to a risk of toxicity in some patients and underdosing in others. Therapeutic drug monitoring of 5-FU was shown to reduce toxicity and increase efficacy. This study assessed the clinical utility of starting treatment with 70–80% of BSA calculated dose and titrating according to 5-FU blood levels and toxicity. Methods: A retrospective analysis of a prospectively collected database of 126 patients treated with regimens containing 5-FU bolus and continuous infusion for 46 h for whom the 5-FU blood level was collected at least once. Response,and date of progression, and death were collected for patients with colon and pancreatic cancer. Results: In multivariate analysis, 5-FU blood levels were correlated with 5-FU dose and with age, albeit a small effect size (coefficient = 0.007). Of patients with colon cancer treated with an initial lower 5-FU dose, 18% had a therapeutic 5-FU blood level. The median survival was similar in patients with metastatic colon cancer treated with lower doses and those treated with a full dose. Of patients with pancreatic cancer treated with lower doses, 40% had therapeutic blood levels. The median survival was 13 months in patients with metastatic pancreatic cancer treated with lower 5-FU doses. Conclusion: Starting treatment with low 5-FU dose was associated with patient survival comparable to other published data, and a sizeable percentage of patients had therapeutic blood levels. This approach can be considered, especially in elderly and frail patients.
Less-Invasive Diagnostic Approaches for Infants with Suspected Differences of Sex Development: A Case Report of a 297-g Neonate with Ambiguous Genitalia
Authors: Sato Takeshi , Nakano Satsuki , Ichihashi Yosuke , Kobayashi Hisato , Hida Mariko , Ishii Tomohiro , Hasegawa Tomonobu
Published: October 2022

Less-invasive diagnostic approaches for low-birthweight preterm neonates with suspected differences of sex development have not been established. Herein, we describe our diagnostic approaches for a 297-g neonate with ambiguous genitalia. Using a fiberscope, the external genitalia were inspected in an incubator to minimize the risk of hypothermia and infection. Endotracheal aspirate, collected during routine care, was used for genetic testing to avoid anemia and vital signs fluctuations caused by peripheral blood sampling. Array comparative genomic hybridization indicated a 46,XY karyotype. No pathogenic variants of AR and SRD5A2 were found. Endocrinological data could not be evaluated owing to the absence of reference data. Identification and structural evaluation of the internal genitalia and gonads were difficult. On postnatal day 42, the parents assigned their baby’s sex as male. Our less-invasive diagnostic approaches of inspection and genetic testing are useful for management, including sex assignment in extremely low-birthweight preterm neonates with ambiguous genitalia.
Plaque and Dental Caries Risk in Midlife
Authors: Benn Angela M.L. , Heng Nicholas C.K. , Thomson W. Murray , Broadbent Jonathan M.
Published: October 2022

Dental caries is an endogenous microbial community-based disease resulting from an ecological shift from dynamic stability to metabolic imbalance in a consortium of acidogenic and aciduric bacteria comprising the dental plaque biofilm. Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of health and behaviour in a cohort born in Dunedin, New Zealand. Oral biofilm samples (collected at age 32 years) from anterior labial supragingival, posterior lingual supragingival, posterior subgingival, and the dorsum of the tongue habitats for 841 participants were analysed using checkerboard DNA-DNA hybridisation (CKB), focussing on 30 ecologically significant bacteria. Associations of CKB data with dental caries at ages 32 and 45 years were assessed using regression modelling, adjusting for potential confounders including sex, xerostomia, and oral hygiene. The putative periodontitis pathobiont Tannerella forsythia (in the anterior supragingival biofilm) was associated with untreated caries at age 32 years. The percentage of total summed cell number counts for two putative periodontitis-associated species (T. forsythia and Micromonas micros) was associated with greater caries experience at age 32 years and the development of new caries between age 32 and 45 years. Additionally, severe caries (3 + cavities) was associated with putative caries pathobionts (Lactobacillus fermentum, Lactobacillus plantarum), periodontitis-associated species, and commensals (M. micros, Campylobacter rectus, Streptococcus mitis biovar I, Streptococcus mitis biovar II) in the subgingival biofilm. Participants with sustained poor oral hygiene through age 32 years not only had greater experience of caries by that age than those with good oral hygiene (fully adjusted incidence risk ratio = 5.10, 95% CI: 3.30, 7.89) but also experienced greater incidence of new caries from age 32 to 45 years (incidence risk ratio = 3.69, 95% CI: 2.62, 5.20). These findings provide evidence in support of the extended caries ecological plaque hypotheses, the polymicrobial aetiology of caries, and the integrated aetiology of dental caries and periodontal diseases. They also underscore the roles of poor oral self-care (particularly over the life course) and xerostomia in the occurrence and progression of caries.
Risk Factors for New Onset Atrial Fibrillation during Thyroid Gland Surgery
Authors: Stojanovic Marina , Kalezic Nevena , Milicic Biljana , Zivkovic Milana , Ivosevic Tjasa , Lakicevic Mirko , Zivaljevic Vladan
Published: October 2022

Objective: Thyroid dysfunction is a common cause of atrial fibrillation (AF). Incidence of AF is high in patients with both expressed and subclinical hyperthyroidism. The aim of our study was to determine the incidence and predictors of new onset atrial fibrillation (NOAF) in euthyroid patients undergoing thyroid surgery. Subject and Methods: The study included 1,252 euthyroid patients with American Society of Anesthesiologists (ASA) physical status ASA 2 and ASA 3, who were 18 years and older and were in sinus rhythm. Patients without comorbidity and patients with persistent AF were excluded. We investigated the influence of the following preoperative characteristics on the occurrence of NOAF: age, sex, body mass index, ASA score, admission diagnoses, and comorbidity. We noted the influence of difficult intubation of trachea, type and duration of surgery, and time under general anaesthesia. Univariate and multivariate logistic regression were used to determine predictors of occurrence of NOAF. Results: NOAF was noted in 0.72% of patients. Patients with NOAF were older (63.11 vs. 56.81 years) than patients without NOAF, but this was not statistically significant. Significantly more patients from the NOAF group had preoperative heart rhythm disturbance and a history of angina pectoris, in contrast to patients without registered NOAF (p = 0.001; p = 0.017). Multivariate analysis showed that a history of heart rhythm disturbance was an independent predictor of NOAF. Conclusions: Incidence of NOAF during thyroid surgery is similar to the other type of surgery, if the values of thyroid hormones are normal.
Association between Thrombin Generation and Clinical Characteristics in COVID-19 Patients
Authors: Cohen Omri , Landau Nitsan , Avisahai Einat , Brutman-Barazani Tami , Budnik Ivan , Livnat Tami , Asraf Keren , Doolman Ram , Levy-Mendelovich Sarina , Efros Orly , Manor Uri , Meltzer Eyal , Segal Gad , Rahav Galia , Kenet Gili
Published: October 2022

Introduction: Coronavirus disease 2019 (COVID-19) disease is associated with coagulopathy and an increased risk of thrombosis. An association between thrombin generation (TG) capacity, disease severity, and outcomes has not been well described. Methods: We assessed the correlation of TG with sequential organ failure assessment (SOFA) and sepsis-induced coagulopathy (SIC) scores and clinical outcomes by analysis of plasma samples obtained from hospitalized COVID-19 patients. Results: 32 patients (68.8% male), whose median age was 69 years, were assessed, of whom only 3 patients did not receive anticoagulant therapy. D-dimers were uniformly increased. During hospitalization, 2 patients suffered thrombosis, 3 experienced bleeding, and 12 died. TG parameters from anticoagulated COVID-19 patients did not significantly differ from the values obtained from non-anticoagulated healthy controls. Patients who received higher than prophylactic doses of anticoagulant therapy had increased lag time (p = 0.003), lower endogenous thrombin potential (ETP) (p = 0.037), and a reduced peak height (p = 0.006). ETP correlated with the SIC score (p = 0.038). None of the TG parameters correlated with the SOFA score or were associated with mortality. Conclusion: TG was not associated with disease severity among patients hospitalized with COVID-19. However, a correlation between ETP and the SIC score was noted and deserves attention.
Histone Lactylation Boosts Reparative Gene Activation Post–Myocardial Infarction
Authors: Wang Naixin , Wang Weiwei , Wang Xiaoqi , Mang Ge , Chen Jianfeng , Yan Xiangyu , Tong Zhonghua , Yang Qiannan , Wang Mengdi , Chen Liangqi , Sun Ping , Yang Yupeng , Cui Jingxuan , Yang Mian , Zhang Yafei , Wang Dongni , Wu Jian , Zhang Maomao , Yu Bo
Published: October 2022

Background:

Inflammation resolution and cardiac repair initiation after myocardial infarction (MI) require timely activation of reparative signals. Histone lactylation confers macrophage homeostatic gene expression signatures via transcriptional regulation. However, the role of histone lactylation in the repair response post-MI remains unclear. We aimed to investigate whether histone lactylation induces reparative gene expression in monocytes early and remotely post-MI.

Methods:

Single-cell transcriptome data indicated that reparative genes were activated early and remotely in bone marrow and circulating monocytes before cardiac recruitment. Western blotting and immunofluorescence staining revealed increases in histone lactylation levels, including the previously identified histone H3K18 lactylation in monocyte-macrophages early post-MI. Through joint CUT&Tag and RNA-sequencing analyses, we identified
Lrg1, Vegf-a
, and
IL-10
as histone H3K18 lactylation target genes. The increased modification and expression levels of these target genes post-MI were verified by chromatin immunoprecipitation-qPCR and reverse transcription-qPCR.

Results:

We demonstrated that histone lactylation regulates the anti-inflammatory and pro-angiogenic dual activities of monocyte-macrophages by facilitating reparative gene transcription and confirmed that histone lactylation favors a reparative environment and improves cardiac function post-MI. Furthermore, we explored the potential positive role of monocyte histone lactylation in reperfused MI. Mechanistically, we provided new evidence that monocytes undergo metabolic reprogramming in the early stage of MI and demonstrated that dysregulated glycolysis and MCT1 (monocarboxylate transporter 1)-mediated lactate transport promote histone lactylation. Finally, we revealed the catalytic effect of IL (interleukin)-1β-dependent GCN5 (general control non-depressible 5) recruitment on histone H3K18 lactylation and elucidated its potential role as an upstream regulatory element in the regulation of monocyte histone lactylation and downstream reparative gene expression post-MI.

Conclusions:

Histone lactylation promotes early remote activation of the reparative transcriptional response in monocytes, which is essential for the establishment of immune homeostasis and timely activation of the cardiac repair process post-MI.
Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVβ6/TGF-β Signaling Cascade
Authors: Schinner Camilla , Xu Lifen , Franz Henriette , Zimmermann Aude , Wanuske Marie-Therès , Rathod Maitreyi , Hanns Pauline , Geier Florian , Pelczar Pawel , Liang Yan , Lorenz Vera , Stüdle Chiara , Maly Piotr I. , Kauferstein Silke , Beckmann Britt M. , Sheikh Farah , Kuster Gabriela M. , Spindler Volker
Published: October 2022

Background:

Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell–cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression.

Methods:

We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell–cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVβ6 antibody.

Results:

The DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVβ6 and subsequent transforming growth factor–β signaling as driver of cardiac fibrosis. Blocking integrin-αVβ6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo.

Conclusions:

We show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVβ6 and transforming growth factor–β signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.