bluuebunny/crossref_metadata_2025 huggingface dataset:
Accountants in family firms—a systematic literature review
Authors: Sandgren Mattias , Uman Timur , Nordqvist Mattias
Published: October 2022

The purpose of this article is to review the body of the literature on the role of individual accountants in the context of family firms, synthesize the findings, outline directions for future research, and to present an integrative framework that summarizes these directions. The study utilizes a systematic literature review approach and is guided by three overarching questions related to the field’s development, a reflection on current state-of-the-art research, and an outlook for the field’s future paths. The questions are answered through the mapping and analysis of 39 key articles over a 20-year period. We show central patterns in theory, data, methods, and findings. Our review reveals that the literature is scattered, and that the role of accountants is found to be context dependent. In existing research, an accountant tends to have the roles of a traditional bean counter, a decision-maker, an advisor, and a protector and mediator. Scholars also show that an accountant influences various organizational outcomes in family firms. The review further reveals that accountants can play a key role in accounting- and strategy-related decisions with impact on family firm’s survival and growth. We offer a map of the research on accountants in family firms and an integrative framework. This work does not only highlight the importance of an accountant’s role in family firms but it also allows us to identify numerous research gaps and a pathway for future research in terms of methods, theories, and models.
On the pure logic of justified belief
Authors: Schuster Daniela , Horsten Leon
Published: October 2022

Justified belief is a core concept in epistemology and there has been an increasing interest in its logic over the last years. While many logical investigations consider justified belief as an operator, in this paper, we propose a logic for justified belief in which the relevant notion is treated as a predicate instead. Although this gives rise to the possibility of liar-like paradoxes, a predicate treatment allows for a rich and highly expressive framework, which lives up to the universal ambitions of investigating epistemological concepts. We start with a base theory for justified belief, and then systematically present putative additional axioms for justified belief. We provide an overview of (in)consistency results when the additional principles are added to the base theory, and discuss their philosophical plausibility.
Seismological footprint of an anomalous atmospheric activity registered in March 2021, in Baja California, Mexico
Authors: Flores-Estrella Hortencia , Ávila-Barrientos Lenin , Gonzalez-Huizar Hector
Published: October 2022

On 11 March 2021, a quite short strong signal was recorded by seismic stations of the CICESE Seismic Network, which cannot be associated with any regional or global earthquake. At the CICESE Campus and all along the city of Ensenada, in Baja California, Mexico, people reported vibration of the windows and even a short strong rumbling. Fortunately, houses and buildings did not report any damage. Due to the interaction between the atmosphere and the shallow earth surface, this anomalous atmospheric activity produced a special seismological footprint, with frequencies between 1 and 10 Hz. In this manuscript, we report on the observations of a multiparameter dataset, including seismic data along with wind velocity, wind density, temperature, humidity, atmospheric pressure, and THSW index. The atmospheric perturbation wave was strong enough to be clearly recorded by seismic stations within an area of almost 80 km and to produce some changes in the recorded meteorological parameters. The results from an FK analysis show that the atmospheric activity occurred to the south of Ensenada City and travelled to the north, as shown in the seismic records. We discuss the characteristics of the seismic signals in the frequency domain and the relation to the changes in the atmospheric parameters that could be related to this anomalous atmospheric activity.
Digoxin Induces Human Astrocyte Reaction In Vitro
Authors: Pamies David , Vujić Tatjana , Schvartz Domitille , Boccard Julien , Repond Cendrine , Nunes Carolina , Rudaz Serge , Sanchez Jean-Charles , González-Ruiz Víctor , Zurich Marie-Gabrielle
Published: October 2022

Astrocyte reaction is a complex cellular process involving astrocytes in response to various types of CNS injury and a marker of neurotoxicity. It has been abundantly studied in rodents but relatively poorly in human cells due to limited access to the brain. Astrocytes play important roles in cerebral energy metabolism and are also key players in neuroinflammation. Astroglial metabolic and inflammatory changes have been reported with age, leading to the hypothesis that mitochondrial metabolism and inflammatory responses are interconnected. However, the relationship between energy metabolism and astrocyte reactivity in the context of neurotoxicity is not known. We hypothesized that changes in energy metabolism of astrocytes will be coupled to their activation by xenobiotics. Astrocyte reaction and associated energy metabolic changes were assessed by immunostaining, gene expression, proteomics, metabolomics, and extracellular flux analyses after 24 h of exposure of human ReN-derived astrocytes to digoxin (1–10 µM) or TNFα (30 ng/ml) used as a positive control. Strong astrocytic reaction was observed, accompanied by increased glycolysis at low concentrations of digoxin (0.1 and 0.5 µM) and after TNFα exposure, suggesting that increased glycolysis may be a common feature of reactive astrocytes, independent of the triggering molecule. In conclusion, whether astrocyte activation is triggered by cytokines or a xenobiotic, it is strongly tied to energy metabolism in human ReN-derived astrocytes. Increased glycolysis might be considered as an endpoint to detect astrocyte activation by potentially neurotoxic compounds in vitro. Finally, ReN-derived astrocytes may help to decipher mechanisms of neurotoxicity in ascertaining the ability of chemicals to directly target astrocytes.
RETRACTED ARTICLE: Silencing of long non-coding RNA TUC338 inhibits the malignant phenotype of nasopharyngeal cancer cells via modulating the miR-1226-3p/FGF2 axis
Authors: Wang Jian , Li Liping , Jiang Xue , Wang Bin , Hu Xiaodong , Liu Weiwei , Zhang Ying
Published: October 2022

Long noncoding RNAs (lncRNAs) have been suggested as essential regulators in the cancer progression. LncRNA TUC338 was found to promote the malignancy of various cancers, however, the involvement of TUC338 in nasopharyngeal cancer (NPC) has not been well characterized. Here, our results found the significant overexpression of TUC338 in NPC tissues. Higher level of TUC338 was also observed in NPC cells. Interestingly, NPC patients harboring overexpressed TUC338 have worse prognosis. Functional study indicated that down-regulated TUC338 remarkably suppressed the NPC cell proliferation and cell migration. Notably, depletion of TUC338 significantly inhibited the in vivo tumor growth. Mechanistically, TUC338 acted as molecular sponge of miR-1226-3p and attenuated the negative regulation of miR-1226-3p on the expression of fibroblast growth factor 2 (FGF2). Down-regulation of TUC338 inhibited FGF2 expression in NPC cells and tumor tissues. Overexpression of FGF2 attenuated the suppressed NPC proliferation upon the depletion of TUC338. Our results demonstrated the novel function of TUC338/miR-1226-3p/FGF2 axis in NPC progression, suggesting the potential diagnosis and therapeutics significance of TUC338 in NPC.
Remdesivir-related cost-effectiveness and cost and resource use evidence in COVID-19: a systematic review
Authors: Murton Molly , Drane Emma , Jarrett James , Cornely Oliver A. , Soriano Alex
Published: October 2022

Background

The coronavirus disease 2019 (COVID-19) pandemic has been a global health emergency since December 2019, leading to millions of deaths worldwide and placing significant pressures, including economic burden, on individual patients and healthcare systems. As of February 2022, remdesivir is the only US Food and Drug Administration (FDA)-approved treatment for severe COVID-19. This systematic literature review (SLR) aimed to summarise economic evaluations, and cost and resource use (CRU) evidence related to remdesivir during the COVID-19 pandemic.

Methods

Searches of MEDLINE, Embase the International Health Technology Assessment (HTA) database, reference lists, congresses and grey literature were performed in May 2021. Articles were reviewed for relevance against pre-specified criteria by two independent reviewers and study quality was assessed using published checklists.

Results

Eight studies reported resource use and five reported costs related to remdesivir. Over time, the prescription rate of remdesivir increased and time from disease onset to remdesivir initiation decreased. Remdesivir was associated with a 6% to 21.3% decrease in bed occupancy. Cost estimates for remdesivir ranged widely, from $10 to $780 for a 10-day course. In three out of four included economic evaluations, remdesivir treatment scenarios were cost-effective, ranging from ~ 8 to ~ 23% of the willingness-to-pay threshold for the respective country.

Conclusions

Economic evidence relating to remdesivir should be interpreted with consideration of the broader clinical context, including patients’ characteristics and the timing of its administration. Nonetheless, remdesivir remains an important option for physicians in aiming to provide optimal care and relieve pressure on healthcare systems through shifting phases of the pandemic.
Fachfremdes Unterrichten und Schulleitungen: Einstellungen und Maßnahmen zur Unterstützung fachfremd tätiger Lehrkräfte
Authors: Porsch Raphaela , Gräsel Fabian
Published: October 2022

Das Phänomen des fachfremd erteilten Unterrichts wurde vielfach in der Forschung unter der Frage nach den Auswirkungen auf Schülerleistungen und dem Umgang durch Lehrkräfte untersucht. Dagegen spielten Schulleitungen, die u. a. im Spannungsfeld von Unterrichtsversorgung, der Gewährleistung qualitätvollen Unterrichts und Personalführung stehen, in der Diskussion und empirischen Forschung bislang kaum eine Rolle. Im Beitrag wird eine Auswertung von elf Interviews mit Schulleitungen an Grundschulen und weiterführenden, nichtgymnasialen Schulen aus Deutschland vorgestellt. Die bislang schmale empirische Befundlage lässt grundsätzlich eine Defizitperspektive seitens der Schulleitungen vermuten. Die Forschungsliteratur verweist zudem auf eine Reihe von Begründungen zur Akzentuierung und Relativierung des Problems, welche sich den Bereichen Kontext, Akteur*innen und Inhalt zuordnen lassen. Die Auswertung der Interviewdaten mithilfe der inhaltlich strukturierenden qualitativen Inhaltsanalyse zeigt, dass die befragten Schulleitungen der Situation grundsätzlich kritisch gegenüberstehen, jedoch ihre Defizitperspektive im Verlauf der Interviews spezifizieren können und vorrangig relativierende Begründungen heranziehen. Ergänzend wurden in dieser explorativen Studie die tatsächlich implementierten Maßnahmen zur Unterstützung der fachfremd tätigen Lehrkräfte an den Schulen herausgearbeitet. Der Beitrag endet mit einem Ausblick und Vorschlägen für Anschlussarbeiten.
Unterrichtsqualität in den Naturwissenschaften. Eine vergleichende Gegenüberstellung von Ansätzen zwischen Fachspezifik und Generik
Authors: Heinitz Benjamin , Szogs Michael , Förtsch Christian , Korneck Friederike , Neuhaus Birgit J. , Nehring Andreas
Published: October 2022

Die Frage danach, was einen guten naturwissenschaftlichen Unterricht ausmacht und die Frage, inwiefern Unterrichtsqualitätsmerkmale fachspezifisch oder generisch betrachtet werden müssen, sind grundlegende Fragestellungen mit denen sich die Unterrichtsqualitätsforschung beschäftigt. Inzwischen zeichnet sich in den Naturwissenschaftsdidaktiken ein breiter Konsens ab, dass die drei Basisdimensionen der Unterrichtsqualität,Klassenführung, konstruktive Unterstützungundkognitive Aktivierung,fachspezifisch ausdifferenziert und ergänzt werden müssen. Zur konkreten fachspezifischen Ausdifferenzierung und Ergänzung existieren in den Naturwissenschaftsdidaktiken jedoch unterschiedliche Ansätze. Im Rahmen dieses Beitrages wurden exemplarisch drei Ansätze zur fachspezifischen Ausdifferenzierung von Unterrichtsqualitätsmerkmalen herausgegriffen und vergleichend betrachtet, um so zu einem umfassenden Bild aus der Perspektive der Naturwissenschaften zu gelangen. Dazu wurden die drei Ansätze aus dem naturwissenschaftlichen Fachbereich hinsichtlich des Verwendungszwecks, der theoretischen Fundierung und der Operationalisierung einzelner Qualitätsmerkmale verglichen. Anschließend wurden die in einem Ansatz genutzten Qualitätsmerkmale jeweils in den beiden anderen Ansätzen verortet. Hierbei konnten fünf Kategorien herausgearbeitet werden, die für einen zukünftigen systematischen Vergleich mit weiteren Ansätzen genutzt werden können. Der Beitrag stellt somit eine Möglichkeit vor, unterschiedliche Forschungsansätze zur Unterrichtsqualität systematisch aufeinander zu beziehen, um so ein umfassendes Bild der Unterrichtsqualität zu erhalten.
Accept it or forget it: mandatory digital learning and technology acceptance in higher education
Authors: Lehmann Thomas , Blumschein Patrick , Seel Norbert M.
Published: October 2022

In early 2020, the COVID-19 pandemic led to a rapid shift to emergency remote teaching and mandatory digital learning in higher education. This study tested an extended causal model built on the Unified Theory of Acceptance and Use of Technology (UTAUT) under the restrictions on higher education stemming from the pandemic. Data collected from a survey among 485 students were analyzed using structural equation modeling. Confirmatory factor analyses were performed to examine the construct validity of the measurement model using polychoric correlations. Path analysis was used to test the causal model. The results indicate a psychologically sound baseline model with nine latent variables that affect students’ behavioral intention to accept and continue using technology for learning. However, the model is only partially in line with the proposed causal model based on UTAUT. The implications of these results are discussed in terms of technology acceptance and use in higher education, both under the restrictions leading to mandatory digital learning and in future.
Das digitale VHS-Angebot im ersten Lockdown der Corona-Pandemie. Analysen zu Veranstaltungsformaten und Programmstrukturen an Volkshochschulen
Authors: Widany Sarah , Reichart Elisabeth , Echarti Nicolas , Hoenig Kerstin
Published: October 2022

Der Beitrag untersucht auf der Grundlage von Leistungsdaten der Volkshochschul-Statistik und einer Sonderbefragung der Volkshochschulen (VHS), wie sich während des ersten Lockdowns im Pandemiejahr 2020 die Programmvielfalt des Angebots verändert hat. Besonderes Augenmerk liegt auf der Programmstruktur, definiert als die Anteile der jeweiligen inhaltlichen Programmbereiche am Gesamtprogramm. Die Analysen zeigen, dass das Veranstaltungsangebot der VHS während des ersten Lockdowns deutlich zurückgegangen ist. Dabei gewannen Einzelveranstaltungen gegenüber Kursen im Lockdown an Bedeutung. Da sich die Umsetzung von digitalen Veranstaltungen zwischen den Programmbereichen stark unterschied, zeigt sich in der Programmstruktur eine deutliche Verschiebung.
Why pay for sustainable housing? Decomposing the green premium of the residential property market in the Canton of Zurich, Switzerland
Authors: Kempf Constantin , Syz Juerg
Published: October 2022

Various studies have shown that green buildings trade at a premium, with estimates of it ranging widely from low single-digits up to 26% for sales values and up to 21% for rents. There is, however, little quantified evidence of why people are willing to pay more for sustainable housing. We investigate the green premium for MINERGIE-certified residential properties in the Canton and City of Zurich, which have among the highest densities of certified green buildings worldwide. Using a comprehensive data set of 17,743 condominiums for sale and 50,075 apartments for rent, we show that the premium can be decomposed and associated with various benefits for owners and tenants. The overall green premia in the canton amount to 2.45% and in the city to 4.91%. From these total premia, 6% (city: insignificant) are attributed to energy savings, 71% (city: 70%) to increased comfort, and 23% (city: 33%) to making the building future proof against regulators and market participants.
Hyperbolic two-temperature generalized thermoelastic infinite medium with cylindrical cavity subjected to the non-Gaussian laser beam
Authors: El-Bary Alaa A. , Youssef Hamdy M. , Nasr Mohamad Abou El
Published: October 2022

The present work is devoted to a study of the induced temperature and stress fields in an elastic infinite medium with a cylindrical cavity under the purview of hyperbolic two-temperature thermoelasticity. The medium is an isotropic homogeneous thermoelastic material. The bounding plane surface of the cavity is loaded thermally by a non-Gaussian laser beam with a pulse duration of two ps. An exact solution to the problem is obtained in the Laplace transform space and the inversions of the Laplace transform have been carried out numerically. The derived expressions are computed numerically for copper and the results are presented in graphical form. The two-temperature parameter has significant effects on all the studied functions and plays a vital role in the speed propagation of the thermomechanical waves.
Research highlights in cancer immunotherapy from basic discovery to clinical trial
Authors: Wang Cun-Yu
Published: October 2022

Cancer research is one of the most active areas in the biomedical sciences. Recently, the tumor immune environment, crosstalk between tumor cells and immune cells, and immunotherapy remain the “hot” topic in the field of cancer research. This short review will highlight the recent interesting findings in cancer research associated with cancer immunology and immunotherapy from basic discovery, translational study to clinical trials.
Diagnostik und Behandlung von Patienten und Patientinnen mit einer Kauf-Shopping-Störung
Authors: Georgiadou Ekaterini , Tahmassebi Nadja
Published: October 2022

Zusammenfassung: Hintergrund: Obwohl die Kauf-Shopping-Störung bereits vor über 100 Jahren von Kraepelin (1909) als Oniomanie beschrieben wurde und von einer geschätzten Prävalenz von 4,9 % in der Bevölkerung ( Maraz, Griffiths & Demetrovics, 2016 ) ausgegangen wird, ist sie weiterhin keine eigenständige Erkrankung in den Klassifikationssystemen. Patienten und Patientinnen mit einer Kauf-Shopping-Störung berichten von unterschiedlichen Konsequenzen die von Konflikten in der Partnerschaft und Schulden bis hin zu delinquentem Verhalten (z. B. Strafverfahren wegen Bestellungen auf falschem Namen) reichen. Weiterhin liegen oft komorbide Störungen vor, v. a. Depressionen, soziale Ängste, zwanghaftes Horten, Binge-Eating-Störung, Glücksspielsucht und Substanzkonsumstörungen ( Müller, Mitchell, Crosby et al., 2010 ; Granero et al., 2016 ). Hinsichtlich der Behandlung der Kauf-Shopping-Störung, ist nach aktuellem Stand keine ausreichende Wirksamkeit von psychopharmakologischen Behandlungen gezeigt worden (e. g. Nicoli de Mattos et al., 2020 ; Koran, Aboujaoude, Solvason, Gamel & Smith, 2007 ). In wenigen randomisiert kontrollierten Studien ( Müller, Arikian, de Zwaan & Mitchell, 2013 ; Müller, Müller et al. 2008 ; Mitchell, Burgard, Faber, Crosby & de Zwaan, 2006 ; Benson, Eisenach, Abrams & van Stolk-Cooke, 2014 ), die durchgeführt worden sind, zeigte sich die kognitive Verhaltenstherapie als wirksam. Ob die Kauf-Shopping-Störung eher als eine Impulskontrollstörung, eine Zwangsstörung oder eine Verhaltenssucht eingeordnet werden kann, wird aktuell noch debattiert. Die Diagnose wird im aktuellen ICD-10 ( Dilling & Freyberger, 2016 ) von Klinikern als eine sonstige (F63.8) oder nicht näher bezeichnete Impulskontrollstörung (F63.9) eingeordnet. Im ICD-11 ( WHO, 2019 ) wird sie ohne Nennung diagnostischer Kriterien als eine andere spezifische Impulskontrollstörung (6C7Y) zugeordnet. Führende Experten sehen jedoch eine bessere Zuordnung der Kauf-Shopping-Störung unter den Störungen durch abhängiges Verhalten ( Müller, Brand et al. 2019 ). Ziel: Ziel dieses Fallberichtes ist es, das Bewusstsein über die Existenz der Kauf-Shopping-Störung zu schaffen, Beispiele zur diagnostischen Einordnung aufzuzeigen, Behandlungsbausteine Therapeuten und Therapeutinnen näher zu bringen und die Notwendigkeit für weitere Forschung zu zeigen.
Constraining CMIP6 Projections of an Ice‐Free Arctic Using a Weighting Scheme
Authors: Zhao Jiazhen , He Shengping , Wang Huijun , Li Fei
Published: October 2022

Employing a model democracy in which each model is equally weighted may lead to a poor estimation of the true uncertainty in climate projections from phase 6 of the Coupled Model Intercomparison Project (CMIP6). The improvement and increase in number of CMIP6 models compared with previous phases of CMIP indicate that both model skill and independence need to be considered to provide convincing projections. In this study, we use a weighting scheme, which weights both the skill and independence of multi‐model simulations, to efficiently constrain the large uncertainty in the projection of the timing of an ice‐free Arctic. The uncertainty‐constrained projections of CMIP6 show that the multi‐model spread of the projected first year of an ice‐free Arctic can be reduced by about 29 years under the Shared Socioeconomic Pathway (SSP)3–7.0 scenario (a regional rivalry scenario), indicating a faster tendency to an ice‐free Arctic summer than projections based solely on model democracy. A fossil‐fuel‐based development scenario (i.e., SSP5‐8.5) leads to an ice‐free Arctic before the 2070s (ranging from 2038 to 2071), while an ice‐free Arctic occurs slightly later (by ∼10 years) under the SSP2‐4.5 scenario (i.e., intermediate scenario) and the SSP3‐7.0 scenario, but is inevitable this century. The sustainable development scenario (i.e., SSP1‐2.6) is likely to prevent the occurrence of an ice‐free Arctic. Internal variability strongly affects the projection estimated by the equally weighted ensemble; however, it has a negligible impact on the results obtained by the weighting scheme, thereby indicating that the results of this study are robust and convincing.
Saturated Hydraulic Conductivity in Northern Peats Inferred From Other Measurements
Authors: Morris P. J. , Davies M. L. , Baird A. J. , Balliston N. , Bourgault M.‐A. , Clymo R. S. , Fewster R. E. , Furukawa A. K. , Holden J. , Kessel E. , Ketcheson S. J. , Kløve B. , Larocque M. , Marttila H. , Menberu M. W. , Moore P. A. , Price J. S. , Ronkanen A.‐K. , Rosa E. , Strack M. , Surridge B. W. J. , Waddington J. M. , Whittington P. , Wilkinson S. L.
Published: October 2022

In northern peatlands, near‐saturated surface conditions promote valuable ecosystem services such as carbon storage and drinking water provision. Peat saturated hydraulic conductivity (Ksat) plays an important role in maintaining wet surface conditions by moderating drainage and evapotranspiration. Peat Ksat can exhibit intense spatial variability in three dimensions and can change rapidly in response to disturbance. The development of skillful predictive equations for peat Ksat and other hydraulic properties, akin to mineral soil pedotransfer functions, remains a subject of ongoing research. We report a meta‐analysis of 2,507 northern peat samples, from which we developed linear models that predict peat Ksat from other variables, including depth, dry bulk density, von Post score (degree of humification), and categorical information such as surface microform type and peatland trophic type (e.g., bog and fen). Peat Ksat decreases strongly with increasing depth, dry bulk density, and humification; and increases along the trophic gradient from bog to fen peat. Dry bulk density and humification are particularly important predictors and increase model skill greatly; our best model, which includes these variables, has a cross‐validated r2 of 0.75 and little bias. A second model that includes humification but omits dry bulk density, intended for rapid field estimations of Ksat, also performs well (cross‐validated r2 = 0.64). Two additional models that omit several predictors perform less well (cross‐validated r2 ∼ 0.5), and exhibit greater bias, but allow Ksat to be estimated from less comprehensive data. Our models allow improved estimation of peat Ksat from simpler, cheaper measurements.
The complex Maxwell stress tensor theorem: The imaginary stress tensor and the reactive strength of orbital momentum. A novel scenery underlying electromagnetic optical forces
Authors: Nieto-Vesperinas Manuel , Xu Xiaohao
Published: October 2022

We uncover the existence of a universal phenomenon concerning the electromagnetic optical force exerted by light or other electromagnetic waves on a distribution of charges and currents in general, and of particles in particular. This conveys the appearence of underlying reactive quantities that hinder radiation pressure and currently observed time-averaged forces. This constitutes a novel paradigm of the mechanical efficiency of light on matter, and completes the landscape of the optical, and generally electromagnetic, force in photonics and classical electrodynamics; widening our understanding in the design of both illumination and particles in optical manipulation without the need of increasing the illuminating power, and thus lowering dissipation and heating. We show that this may be accomplished through the minimization of what we establish as the reactive strength of orbital (or canonical) momentum, which plays against the optical force a role analogous to that of the reactive power versus the radiation efficiency of an antenna. This long time overlooked quantity, important for current progress of optical manipulation, and that stems from the complex Maxwell theorem of conservation of complex momentum that we put forward, as well as its alternating flow associated to the imaginary part of the complex Maxwell stress tensor, conform the imaginary Lorentz force that we introduce in this work, and that like the reactive strength of orbital momentum, is antagonistic to the well-known time-averaged force; thus making this reactive Lorentz force indirectly observable near wavelengths at which the time-averaged force is lowered. The Minkowski and Abraham momenta are also addressed.
Identity-by-descent analysis of a large Tourette’s syndrome pedigree from Costa Rica implicates genes involved in neuronal development and signal transduction
Authors: Ryan Niamh , Ormond Cathal , Chang Yi-Chieh , Contreras Javier , Raventos Henriette , Gill Michael , Heron Elizabeth , Mathews Carol A. , Corvin Aiden
Published: October 2022

Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data.
Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior
Authors: Cherix Antoine , Poitry-Yamate Carole , Lanz Bernard , Zanoletti Olivia , Grosse Jocelyn , Sandi Carmen , Gruetter Rolf , Cardinaux Jean-René
Published: October 2022

Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying a deficiency in hippocampal glucose metabolism as the underlying molecular/physiological origin of the markers, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point toward the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1’s and MeS’s relationship to MD and establishes depression-related markers with clinical potential.
Analysis of hyperforin (St. John’s wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs
Authors: El Hamdaoui Yamina , Zheng Fang , Fritz Nikolas , Ye Lian , Tran Mai Anh , Schwickert Kevin , Schirmeister Tanja , Braeuning Albert , Lichtenstein Dajana , Hellmich Ute A. , Weikert Dorothee , Heinrich Markus , Treccani Giulia , Schäfer Michael K. E. , Nowak Gabriel , Nürnberg Bernd , Alzheimer Christian , Müller Christian P. , Friedland Kristina
Published: October 2022

St. John’s wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.
The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)—results from the UK Sloane Project
Authors: Shaaban Abeer M. , Hilton Bridget , Clements Karen , Dodwell David , Sharma Nisha , Kirwan Cliona , Sawyer Elinor , Maxwell Anthony , Wallis Matthew , Stobart Hilary , Mylvaganam Senthurun , Litherland Janet , Brace-McDonnell Samantha , Dulson-Cox Joanne , Kearins Olive , Provenzano Elena , Ellis Ian O. , Pinder Sarah E. , Thompson Alastair M.
Published: October 2022

Background

The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial.

Methods

We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project.

Results

Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0–25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P <  0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P <  0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P = 0.68). Following median follow-up of 110 months, 3% of patients had recurrent ipsilateral high-grade DCIS, and 4.2% developed invasive carcinoma. The subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (P = 0.02). Distant metastasis and breast cancer mortality were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, P = 0.01 and 2.1% vs 0.8%; P = 0.005).

Conclusions

The higher breast cancer mortality with microinvasion indicates a more aggressive disease.
Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB
Authors: Lin Dengna , Chen Hao , Xiong Jing , Zhang Jing , Hu Zhaoxia , Gao Juan , Gao Bin , Zhang Shaoquan , Chen Junfeng , Cao Huijuan , Li Zhihui , Lin Bingliang , Gao Zhiliang
Published: October 2022

Acute-on-chronic liver failure is a distinct clinical syndrome characterized by a dysregulated immune response and extensive hepatocyte death without satisfactory therapies. As a cytoplasmic degradative and quality-control process, autophagy was implicated in maintaining intracellular homeostasis, and decreased hepatic autophagy was found in many liver diseases and contributes to disease pathogenesis. Previously, we identified the therapeutic potential of mesenchymal stem cells (MSCs) in ACLF patients; however, the intrinsic mechanisms are incompletely understood. Herein, we showed that MSCs restored the impaired autophagic flux and alleviated liver injuries in ACLF mice, but these effects were abolished when autophago-lysosomal maturation was inhibited by leupeptin (leu), suggesting that MSCs exerted their hepatoprotective function in a pro-autophagic dependent manner. Moreover, we described a connection between transcription factor EB (TFEB) and autophagic activity in this context, as evidenced by increased nuclei translocation of TFEB elicited by MSCs were capable of promoting liver autophagy. Mechanistically, we confirmed that let-7a-5p enriched in MSCs derived exosomes (MSC-Exo) could activate autophagy by targeting MAP4K3 to reduce TFEB phosphorylation, and MAP4K3 knockdown partially attenuates the effect of anti-let-7a-5p oligonucleotide via decreasing the inflammatory response, in addition, inducing autophagy. Altogether, these findings revealed that the hepatoprotective effect of MSCs may partially profit from its exosomal let-7a-5p mediating autophagy repairment, which may provide new insights for the therapeutic target of ACLF treatment.
Diagnostic imaging of retinal astrocytomas: A case-series
Authors: McLean Keri , Hussain Rumana , Heimann Heinrich
Published: October 2022

Objectives

To use multimodal imaging techniques to characterise features of retinal astrocytomas (RA) which would aid practitioners distinguish them from other causes of non-pigmented fundal lesions.

Methods

Retrospective analysis of notes and imaging of 17 patients diagnosed with RA at a single centre between January 2012 and June 2021 was conducted. Demographics, examination findings and imaging including colour fundus photography, optical coherence tomography (OCT), infra-red (IR) and ultrasound (US) were analysed. These were compared to differential diagnoses, including retinoblastomas, amelanotic choroidal melanomas, choroidal metastases and idiopathic scleromas.

Results

Fourteen patients (82%; 14/17) had idiopathic RA and three (18%; 3/17) were associated with tuberous sclerosis. Mean age at presentation was 43 years. Twelve patients (71%; 12/17) were asymptomatic. Thirteen (76%; 13/17) had better than 6/12 vision, with 41% (7/17) better than 6/6. All lesions were creamy-white. There were two distinct appearances, seven (39%; 7/18) were poorly-defined translucent retinal elevations and eleven (61%; 11/18) were well-defined solid opaque retinal masses. Six (33%; 6/18) displayed clustered, calcified spherules giving them the pathognomonic ‘mulberry-like’ appearance. On OCT, all appeared as dome-shaped retinal thickening with disruption of the inner retinal layers and nine (60%; 9/15) had intra-retinal cystic spaces giving a ‘moth-eaten’ appearance. Mean basal diameter and thickness on OCT was 2.93 mm and 0.86 mm, respectively. High internal reflectivity on US was noted in 92% (11/12).

Conclusions

RAs display characteristic clinical, demographic and imaging features which can aid differentiating them from other non-pigmented fundal lesions. We advise using multiple imaging modalities when diagnosing these lesions.
Stereodivergent dehydrative allylation of β-keto esters using a Ru/Pd synergistic catalyst
Authors: Le Thien Phuc , Tanaka Shinji , Yoshimura Masahiro , Sato Kazuhiko , Kitamura Masato
Published: October 2022

α-Alkylation of a β-keto ester is a frequently used reaction for carbon–carbon bond formation. However, extension to a stereoselective reaction remains a significant challenge, because the product easily racemizes under acidic or basic conditions. Here, we report a hybrid system consisting of Pd and Ru complexes that catalyzes the asymmetric dehydrative condensation between cinnamyl-type allylic alcohols and β-keto esters. α-Non-substituted β-keto ester can be allylated to afford an α-mono-substituted product with high regio-, diastereo-, and enantioselectivity. No epimerization occurs owing to the nearly neutral conditions, which is achieved by a rapid proton transfer from Pd-enolate formation to Ru π-allyl complex formation. Four diastereomers can be synthesized on demand by changing the stereochemistry of the Pd or Ru complex. Eight stereoisomers with three adjacent stereogenic centers can be synthesized by employing diastereoselective reduction of the ketone in the products. The formal synthesis of (+)-pancratistatin demonstrates the utility of the reaction.
The coilin N-terminus mediates multivalent interactions between coilin and Nopp140 to form and maintain Cajal bodies
Authors: Courchaine Edward , Gelles-Watnick Sara , Machyna Martin , Straube Korinna , Sauyet Sarah , Enright Jade , Neugebauer Karla M.
Published: October 2022

Cajal bodies (CBs) are ubiquitous nuclear membraneless organelles (MLOs) that concentrate and promote efficient biogenesis of snRNA-protein complexes involved in splicing (snRNPs). Depletion of the CB scaffolding protein coilin disperses snRNPs, making CBs a model system for studying the structure and function of MLOs. Although it is assumed that CBs form through condensation, the biomolecular interactions responsible remain elusive. Here, we discover the unexpected capacity of coilin’s N-terminal domain (NTD) to form extensive fibrils in the cytoplasm and discrete nuclear puncta in vivo. Single amino acid mutational analysis reveals distinct molecular interactions between coilin NTD proteins to form fibrils and additional NTD interactions with the nuclear Nopp140 protein to form puncta. We provide evidence that Nopp140 has condensation capacity and is required for CB assembly. From these observations, we propose a model in which coilin NTD–NTD mediated assemblies make multivalent contacts with Nopp140 to achieve biomolecular condensation in the nucleus.
Joint control of meiotic crossover patterning by the synaptonemal complex and HEI10 dosage
Authors: Durand Stéphanie , Lian Qichao , Jing Juli , Ernst Marcel , Grelon Mathilde , Zwicker David , Mercier Raphael
Published: October 2022

Meiotic crossovers are limited in number and are prevented from occurring close to each other by crossover interference. In many species, crossover number is subject to sexual dimorphism, and a lower crossover number is associated with shorter chromosome axes lengths. How this patterning is imposed remains poorly understood. Here, we show that overexpression of the Arabidopsis pro-crossover protein HEI10 increases crossovers but maintains some interference and sexual dimorphism. Disrupting the synaptonemal complex by mutating ZYP1 also leads to an increase in crossovers but, in contrast, abolishes interference and disrupts the link between chromosome axis length and crossovers. Crucially, combining HEI10 overexpression and zyp1 mutation leads to a massive and unprecedented increase in crossovers. These observations support and can be predicted by, a recently proposed model in which HEI10 diffusion along the synaptonemal complex drives a coarsening process leading to well-spaced crossover-promoting foci, providing a mechanism for crossover patterning.
Post-acute sequelae of SARS-CoV-2 with clinical condition definitions and comparison in a matched cohort
Authors: Horberg Michael A. , Watson Eric , Bhatia Mamta , Jefferson Celeena , Certa Julia M. , Kim Seohyun , Fathi Lily , Althoff Keri N. , Williams Carolyn , Moore Richard
Published: October 2022

Disease characterization of Post-Acute Sequelae of SARS-CoV-2 (PASC) does not account for pre-existing conditions and time course of incidence. We utilized longitudinal data and matching to a COVID PCR-negative population to discriminate PASC conditions over time within our patient population during 2020. Clinical Classification Software was used to identify PASC condition groupings. Conditions were specified acute and persistent (occurring 0-30 days post COVID PCR and persisted 30–120 days post-test) or late (occurring initially 30-120 days post-test). We matched 3:1 COVID PCR-negative COVIDPCR-positive by age, sex, testing month and service area, controlling for pre-existing conditions up to four years prior; 28,118 PCR-positive to 70,293 PCR-negative patients resulted. We estimated PASC risk from the matched cohort. Risk of any PASC condition was 12% greater for PCR-positive patients in the late period with a significantly higher risk of anosmia, cardiac dysrhythmia, diabetes, genitourinary disorders, malaise, and nonspecific chest pain. Our findings contribute to a more refined PASC definition which can enhance clinical care.
Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine
Authors: Wang Kai-Bo , Liu Yushuang , Li Jinzhu , Xiao Chengmei , Wang Yingying , Gu Wei , Li Yipu , Xia Yuan-Zheng , Yan Tingdong , Yang Ming-Hua , Kong Ling-Yi
Published: October 2022

KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a “quasi-triad plane” that stacks over the two external G-tetrads. The binding involves both π-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS-G4 and is beneficial for the design of specific KRAS-G4-interactive drugs.
Performance and mechanisms of greywater treatment in a bio-enhanced granular-activated carbon dynamic biofilm reactor
Authors: Wang Ziqi , Yang Ying , Xiang Wanchen , Wu Beibei , Cui Xiaocai , Zhou Yun
Published: October 2022

The potential of source-diverted graywater reuse mainly relies on the efficiency and cost of graywater treatment technology. Oxygen (O2) supply and utilization rate directly determine the energy consumption and pollutants removal rate in the biological graywater treatment. This study developed a gravity flow self-supplying O2 and easy-to-maintain bio-enhanced granular-activated carbon dynamic biofilm reactor (BhGAC-DBfR) for on-site graywater treatment. Results showed that increasing of saturated/unsaturated ratio led to the continuous growth of biomass on GAC surface. Division of saturated and unsaturated zones favors the formation of aerobic-anoxic-anaerobic biofilm in the reactor. A saturated/unsaturated ratio of 1:1.1 achieved the maximum removal rate of chemical oxygen demand (COD), linear alkylbenzene sulfonates (LAS), ammonia nitrogen, and total nitrogen at 98.3%, 99.4%, 99.8%, and 83.5%, respectively. Key is that adsorption and biodegradation play important and distinct roles in the quick uptake and continuous removal of both organics and N in the system. The related genus and enzymes functional for LAS mineralization, deamination of organic N, ammonium oxidation, and nitrate respiration enabled the efficient and simultaneous removal of organics and N in the BhGAC-DBfR. This study offers a promising engineering alternative technology with great potential to achieve efficient and low-energy-input graywater treatment.
Structures of the TMC-1 complex illuminate mechanosensory transduction
Authors: Jeong Hanbin , Clark Sarah , Goehring April , Dehghani-Ghahnaviyeh Sepehr , Rasouli Ali , Tajkhorshid Emad , Gouaux Eric
Published: October 2022

The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel1. Despite the profound socioeconomic impacts of hearing disorders and the fundamental biological significance of understanding mechanosensory transduction, the composition, structure and mechanism of the mechanosensory transduction complex have remained poorly characterized. Here we report the single-particle cryo-electron microscopy structure of the native transmembrane channel-like protein 1 (TMC-1) mechanosensory transduction complex isolated from Caenorhabditis elegans. The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE. CALM-1 makes extensive contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes additionally includes a single arrestin-like protein, arrestin domain protein (ARRD-6), bound to a CALM-1 subunit. Single-particle reconstructions and molecular dynamics simulations show how the mechanosensory transduction complex deforms the membrane bilayer and suggest crucial roles for lipid–protein interactions in the mechanism by which mechanical force is transduced to ion channel gating.