bluuebunny/crossref_metadata_2025 huggingface dataset:
Choosing Wisely – unbedingt im gesamten
Gesundheitssystem
Authors: Gürkan Irmtraut , Gürkan Irmtraut
Published: August 2022

Die Choosing Wisely Bewegung hat ihren Ursprung in den USA und verfolgt das Ziel,
Überversorgung in der Patientenbehandlung abzubauen. Die Grundidee von
Choosing Wisely – auf Deutsch meist mit „klug entscheiden“
übersetzt – stammt von dem Arzt und Medizinethiker Howard Brody. Er
forderte die Ärzteschaft 2010 im New England Journal of Medicine auf,
stärker ihrem Anspruch gerecht zu werden, das Patientenwohl an die erste
Stelle zu setzen und die Verantwortung für die großen regionalen
Unterschiede in der Gesundheitsversorgung zu übernehmen, die zu erheblichen
Teilen aus Überversorgung bzw. unnötigen Behandlungen resultieren.
Dem Aufruf Brodys folgten zunächst Allgemeinmediziner, Internisten und
Pädiater. Sie haben sogenannte Top-5-Listen mit Empfehlungen zu
Untersuchungen und Behandlungen mit fragwürdigem Zusatznutzen erstellt. Die
Ärzteschaft bestätigt, dass mehr Medizin nicht immer besser ist,
sondern im Gegenteil oft schadet, und auch die Patienten sind davon
überzeugt. Wie in den USA weisen auch in Deutschland regionale Unterschiede
auf Überversorgung hin. In Deutschland ist ein bekanntes Beispiel die
Entfernung der Gaumenmandeln bei Kindern, aber auch die Daten über den im
internationalen Vergleich hohen Verbrauch an Blutkonserven stimmen nachdenklich.
Fettleber, Prädiabetes und Arteriosklerose – Darmmikrobiom als Marker und Therapieziel
Authors: Ellwanger Thomas
Published: August 2022

In der westlichen Welt leiden immer mehr Menschen an einer Fettlebererkrankung (NAFLD) und an Typ-2-Diabetes 1. Dabei sind es nicht immer „die Dicken“, die ein erhöhtes Risiko für Wohlstandserkrankungen haben. Falsche Ernährungsgewohnheiten und Stress verändern auch bei scheinbar Gesunden die Darmmikrobiota, die über ihre Metaboliten und Oberflächenmoleküle den menschlichen Stoffwechsel negativ beeinflussen kann. Mit der Therapie des intestinalen Ökosystems und damit der Mikrobiota-Darm-Leber-Achse sowie der Mikrobiota-Darm-Stoffwechsel-Achse können erfreuliche Verbesserungen – ja sogar Remissionen – drohender Stoffwechselentgleisungen sowie Fettlebererkrankungen erreicht werden. Hilfreich erweist sich dabei die gezielte Diagnostik umfangreicher Störeinflüsse der intestinalen Mikrobiota – anhand funktioneller Gruppen, Schlüsselorganismen und ihrer Stoffwechselprodukte mittels des KyberBiom und der CardioHeparMetabolic-Erweiterung.
Ethical Aspects of Prenatal DNA Testing
Authors: Stanić Žana , Hrgović Zlatko , Fureš Rajko , Vusić Iva , Lagančić Marko
Published: August 2022

Cell-free DNA (cfDNA) first-trimester screening for fetal aneuploidies, as a
non-invasive, safe, and rather accurate method, has changed prenatal screening
policies all over the world. Owing to aggressive marketing, cfDNA screening
tests exhibit global popularity and a rapid spread in routine prenatal care.
However, wide availability of the tests, together with observed difficulties in
the test’s interpretation, bring to light several serious ethical
concerns. To date it is vital to identify and address the most important
ethical, legal, and social issues regarding prenatal screening tests.
Furthermore, guidelines and restrictions in certain cfDNA screening advancements
that may provide information regarding fetal genetic traits of unknown clinical
significance, conditions with variable penetrance, or late-onset conditions,
should be considered.
Kräuter aus Sicht der TCM gegen Blutstagnationen zur Behandlung chronischer Durchblutungsstörungen
Authors: Ploberger Florian
Published: August 2022

Entsprechend dem Thema „Durchblutungsstörungen“ sollen im folgenden Artikel zwei TCM-Rezepturen und ihre Entsprechungen aus westlichen Kräutern, die Blutstagnationen entgegenwirken und somit zur Behandlung chronischer Durchblutungsstörungen eingesetzt werden können, vorgestellt werden.
A Method for Pyrrole Synthesis through Intramolecular Cyclization of γ-Alkynyl Oximes Promoted by SmI2
Authors: Zhang Songlin , Wang Yiqiong , Zhang Lingyu
Published: August 2022

A new strategy for the synthesis of pyrrole through intramolecular cyclization of γ-alkynyl oximes promoted by SmI2 is reported for the first time. In contrast to the prior methods, the selection of oxime instead of oxime ether or ester as substrate makes the synthetic method without accompaniment of organic waste (ArCO2H, AcOH, or ROH) because the hydroxyl group in oxime acts as the leaving group and is finally removed in the form of water molecule in the reaction. From a synthetic point of view, a series of pyrroles were obtained in this one-pot reaction with a broad scope of substrates and feasible reaction conditions.
A Consecutive Ring-Expansion Strategy towards the Macrocyclic Core of the Solomonamide Natural Products
Authors: Unsworth William P. , Yang Zhongzhen , Swanson Christopher R. B.
Published: August 2022

A synthetic strategy based on the application of three consecutive ring-expansion reactions has been used in the synthesis of analogues of the macrocyclic core of the solomonamide natural products. Starting from a simple, readily available tetrahydrocarbazole, oxidative ring expansion is followed by two further 3- and 4-atom ring-expansion reactions, enabling the insertion of amino acid and hydroxy acid derived linear fragments into 15- to 17-membered-ring-enlarged macrocyclic products.
A 360 Evaluation of Neonatal Care Quality at a Level II Neonatal Intensive Care Unit when Delivered Using a Hybrid Telemedicine Service
Authors: Hallford Henry G. , Szyld Edgardo , McCoy Michael , Makkar Abhishek
Published: August 2022

Objective In 2013, the Section of Neonatal and Perinatal Medicine at the University of Oklahoma's Children's Hospital began providing advanced care to a regional level II neonatal intensive care unit (NICU), using a hybrid telemedicine program. This project compares health care providers' and parents' assessments of health care quality using this program.

Study Design This is a prospective, anonymous, nonrandomized survey of health care providers and parents of neonates using our hybrid telemedicine services. Physicians, neonatal nurse practitioners (NNPs), nurses, and parents completed pencil-and-paper surveys based on their participatory roles. Institutional Review Board approval was obtained at OU Medical Center and Comanche County Memorial Hospital. Surveys consisted of 5-point Likert's scale questions. Descriptive statistics compared the level of agreement with each question across participant groups. A service quality (SQ) composite score was created by summing responses from six SQ questions. Between-group analysis was done on the SQ score using the Mann–Whitney U-test.

Results Nine physicians, 10 NNPs, 12 nurses, and 40 parents completed the survey. Providers agreed (90%) that telemedicine can effectively deliver advanced neonatal care; the care patients receive is comparable to direct patient care (87%); telemedicine enhanced overall patient care quality (90%); providers can effectively interact with each other and families using telemedicine (90.3%), and overall telemedicine experience was good (90%). In total, 61% of providers reported telemedicine improves physician-patient interaction. Parents of newborns agreed that they were well informed about telemedicine use for their child's care (88%), were able to communicate routinely with neonatologists (85%), and were comfortable with their child's physical examinations (93%). Provider's versus family's (SQ) score was not significantly different.

Conclusion All survey participants, including neonatologists, NNPs, nurses, and patient families, reported high levels of satisfaction with the hybrid telemedicine model developed and implemented at this institution which may be comparable to in-person direct patient care.

Key Points
Just-in-Time Electronic Health Record Retraining to Support Clinician Redeployment during the COVID-19 Surge
Authors: Jin Da P. , Samuel Sunil , Bowden Kristin , Mohan Vishnu , Gold Jeffrey A.
Published: August 2022

Background In response to surges in demand for intensive care unit (ICU) care related to the COVID-19 pandemic, health care systems have had to increase hospital capacity. One institution redeployed certified registered nurse anesthetists (CRNAs) as ICU clinicians, which necessitated training in ICU-specific electronic health record (EHR) workflows prior to redeployment. Under time- and resource-constrained settings, clinical informatics (CI) fellows could effectively be lead instructors for such training.

Objective This study aimed to deploy CI fellows as lead EHR instructional trainers for clinician redeployment as part of an organization's response to disaster management.

Methods CI fellows led a multidisciplinary team alongside subject matter experts to develop and deploy a tailored EHR curriculum comprising in-person classes and online video modules, leveraging high-fidelity simulated patient cases. The participants completed surveys immediately after the in-person training session and after deployment.

Results Eighteen CRNAs participated, with 15 completing the postactivity survey (83%). All felt the training was useful and improved their EHR skills with a Net Promoter score of +87. Most (93%) respondents indicated the pace of the session was “just right,” and 100% felt the clarity of instruction was “just right” or “extremely easy” to understand. Twelve participants (67%) completed the postdeployment survey. The training increased comfort in the ICU for all respondents, and 91% felt the training prepared them to work in the ICU with minimal guidance. All stated that the concepts learned would be useful in their anesthesia role. Fifty-eight percent viewed the online video library.

Conclusion This case report demonstrates that CI fellows with dual domain expertise in their clinical specialty and informatics are uniquely poised to deliver clinician redeployment EHR training in response to operational crises. Such opportunities can achieve fellowship educational goals while conserving physician resources which can be a strategic option as organizations plan for disaster management.
Current Landscape of Uveitis Specialists in the United States
Authors: Tsui Edmund , Crowell Eric L. , Gangaputra Sapna , Moussa Kareem , Shantha Jessica G. , Shusko Alexander J. , Thompson Ian A. , Pham Derek C. , Jackson Nicholas J. , Venkat Arthi G.
Published: August 2022

Purpose This study characterizes the current landscape of uveitis specialists and their practice settings in the United States.

Methods An anonymous Internet-based survey with questions pertaining to training history and practice characteristics was distributed via REDCap to the American Uveitis Society and Young Uveitis Specialists listservs.

Results Forty-eight uveitis specialists in the United States responded to the survey out of 174 uveitis specialists that identify as practicing in the United States. Twenty-five of 48 respondents (52%) completed an additional fellowship. These additional fellowships ranged from surgical retina (12/25, 48%), cornea (8/25, 32%), and medical retina (4/25, 16%). Two-thirds of uveitis specialists managed their own immunosuppression, while one-third comanaged immunosuppression with rheumatologists. Thirty-three of 48 (69%) maintained a surgical practice.

Conclusion This is the first survey of uveitis specialists across the United States to provide understanding into training and practice characteristics. These data will provide insight into career planning, practice building, and assist in resource allocation.
Fuzzy Schwarzschild (2 + 1)-spacetime
Authors: Viennot David
Published: August 2022

We present a toy model of a fuzzy Schwarzschild space slice (as a noncommutative manifold), in which quantum mean values and quantum quasi-coherent states (states minimizing the quantum uncertainties) have properties close to the classical slice of (r, θ) Schwarzschild coordinates (the so-called Flamm’s paraboloid). This fuzzy Schwarzschild slice is built as a deformation of the noncommutative plane. Quantum time observables are introduced to add a time quantization in the model. We study the structure of the quasi-coherent state of the fuzzy Schwarzschild slice with respect to the quasi-coherent state and the deformation states of the noncommutative plane. The quantum dynamics of a fermion interacting with a fuzzy black hole described by the present model is studied. In particular, we study the decoherence effects appearing in the neighborhood of the fuzzy event horizon. An extension of the model to describe a quantum wormhole is also proposed, where we show that fermions cross the wormhole not by traveling by its internal space but by quantum tunneling, in accordance with the non-traversable character of classical Einstein–Rosen bridges.
Improved resonance method for fatigue test of full-scale wind turbine blades
Authors: Zhou Aiguo , Shi Jinlei , Ma Yi , Xu Xiufeng
Published: August 2022

To further reduce the power of exciter in the common fatigue testing methods and increase the testing frequency to decrease the fatigue testing time, this paper proposes an improved fatigue testing method—Tug Fatigue Testing system (TFTs). The advantages of this new fatigue testing method are low power and high testing frequency of its exciter due to no exciter with moving masses attached to the blade. In TFTs, exciters mounted on the ground or fixed bracket can be used to excite the blade in the uniaxial or biaxial fatigue test. In this paper, the mechanical model of TFTs is established to compare the motor power required by exciters in TFTs and the inertial exciters and the shear load on the blades in both ways. Furthermore, a test of a 56.5 m blade will be performed to verify the feasibility of the new method. In addition, the bending moment distribution of an 80 m blade excited by TFTs was measured and compared with the bending moment distribution of the same blade excited by inertial resonance excitation to evaluate its excitation effect. The test results prove that this improved method needs lower power of exciter, produces smaller shear loads, and provides a higher test frequency in the flap-wise test direction than common inertial resonance excitation. Biaxial fatigue tests can also be conducted by this new method.
Development of a controlled-atmosphere, rapid-cooling cryogenic chamber for tribological and mechanical testing
Authors: Vaught Louis , Tsigkis Vasilis , Polycarpou Andreas A.
Published: August 2022

Mechanical testing of seals, bearing materials, and mechanisms in cryogenic environments is a rapidly growing field of research, as it promises improvements in equipment performance and reliability for applications such as space exploration, liquid hydrocarbon storage, and superconducting devices. Cooling of test equipment is usually performed within a well-insulated test chamber, via direct or indirect evaporation of liquid cryogen. State-of-the-art equipment is frequently insufficient for rigorous testing, being expensive and cumbersome, cooling slowly, struggling to replicate relevant environmental conditions, and/or failing to reach the temperature of the cryogen. Herein, we employ a rapid prototyping approach using polymer 3D printing to iteratively refine cryogen-based cooling of a tribometer. The final design greatly exceeds the minimum temperature of state-of-the-art equipment, cooling a chamber to liquid nitrogen temperatures (−196 °C) while maintaining dry test conditions. When modified for use on a cryogenic tensile tester, the design cools to −150 °C in 149 s, significantly improving upon state-of-the-art performance. By utilizing this 3D-printed equipment, we find that components produced via Fused Deposition Modeling with unmodified, commodity polylactic acid have favorable mechanical properties in a cryogenic environment: tensile strength of 110 MPa, elongation at break of 10%, and specific wear of 5.6 × 10−5 mm3/Nm against stainless steel. By leveraging 3D printing for rapid manufacture of production-quality parts, highly refined cooling chamber designs have been experimentally developed for both a tribometer and a load frame in rapid succession, enabling significant improvements in cryogenic test capabilities.
On the construction of Euclidean invariant and reflection positive measures on the cylindrical compactification of distributions
Authors: Tlas T.
Published: August 2022

A simple construction of Euclidean invariant and reflection positive measures on the cylindrical compactification is performed under a weaker hypothesis than has recently been obtained. Moreover, the results are extended to the case when the theory under consideration has finitely many constraints.
Nitrogen reduction on crystalline carbon nitride supported by homonuclear bimetallic atoms
Authors: Le Yaqian , Wei Changgeng , Xue Weichao , Li Yi , Zhang Yongfan , Lin Wei
Published: August 2022

Electrocatalytic nitrogen reduction reaction (eNRR) is a new method for sustainable NH3 production, which has attracted much attention in recent years. However, the low Faradaic efficiency due to the competitive hydrogen evolution reaction (HER) and inert N≡N triple bond activation hinders its practical application. To find highly efficient electrocatalysts with excellent activity, stability and selectivity, we have studied a series of transition metal dimers (TM2) loaded on poly triazine imide, (PTI) a crystalline carbon nitride, by density functional theory calculations. The results show that most of the metal dimers have good stability. Finally, among 26 homonuclear diatomic catalysts, Mo2@PTI, Re2@PTI, and Pt2@PTI exhibit strong capability for suppressing HER, with a favorable limiting potential of −0.53, −0.36, and −0.63 V, respectively, and hence, can be used as efficient electrocatalysts for NRR. In this study, a homonuclear diatomic eNRR catalyst was designed and screened to provide not only a theoretical basis for the experiments but also an alternative approach for sustainable synthesis of ammonia.
Diploid-dominant life cycles characterize the early evolution of Fungi
Authors: Amses Kevin R. , Simmons D. Rabern , Longcore Joyce E. , Mondo Stephen J. , Seto Kensuke , Jerônimo Gustavo H. , Bonds Anne E. , Quandt C. Alisha , Davis William J. , Chang Ying , Federici Brian A. , Kuo Alan , LaButti Kurt , Pangilinan Jasmyn , Andreopoulos William , Tritt Andrew , Riley Robert , Hundley Hope , Johnson Jenifer , Lipzen Anna , Barry Kerrie , Lang B. Franz , Cuomo Christina A. , Buchler Nicolas E. , Grigoriev Igor V. , Spatafora Joseph W. , Stajich Jason E. , James Timothy Y.
Published: August 2022

Most of the described species in kingdom Fungi are contained in two phyla, the Ascomycota and the Basidiomycota (subkingdom Dikarya). As a result, our understanding of the biology of the kingdom is heavily influenced by traits observed in Dikarya, such as aerial spore dispersal and life cycles dominated by mitosis of haploid nuclei. We now appreciate that Fungi comprises numerous phylum-level lineages in addition to those of Dikarya, but the phylogeny and genetic characteristics of most of these lineages are poorly understood due to limited genome sampling. Here, we addressed major evolutionary trends in the non-Dikarya fungi by phylogenomic analysis of 69 newly generated draft genome sequences of the zoosporic (flagellated) lineages of true fungi. Our phylogeny indicated five lineages of zoosporic fungi and placed Blastocladiomycota, which has an alternation of haploid and diploid generations, as branching closer to the Dikarya than to the Chytridiomyceta. Our estimates of heterozygosity based on genome sequence data indicate that the zoosporic lineages plus the Zoopagomycota are frequently characterized by diploid-dominant life cycles. We mapped additional traits, such as ancestral cell-cycle regulators, cell-membrane– and cell-wall–associated genes, and the use of the amino acid selenocysteine on the phylogeny and found that these ancestral traits that are shared with Metazoa have been subject to extensive parallel loss across zoosporic lineages. Together, our results indicate a gradual transition in the genetics and cell biology of fungi from their ancestor and caution against assuming that traits measured in Dikarya are typical of other fungal lineages.
Exploring the associations between discrimination, coping, skin tone, and the psychosocial health of young adults of color
Authors: Brown Alaysia M. , Landor Antoinette M. , Zeiders Katharine H. , Sarsar Evelyn D.
Published: August 2022

Although valuable strides have been made in linking racial and ethnic discrimination to health outcomes, scholars have primarily used between-person methodological approaches, which assess the implications of reporting high or low mean levels of discrimination. Alternatively, within-person approaches assess the implications of intraindividual variation, or acute changes, in an individual’s exposure to discrimination. These approaches pose two fundamentally different questions about the association between discrimination and health, and empirical work that disaggregates these effects remains scarce. Scholars have also called for research exploring whether sociocultural factors—such as race-related coping and skin tone—contour these associations. To address gaps in extant literature, the current study examined 1) how an individual’s average level of exposure to discrimination (between-person) and weekly fluctuations in these encounters (within-person) relate to psychosocial health and 2) whether race-related coping (confrontational and passive coping) and skin tone moderate these associations. Analyses were conducted using weekly diary data from African American and Latinx young adults (
n
= 140). Findings indicated that reporting higher mean levels of exposure to discrimination and encountering more discrimination than usual on a given week were both associated with poorer psychosocial health. Results also suggest that the efficacy of young adults’ coping mechanisms may depend on their skin tone and the nature of the discriminatory events encountered.
Multicurvature viscous streaming: Flow topology and particle manipulation
Authors: Bhosale Yashraj , Vishwanathan Giridar , Upadhyay Gaurav , Parthasarathy Tejaswin , Juarez Gabriel , Gazzola Mattia
Published: August 2022

Viscous streaming refers to the rectified, steady flows that emerge when a liquid oscillates around an immersed microfeature. Relevant to microfluidics, the resulting local, strong inertial effects allow manipulation of fluid and particles effectively, within short time scales and compact footprints. Nonetheless, practically, viscous streaming has been stymied by a narrow set of achievable flow topologies, limiting scope and application. Here, by moving away from classically employed microfeatures of uniform curvature, we experimentally show how multicurvature designs, computationally obtained, give rise, instead, to rich flow repertoires. The potential utility of these flows is then illustrated in compact, robust, and tunable devices for enhanced manipulation, filtering, and separation of both synthetic and biological particles. Overall, our mixed computational/experimental approach expands the scope of viscous streaming application, with opportunities in manufacturing, environment, health, and medicine, from particle self-assembly to microplastics removal.
Sequence-dependent mechanochemical coupling of helicase translocation and unwinding at single-nucleotide resolution
Authors: Laszlo Andrew H. , Craig Jonathan M. , Gavrilov Momčilo , Tippana Ramreddy , Nova Ian C. , Huang Jesse R. , Kim Hwanhee C. , Abell Sarah J. , deCampos-Stairiker Mallory , Mount Jonathan W. , Bowman Jasmine L. , Baker Katherine S. , Higinbotham Hugh , Bobrovnikov Dmitriy , Ha Taekjip , Gundlach Jens H.
Published: August 2022

We used single-molecule picometer-resolution nanopore tweezers (SPRNT) to resolve the millisecond single-nucleotide steps of superfamily 1 helicase PcrA as it translocates on, or unwinds, several kilobase-long DNA molecules. We recorded more than two million enzyme steps under various assisting and opposing forces in diverse adenosine tri- and diphosphate conditions to comprehensively explore the mechanochemistry of PcrA motion. Forces applied in SPRNT mimic forces and physical barriers PcrA experiences
in vivo
, such as when the helicase encounters bound proteins or duplex DNA. We show how PcrA’s kinetics change with such stimuli. SPRNT allows for direct association of the underlying DNA sequence with observed enzyme kinetics. Our data reveal that the underlying DNA sequence passing through the helicase strongly influences the kinetics during translocation and unwinding. Surprisingly, unwinding kinetics are not solely dominated by the base pairs being unwound. Instead, the sequence of the single-stranded DNA on which the PcrA walks determines much of the kinetics of unwinding.
Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3
Authors: The Erlinda , de Graaf Dennis M. , Zhai Yufeng , Yao Qingzhou , Ao Lihua , Fullerton David A. , Dinarello Charles A. , Meng Xianzhong
Published: August 2022

Calcific aortic valve disease (CAVD) is common in people over the age of 65. Progressive valvular calcification is a characteristic of CAVD and due to chronic inflammation in aortic valve interstitial cells (AVICs) resulting in CAVD progression. IL-38 is a naturally occurring anti-inflammatory cytokine; here, we report lower levels of endogenous IL-38 in AVICs isolated from patients’ CAVD valves compared to AVICs from non-CAVD valves. Recombinant IL-38 suppressed spontaneous inflammatory activity and calcium deposition in cultured AVICs. In mice, knockdown of IL-38 enhanced the production of inflammatory mediators in murine AVICs exposed to the proinflammatory stimulant matrilin-2. We also observed that in cultured AVICs matrilin-2 stimulation activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome with procaspase-1 cleavage into active caspase-1. The addition of IL-38 to matrilin-2–treated AVICs suppressed caspase-1 activation and reduced the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, runt-related transcription factor 2, and alkaline phosphatase. Aged IL-38–deficient mice fed a high-fat diet exhibited aortic valve lesions compared to aged wild-type mice fed the same diet. The interleukin-1 receptor 9 (IL-1R9) is the putative receptor mediating the anti-inflammatory properties of IL-38; we observed that IL-1R9–deficient mice exhibited spontaneous aortic valve thickening and greater calcium deposition in AVICs compared to wild-type mice. These data demonstrate that IL-38 suppresses spontaneous and stimulated osteogenic activity in aortic valve via inhibition of the NLRP3 inflammasome and caspase-1. The findings of this study suggest that IL-38 has therapeutic potential for prevention of CAVD progression.
Novel antiinflammatory biologics shaped by parasite–host coevolution
Authors: Ryan Stephanie M. , Ruscher Roland , Johnston Wayne A. , Pickering Darren A. , Kennedy Malcolm W. , Smith Brian O. , Jones Linda , Buitrago Geraldine , Field Matt A. , Esterman Adrian J. , McHugh Connor P. , Browne Daniel J. , Cooper Martha M. , Ryan Rachael Y. M. , Doolan Denise L. , Engwerda Christian R. , Miles Kim , Mitreva Makedonka , Croese John , Rahman Tony , Alexandrov Kirill , Giacomin Paul R. , Loukas Alex
Published: August 2022

Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host’s immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm’s excretory–secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.
3D chromatin remodeling potentiates transcriptional programs driving cell invasion
Authors: Lebeau Benjamin , Jangal Maïka , Zhao Tiejun , Wong Cheng Kit , Wong Nolan , Cañedo Eduardo Cepeda , Hébert Steven , Aguilar-Mahecha Adriana , Chabot Catherine , Buchanan Marguerite , Catterall Rachel , McCaffrey Luke , Deblois Geneviève , Kleinman Claudia , Park Morag , Basik Mark , Witcher Michael
Published: August 2022

The contribution of deregulated chromatin architecture, including topologically associated domains (TADs), to cancer progression remains ambiguous. CCCTC-binding factor (CTCF) is a central regulator of higher-order chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains unclear. We find that under physiological conditions, CTCF organizes subTADs to limit the expression of oncogenic pathways, including phosphatidylinositol 3-kinase (PI3K) and cell adhesion networks. Loss of a single CTCF allele potentiates cell invasion through compromised chromatin insulation and a reorganization of chromatin architecture and histone programming that facilitates de novo promoter-enhancer contacts. However, this change in the higher-order chromatin landscape leads to a vulnerability to inhibitors of mTOR. These data support a model whereby subTAD reorganization drives both modification of histones at de novo enhancer-promoter contacts and transcriptional up-regulation of oncogenic transcriptional networks.
Hippo signaling cofactor, WWTR1, at the crossroads of human trophoblast progenitor self-renewal and differentiation
Authors: Ray Soma , Saha Abhik , Ghosh Ananya , Roy Namrata , Kumar Ram P. , Meinhardt Gudrun , Mukerjee Abhirup , Gunewardena Sumedha , Kumar Rajnish , Knöfler Martin , Paul Soumen
Published: August 2022

Healthy progression of human pregnancy relies on cytotrophoblast (CTB) progenitor self-renewal and its differentiation toward multinucleated syncytiotrophoblasts (STBs) and invasive extravillous trophoblasts (EVTs). However, the underlying molecular mechanisms that fine-tune CTB self-renewal or direct its differentiation toward STBs or EVTs during human placentation are poorly defined. Here, we show that Hippo signaling cofactor WW domain containing transcription regulator 1 (WWTR1) is a master regulator of trophoblast fate choice during human placentation. Using human trophoblast stem cells (human TSCs), primary CTBs, and human placental explants, we demonstrate that WWTR1 promotes self-renewal in human CTBs and is essential for their differentiation to EVTs. In contrast, WWTR1 prevents induction of the STB fate in undifferentiated CTBs. Our single-cell RNA sequencing analyses in first-trimester human placenta, along with mechanistic analyses in human TSCs revealed that WWTR1 fine-tunes trophoblast fate by directly regulating WNT signaling components. Importantly, our analyses of placentae from pathological pregnancies show that extreme preterm births (gestational time ≤28 wk) are often associated with loss of WWTR1 expression in CTBs. In summary, our findings establish the critical importance of WWTR1 at the crossroads of human trophoblast progenitor self-renewal versus differentiation. It plays positive instructive roles in promoting CTB self-renewal and EVT differentiation and safeguards undifferentiated CTBs from attaining the STB fate.
LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway
Authors: Wang Ying , Liu Jun , Akatsu Chizuru , Zhang Runyun , Zhang Hai , Zhu Han , Liu Kangwei , Zhu Han-Ying , Min Qing , Meng Xin , Cui Chaoqun , Tang Yue , Yu Meiping , Li Yaxuan , Feng Xiaoqian , Wei Hao , Wen Zichao , Ji Sihan , Weigert Martin G. , Tsubata Takeshi , Wang Ji-Yang
Published: August 2022

Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance.
Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses
Authors: Toba Shinsuke , Sato Akihiko , Kawai Makoto , Taoda Yoshiyuki , Unoh Yuto , Kusakabe Shinji , Nobori Haruaki , Uehara Shota , Uemura Kentaro , Taniguchi Keiichi , Kobayashi Masanori , Noshi Takeshi , Yoshida Ryu , Naito Akira , Shishido Takao , Maruyama Junki , Paessler Slobodan , Carr Michael J. , Hall William W. , Yoshimatsu Kumiko , Arikawa Jiro , Matsuno Keita , Sakoda Yoshihiro , Sasaki Michihito , Orba Yasuko , Sawa Hirofumi , Kida Hiroshi
Published: August 2022

Viral hemorrhagic fevers caused by members of the order
Bunyavirales
comprise endemic and emerging human infections that are significant public health concerns. Despite the disease severity, there are few therapeutic options available, and therefore effective antiviral drugs are urgently needed to reduce disease burdens. Bunyaviruses, like influenza viruses (IFVs), possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We screened compounds from our CEN inhibitor (CENi) library and identified specific structural compounds that are 100 to 1,000 times more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. To investigate their inhibitory mechanism of action, drug-resistant viruses were selected in culture. Whole-genome sequencing revealed that amino acid substitutions in the CEN region of drug-resistant viruses were located in similar positions as those of the CEN α3-helix loop of IFVs derived under drug selection. Thus, our studies suggest that CENi compounds inhibit both bunyavirus and IFV replication in a mechanistically similar manner. Structural analysis revealed that the side chain of the carboxyl group at the seventh position of the main structure of the compound was essential for the high antiviral activity against bunyaviruses. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. These data suggest a potential broad-spectrum clinical utility of CENis for the treatment of both severe influenza and hemorrhagic diseases caused by bunyaviruses.
A quantitative and spatial analysis of cell cycle regulators during the fission yeast cycle
Authors: Curran Scott , Dey Gautam , Rees Paul , Nurse Paul
Published: August 2022

We have carried out a systems-level analysis of the spatial and temporal dynamics of cell cycle regulators in the fission yeast
Schizosaccharomyces pombe
. In a comprehensive single-cell analysis, we have precisely quantified the levels of 38 proteins previously identified as regulators of the G2 to mitosis transition and of 7 proteins acting at the G1- to S-phase transition. Only 2 of the 38 mitotic regulators exhibit changes in concentration at the whole-cell level: the mitotic B-type cyclin Cdc13, which accumulates continually throughout the cell cycle, and the regulatory phosphatase Cdc25, which exhibits a complex cell cycle pattern. Both proteins show similar patterns of change within the nucleus as in the whole cell but at higher concentrations. In addition, the concentrations of the major fission yeast cyclin-dependent kinase (CDK) Cdc2, the CDK regulator Suc1, and the inhibitory kinase Wee1 also increase in the nucleus, peaking at mitotic onset, but are constant in the whole cell. The significant increase in concentration with size for Cdc13 supports the view that mitotic B-type cyclin accumulation could act as a cell size sensor. We propose a two-step process for the control of mitosis. First, Cdc13 accumulates in a size-dependent manner, which drives increasing CDK activity. Second, from mid-G2, the increasing nuclear accumulation of Cdc25 and the counteracting Wee1 introduce a bistability switch that results in a rapid rise of CDK activity at the end of G2 and thus, brings about an orderly progression into mitosis.
CoRa—A general approach for quantifying biological feedback control
Authors: Gómez-Schiavon Mariana , El-Samad Hana
Published: August 2022

Feedback control is a fundamental underpinning of life, underlying homeostasis of biological processes at every scale of organization, from cells to ecosystems. The ability to evaluate the contribution and limitations of feedback control mechanisms operating in cells is a critical step for understanding and ultimately designing feedback control systems with biological molecules. Here, we introduce CoRa—or Control Ratio—a general framework that quantifies the contribution of a biological feedback control mechanism to adaptation using a mathematically controlled comparison to an identical system that does not contain the feedback. CoRa provides a simple and intuitive metric with broad applicability to biological feedback systems.
Mechanism of temperature-induced asymmetric swelling and shrinking kinetics in self-healing hydrogels
Authors: Cui Kunpeng , Yu Chengtao , Ye Ya Nan , Li Xueyu , Gong Jian Ping
Published: August 2022

Understanding the physical principle that governs the stimuli-induced swelling and shrinking kinetics of hydrogels is indispensable for their applications. Here, we show that the shrinking and swelling kinetics of self-healing hydrogels could be intrinsically asymmetric. The structure frustration, formed by the large difference in the heat and solvent diffusions, remarkably slows down the shrinking kinetics. The plateau modulus of viscoelastic gels is found to be a key parameter governing the formation of structure frustration and, in turn, the asymmetric swelling and shrinking kinetics. This work provides fundamental understandings on the temperature-triggered transient structure formation in self-healing hydrogels. Our findings will find broad use in diverse applications of self-healing hydrogels, where cooperative diffusion of water and gel network is involved. Our findings should also give insight into the molecular diffusion in biological systems that possess macromolecular crowding environments similar to self-healing hydrogels.
Key role of exportin 6 in exosome-mediated viral transmission from insect vectors to plants
Authors: Lu Hong , Zhu Jiaming , Yu Jinting , Li Qiong , Luo Lan , Cui Feng
Published: August 2022

Exosomes play a key role in virus exocytosis and transmission. The exportin family is usually responsible for cargo nucleocytoplasmic trafficking, and they are frequently found in exosomes. However, the function of exportins sorted in exosomes remains unknown. Here, we successfully isolated “cup holder”-like exosomes from the saliva of ∼30,000 small brown planthoppers, which are vectors of rice stripe virus (RSV). RSV virions were packed in comparatively large exosomes. Four viral genomic RNAs at a certain ratio were identified in the saliva exosomes. The virions contained in the saliva exosomes were capable of replicating and causing disease in rice plants. Interference with each phase of the insect exosome system affected the transmission of RSV from the insect vectors to rice plants. Fragmented exportin 6 was coimmunoprecipitated with viral nucleocapsid protein in saliva and sorted to exosomes via interactions with the cargo sorting protein VPS37a. When the expression of
exportin 6
was knocked down, the amounts of RSV secreted in saliva and rice plants were reduced by 60% and 74%, respectively. These results showed that exportin 6 acted as a vehicle for transporting RSV into exosomes to overcome the barrier of insect salivary glands for horizontal transmission. Exportin 6 would represent an ideal target that could be manipulated to control the outbreak of insect-borne viruses in the future.
Driving force and pathway in polyelectrolyte complex coacervation
Authors: Chen Shensheng , Wang Zhen-Gang
Published: August 2022

There is notable discrepancy between experiments and coarse-grained model studies regarding the thermodynamic driving force in polyelectrolyte complex coacervation: experiments find the free energy change to be dominated by entropy, while simulations using coarse-grained models with implicit solvent usually report a large, even dominant energetic contribution in systems with weak to intermediate electrostatic strength. Here, using coarse-grained, implicit-solvent molecular dynamics simulation combined with thermodynamic analysis, we study the potential of mean force (PMF) in the two key stages on the coacervation pathway for symmetric polyelectrolyte mixtures: polycation–polyanion complexation and polyion pair–pair condensation. We show that the temperature dependence in the dielectric constant of water gives rise to a substantial entropic contribution in the electrostatic interaction. By accounting for this electrostatic entropy, which is due to solvent reorganization, we find that under common conditions (monovalent ions, room temperature) for aqueous systems, both stages are strongly entropy-driven with negligible or even unfavorable energetic contributions, consistent with experimental results. Furthermore, for weak to intermediate electrostatic strengths, this electrostatic entropy, rather than the counterion-release entropy, is the primary entropy contribution. From the calculated PMF, we find that the supernatant phase consists predominantly of polyion pairs with vanishingly small concentration of bare polyelectrolytes, and we provide an estimate of the spinodal of the supernatant phase. Finally, we show that prior to contact, two neutral polyion pairs weakly attract each other by mutually induced polarization, providing the initial driving force for the fusion of the pairs.
A Stellar Life
Authors: Abt Helmut A.
Published: August 2022

In this autobiography of 70+ yr of publishing astronomical papers, I summarize some of my major fields of research, such as (1) hfs in the solar spectrum, (2) the atmospheres of supergiants, (3) shock waves in Cepheids, (4) the Crab Nebula, (5) frequencies of binaries, (6) exoplanets, (7) starting Kitt Peak National Observatory, (8) catalogs, (9) China, (10) editing the Astrophysical Journal, (11) blue stragglers, (12) the Local Interstellar Bubble, and (13) publication studies.
Revealing Double White Dwarf Mergers with Multi-messenger Signals
Authors: Yang He-Wen , Thomas Tam Pak-Hin , Yang Lili
Published: August 2022

A significant number of double white dwarfs (DWDs) are believed to merge within the Hubble time due to the gravitational wave (GW) emission during their inspiraling phase. The outcome of a DWD system is either a type Ia Supernova as the double-degenerate model, or a massive, long-lasting merger remnant. Expected multi-messenger signals of these events will help us to distinguish detailed merging physical processes. In this work, we aim to provide a generic scenario of DWD merging, investigate the emission of all major messengers, with a focus on GWs and neutrinos. Our goal is to provide some guidance for current and future (collaborative) efforts of multi-messenger observations. Throughout the merging evolution of a DWD system, different messengers (GW, neutrino and electromagnetic wave) will dominate at different times. In this work, we show that DWD merger events located at the distance of 1 kpc can indeed produce detectable signals of GWs and neutrinos. The GW frequency is in 0.3–0.6 Hz band around 10 days before tidal disruption begins. We estimate that in optimistic situations, the neutrino number detected by upcoming detectors such as JUNO and Hyper-Kamiokande can reach O(1) for a DWD merging event at ∼1 kpc.
Unveiling the Nature of Polar-ring Galaxies from Deep Imaging
Authors: Mosenkov Aleksandr V. , Reshetnikov Vladimir P. , Skryabina Maria N. , Shakespear Zacory
Published: August 2022

General structural properties and low surface brightness tidal features hold important clues to the formation of galaxies. In this paper, we study a sample of polar-ring galaxies (PRGs) based on optical imaging from the Sloan Digital Sky Survey Stripe 82 and other deep surveys. We investigate the deepest images of candidates for PRGs to date. We carry out photometric decomposition on the host galaxies and associated polar structures that allows us to derive the structural properties of both components. We are able to detect very faint tidal structures around most PRGs in our sample. For several galaxies, we can directly observe the formation of the polar ring due to merging, which is manifested in debris of the victim galaxy and an arc-like polar structure made up of its material. In a few cases, we can discern signs of tidal accretion. The results obtained indicate that the gravitational interaction and merging of galaxies are the most plausible mechanisms for the formation of PRGs.