bluuebunny/crossref_metadata_2025 huggingface dataset:
TESOL teacher educators in higher education: A review of studies from 2010 to 2020
Authors: Yuan Rui , Lee Icy , De Costa Peter I. , Yang Min , Liu Shuwen
Published: July 2022

Despite the wide recognition of language teacher educators’ contributions in the field of Teaching English to Speakers of Other Languages (TESOL), research on language teacher educators has only picked up the pace in the last decade, shedding light on their cognition, practices, and identities in relation to various personal, interpersonal, and contextual factors. This article provides a systematic and critical review of 69 empirical studies on university-based TESOL teacher educators from 2010 and 2020. A methodological review was also conducted to analyze the different research approaches employed by previous researchers. A synthesis of the identified research led to four major themes, namely: (1) a general professional state (including responsibilities, challenges and quality), (2) professional engagement (including teaching, practicum supervision, and research and publishing), (3) cognition (including beliefs, knowledge, and expertise), as well as (4) continuous learning and identity development. Through a critical discussion of the themes, the review argues against the implicit yet powerful discourse that characterizes language teacher educators as ‘supermen/superwomen’ and emphasizes the need to humanize them aswhole peopleby recognizing their unique strengths and struggles as well as diverse learning needs. The review also proposes a new research agenda to stimulate and deepen future investigations on language teacher educators in TESOL.
Remote use of shiphandling simulator: BRM skill acquisition
Authors: Hiroaki Seta , Shingo Yoshino , Kyoko Takashima , Teppei Unno
Published: July 2022

Cadets training to become licensed mariners based on the International Convention on Standards of Training, Certification and Watchkeeping for Seafarers (STCW) Code have been under pressure to keep up with the countermeasures against COVID-19 from the Spring of 2020. For several reasons, sea training voyages were restricted or cancelled, and the schooling style was drastically changed from face-to-face to remote. Since the research vessel owned by Tokai University is not a training vessel exclusively for cadets, the decision was inevitably made to make more effective use of the shiphandling simulator. Because training in the simulator also had to be done remotely, new ideas were put into practice to explore the possibility of building new educational methods. Numerous open-ended evaluation comments were submitted by the cadets who received remote training on the simulator. The results suggested that the remote use of the simulator is likely to be an effective method for training in bridge resource management (BRM).
Surviving Administrative Mandates (from a Department Chair's
Perspective)
Authors: Majeski Stephen
Published: July 2022

It should come as no surprise that both the amount and pace of administrative work that
departments must accomplish at almost all higher education institutions has increased
substantially over the past 10 years. If this is news to you just talk to your department
administrator—if she/he has time to have a pleasant conversation. After all, for most
institutions, operations budgets have been cut and professional and classified staff have
been reduced, while at the same time, administrative work has escalated in response to
increases in student enrollments, greater demands for accountability, the increasing
importance of fund raising efforts, and the generation of sponsored research. No wonder that
the lives of department chairs, administrators, and other professional and classified staff
have become more challenging. The increase in administrative work at the department level is
largely a function of increases in administrative mandates.
Global trends in added sugars and non-nutritive sweetener use in the packaged food supply: drivers and implications for public health
Authors: Russell Cherie , Baker Phillip , Grimes Carley , Lindberg Rebecca , Lawrence Mark A
Published: July 2022

Objective:

The health implications of excessive added sugar intakes have led to national policy actions to limit their consumption. Subsequently, non-nutritive sweeteners (NNS) may be used to maintain product sweetness. We aimed to assess trends in quantities of added sugars and NNS sold in packaged food and beverages worldwide, and the association between these trends and the number of national policy actions across regions to reduce added sugar consumption.

Design:

(i) Longitudinal analysis of Euromonitor sales data (2007–2019) to assess the quantity of added sugars (kg) and NNS (g) sold in packaged foods and beverages globally, across regions, and across country income categories; (ii) policy-mapping of policy actions targeting added sugar consumption globally from the NOURISHING database; and (iii) Spearman’s correlations to assess the association between national policy actions across regions and changes in added sugar/NNS sales.

Setting:

Worldwide.

Participants:

Not applicable.

Results:

Per capita volumes of NNS from beverage sales increased globally (36 %). Added sugars from beverage sales decreased in high-income countries (22 %) but increased in upper-middle-income countries (UMIC) and lower-middle-income countries (LMIC) (13–40 %). Added sugars from packaged food sales increased globally (9 %). Regions with more policy actions had a significant increase in NNS quantities from beverage sales (r= 0·68,P= 0·04). The sweetness of the packaged food supply (the sweetness of each NNS and added sugar, relative to sucrose, multiplied by sales volume) increased over time.

Conclusions:

The increasing use of NNS to sweeten beverages globally, and in packaged food in UMIC and LMIC, may have health and dietary implications in the future. Their use as a substitute for added sugar should be considered in public health nutrition policymaking.
The 1954 Hague Convention for the Protection of Cultural Property in the
Event of Armed Conflict and the notion of military necessity
Authors: Hladík Jan
Published: July 2022

La Convention de La Haye 1954 permet une dérogation à l'obligation de
respecter un bien culturel si une nécessité militaire l'exige. Si l'objet
est sous protection spéciale, les conditions permettant une dérogation sont
plus strides. La notion de « nécessité militaire » et la signification à y
donner ont toujours suscité la controverse des experts en la matière. Dans
son article, l'auteur retrace l'histoire de cette disposition, à partir des
premiers projets jusqu'a l'adoption de la Convention de 1954. Il examine
ensuite différentes propositions qui tentent de définir la notion de «
nécessité militaire » d'une manière plus précise. Le Deuxième Protocole
additionnel à la Convention de 1954, adopté le 26 mars 1999par une
conférence diplomatique à La Haye, inclut de nouveaux textes qui
représentent un pas en avant dans la protection des biens culturels en cas
de conflit armé.
The International Criminal Tribunal for the former Yugoslavia and the Kosovo conflict
Authors: Boelaert-Suominen Sonja
Published: July 2022

Le Tribunal pénal international pour l'ex-Yougoslavie a été créé en 1993 en application de décisions prises par le Conseil de sécurité sur la base du Chapitre VII de la Charte des Nations Unies. En vertu de son mandat statutaire, le Tribunal est habilité à instruire des dossiers et à engager des poursuites contre les auteurs de toutes les violations graves du droit international humanitaire commises sur l'ensemble du territoire de l'ex-Yougoslavie depuis 1991. Jusque récemment, les activités du Tribunal ont porté essentiellement sur des crimes commis entre 1991 et 1995 en Croatie et en Bosnie-Herzégovine. L'accent a été mis publiquement sur le Kosovo à partir de 1998, lorsque le procureur a constitué une première équipe chargée de mener une enquête portant essentiellement sur ce territoire. Le rôle du Tribunal au Kosovo repose sur des bases juridiques solides étant donné son mandat et sa compétence statutaire, qui est limitée sur le plan géographique mais non dans le temps. Toutefois, il ne fait pas de doute que, si l'on s'en tient aux faits, la crise du Kosovo a ouvert un nouveau chapitre de l'histoire du Tribunal.
Economic sanctions: legal and policy constraints
Authors: Segall Anna
Published: July 2022

Depuis la fin de la guerre froide, le Conseil de sécurité des Nations
Unies a décidé à plusieurs reprises d'imposer des sanctions économiques à
des États qui ne respectent pas une décision prise en vertu du chapitre VII
de la Charte. Les exemples les plus flagrants sont les sanctions économiques
décidées dans le contexte des conflits du Golfe (Irak) et des Balkans
(ex-Yougoslavie). Or, ces sanctions affectent très directement les
conditions de vie de la population civile du pays frappé par l'embargo. Il
est donc nécessaire d'examiner quelles sont les limites à ne pas dépasser,
pour des raisons humanitaires. L'auteur analyse séparément les règles
internationales qui déterminent ces limites, d'une part, pour les sanctions
prises en temps de paix et, d'autre pan, pour celles en temps de conflit
armé. Le texte passe ensuite en revue les dispositions pertinentes du droit
de la Charte, du droit des droits de l'homme et du droit international
humanitaire. Une analyse des facteurs politiques, économiques et
sociologiques à prendre en compte lors de sanctions économiques conduit à la
conclusion que la décision d'imposer celle-ci ne doit pas mettre en péril la
survie de la population civile. Le respect des obligations relatives aux
actions de secours est d'ailleurs un élément essentiel de tout régime de
sanctions imposé par le Conseil de sécurité.
The ICRC and the 1962 Cuban missile crisis
Authors: Fischer Thomas
Published: July 2022

L'ouverture d'un grand nombre d'archives depuis la fin de la guerre froide et la publication d'informations inédites permettent aujourd'hui aux historiens de Jeter un regard nouveau sur la crise qui a résulté de l'installation par l'Union soviétique de missiles nucléaires à Cuba en octobre 1962. Ainsi, il est pour la première fois possible d'analyser en détail le rôle exceptionnel joué par le CICR pendant la crise des missiles. Le CICR a en effet offert ses bons offices afin de donner aux États concernés et au secrétaire général des Nations Unies la possibilité de résoudre la crise sans recourir à la force. Il s'est notamment déclaré prêt à mettre à la disposition de l'ONU des délégués qui auraient pour tâche de s'assurer que les navires soviétiques se rendant à Cuba ne transportaient pas d'armes. Toutefois, sa proposition est devenue sans objet, la crise ayant été résolue à temps. L'auteur examine les implications de la position prise alors par le CICR pour l'avenir de l'institution et ses activités humanitaires.
Zones grises, crises durables, conflits oubliés: les défis
humanitaires
Authors: Grunewald François , Tessier Laurence
Published: July 2022

Grey zones, lasting crises and forgotten conflicts are typical of our
times. Even though certain conflicts come to an end, many do not because no
solution is found for the underlying causes. The great majority of these
conflicts are internal and involve non-State entities; they are civil wars.
Such complex and interminable crises are a challenge not only for statesmen
and diplomats but also for “humanitarians”, in particular the international
organizations in charge of humanitarian action. The authors examine the
causes and characteristics of such conflicts. They particularly highlight
the fact that unending wars not only create short-term humanitarian problems
but in the long run destroy civil society. What are the solutions to such
conflicts? The authors call for a change of attitudes and a new approach to
lasting crises and suggest various forms of action to be taken by the
international community. While adequate measures for dealing with
humanitarian issues have been found for traditional wars, lasting crises and
forgotten conflicts are still awaiting a response by the humanitarian
community.
La Commission internationale humanitaire d'établissement des faits : un
outil obsolète ou un moyen utile de mise en œuvre du droit international
humanitaire?
Authors: Condorelli Luigi
Published: July 2022

The International Fact-Finding Commission mentioned by Article 90 of
Additional Protocol I is the only new measure introduced by the Diplomatic
Conference of 1914-1911 intended to strengthen implementation of
international humanitarian law. (The word ‘humanitarian’ was added to the
title by the Commission itself, in order to better express the Commission's
limited jurisdiction.) The Commission was established and its rules of
procedure were adopted, but never since 1977 has any party to an armed
conflict or any other State ever asked the Commission to exercise its
activity in a concrete situation. The author (a member of the Commission)
examines the reasons of this apparent failure and suggests new ways of
understanding Article 90. He has no doubts about the Commission's
usefulness, and he calls upon States and the other members of the
international community – in particular the United Nations – to accept the
Commission as a tool for strengthening respect for international
humanitarian law.
Enforcing international humanitarian law: Catching the
accomplices
Authors: Schabas William A.
Published: July 2022

La récente décision d'etablir la Cour pénale internationale et
l'adoption de son Statut (Statut de Rome) a, une fois de plus, soulevé la
question de la responsabilité pénale, en droit international, du complice
dans un crime. L'auteur examine d'abord l'interprétation que le Tribunal de
Nuremberg a donnée de la notion de complice, pour passer ensuite à Vanalyse
de la jurisprudence des Tribunaux pénaux internationaux pour
l'ex-Yougoslavie et pour le Rwanda. Il constate que ces Tribunaux ont eu
l'occasion d'affiner leur jurisprudence par rapport aux complices, car,
jusqu'à ce jour, ils se sont davantage occupés d'executants que des vrais
instigateurs des crimes. La compétence du Tribunal pénal international en
matière de responsabilite penale des complices ne differe guère de celle
qu'on trouve dans le Statut de chacun des deux Tribunaux ad hoc. Selon
l'auteur, il n'est cependant pas exclu que la notion de complicité ne soit
élargie à l'avenir pour englober, par exemple, la responsabilité des
fournisseurs d'armes ou d'autres activités dans l'ombre des guerres
modernes. Une telle évolution de la pratique des Tribunaux pénaux
internationaux renforcerait la position du droit international
humanitaire.
Legal aspects of Australia's involvement in the International Force for
East Timor
Authors: Kelly Michael J. , McCormack Timothy L. H. , Muggleton Paul , Oswald Bruce M.
Published: July 2022

Sur la base de la résolution 1264 du Conseil de sécurité (du 15
septembre 1999), une force multinationale a été déployée au Timor Oriental,
afin de rétablir l'ordre et de parer à l'écroulement de l'administration
locale; il s'agit de l'International Force for East Timor
(INTERFET). L'Australie a assumé le rôle de pays
responsable dans une force qui était composée de contingents militaires de
plusieurs pays de la région. Après avoir analysé la situation juridique du
territoire et les conséquences qui en découlent, les auteurs passent en
revue un nombre considérable de problèmes d'ordre juridique qu'il fallait
résoudre dans cette opération internationale de type nouveau (même si les
forces australiennes ont fait leurs premières expériences lors de
l'engagement en Somalie). De l'avis des auteurs, l'intervention de
l'INTERFRET conservera «une place honorable» dans l'histoire des missions
des Nations Unies.
The Chinese humanitarian heritage and the dissemination of and education
in international humanitarian law in the Chinese People's Liberation
Army
Authors: Xiaodong He
Published: July 2022

Un bref regard sur l'histoire de la Chine montre que les princes et les
stratèges ont toujours insisté sur la nécessité de ménager la population
civile dans la guerre, car, sans le soutien du peuple, il ne serait pas
possible de contrôler un pays. Un proverbe chinois dit: «Pour gagner une
guerre, il faut d'abord gagner le cœur des gens». Au début de la guerre
révolutionnaire en Chine, Mao Zedong a promulgué des directives qui vont
dans le même sens, en insistant particulièrement sur la discipline des
soldats. Sous une forme adaptée, ces directives sont valables encore
aujourd'hui. L'auteur décrit les mesures prises et les programmes en cours
actuellement au sein de l'armée chinoise pour diffuser les connaissances
nécessaires en droit international humanitaire parmi les officiers et la
troupe. Il conclut en constatant que même après la fin de la guerre froide,
les Conventions de Genève n'ont rien perdu de leur importance.
Protection of internally displaced persons affected by armed conflict:
concept and challenges
Authors: Hickel Marguerite Contat
Published: July 2022

Cet article propose quelques réflexions sur la notion de protection des
personnes déplacées à l'intérieur de leur pays dans une situation de conflit
armé. Après avoir rappelé le contexte qui a amené la communauté
internationale à s'intéresser aux personnes déplacées, l'auteur porte son
attention sur le concept de protection et les modes d'action auxquels
peuvent se référer les organisations humanitaires, dont le CICR, dans leur
activité de protection. Analysant les enjeux liés à cette problématique, en
particulier le lien entre la consolidation de la notion de personnes
déplacées et la mise en péril du statut de réfugié, elle relève le rôle
assigné aux organisations humanitaires par les États. Toutefois, ce n'est
pas «l'humanitaire» qui pourra prévenir les déplacements massifs de
population ou résoudre les problèmes qu'ils posent, mais bien «le
politique»: les États doivent s'employer avec une détermination accrue à
créer un ordre politique juste qui contribue à prévenir le phénomène des
personnes déplacées dans leur propre pays.
A brief course of digitally delivered cognitive behavioural therapy for the treatment of blood contamination-based obsessive-compulsive disorder: a structured case report
Authors: Purrington Jack
Published: July 2022

The lifetime prevalence of OCD in the UK is estimated to be between 1 in 100 and 1 in every 50 people. It is therefore necessary to explore innovations in practice to expand the reach of the gold standard therapeutic approaches of exposure with response prevention (ERP) and cognitive behavioural therapy (CBT). The COVID-19 pandemic has facilitated such innovations with several services accommodating changes to routine practice by utilising digital platforms to provide videoconference-delivered therapy. Despite a growing evidence base demonstrating efficacy and scope for the use of videoconference-delivered CBT for obsessive-compulsive disorder (OCD), there remains qualitative research collated from clinicians which suggests that a lack of practitioner confidence and a low belief in positive outcomes are barriers to adopting remote therapy practices for clinicians. Therefore, this structured case report describes the assessment, formulation, intervention and outcome of an 11-week videoconference-delivered therapeutic intervention. Reflections are made regarding the use of the digital platform throughout the intervention, alongside the strengths and difficulties of applying videoconference-delivered CBT for OCD.

Key learning aims

(1)

To illustrate a digital treatment of OCD through flexible application of the current evidence base.

(2)

To gain an understanding of the strengths and weaknesses of delivering digital out-patient CBT for OCD.

(3)

To consider the utility of structured case reports in routine practice when delivering digital therapy.
ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia
Authors: Schönfeld Lioba , Rinke Jenny , Hinze Anna , Nagel Saskia N. , Schäfer Vivien , Schenk Thomas , Fabisch Christian , Brümmendorf Tim H. , Burchert Andreas , le Coutre Philipp , Krause Stefan W. , Saussele Susanne , Safizadeh Fatemeh , Pfirrmann Markus , Hochhaus Andreas , Ernst Thomas
Published: July 2022

Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected (n = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis.
Identification of proliferative and non-proliferative subpopulations of leukemic cells in CLL
Authors: Cuthill Kirsty M. , Zhang Yan , Pepper Andrea , Boelen Lies , Coulter Eve , Asquith Becca , Devereux Stephen , Macallan Derek C.
Published: July 2022

Pathogenesis in chronic lymphocytic leukemia (CLL) is strongly linked to the potential for leukemic cells to migrate to and proliferate within lymph-nodes. Previous in vivo studies suggest that all leukemic cells participate in cycles of migration and proliferation. In vitro studies, however, have shown heterogeneous migration patterns.

To investigate tumor subpopulation kinetics, we performed in vivo isotope-labeling studies in ten patients with IgVH-mutated CLL (M-CLL). Using deuterium-labeled glucose, we investigated proliferation in sub-populations defined by CXCR4/CD5 and surface (sIgM) expression. Mathematical modeling was performed to test the likelihood that leukemic cells exist as distinct sub-populations or as a single population with the same proliferative capacity. Further labeling studies in two patients with M-CLL commencing idelalisib investigated the effect of B-cell receptor (BCR) antagonists on sub-population kinetics.

Modeling revealed that data were more consistent with a model comprising distinct sub-populations (p = 0.008) with contrasting, characteristic kinetics. Following idelalisib therapy, similar labeling suppression across all sub-populations suggested that the most proliferative subset is the most sensitive to treatment. As the quiescent sub-population precedes treatment, selection likely explains the persistence of such residual non-proliferating populations during BCR-antagonist therapy. These findings have clinical implications for discontinuation of long-term BCR-antagonist treatment in selected patients.
Metasurface for highly-efficient on-chip classical and quantum all-optical modulation
Authors: Yan Siqi , Dong Jianji
Published: July 2022

Metasurface made of artificially two-dimensional structured subwavelength-scaled nanostructures gives rise to unprecedented efficient way to realize on-chip all-optical modulation, in both classical regime and quantum regime.
Alterations in TRN-anterodorsal thalamocortical circuits affect sleep architecture and homeostatic processes in oxidative stress vulnerable Gclm−/− mice
Authors: Czekus Christina , Steullet Pascal , Orero López Albert , Bozic Ivan , Rusterholz Thomas , Bandarabadi Mojtaba , Do Kim Q. , Gutierrez Herrera Carolina
Published: July 2022

Schizophrenia is associated with alterations of sensory integration, cognitive processing and both sleep architecture and sleep oscillations in mouse models and human subjects, possibly through changes in thalamocortical dynamics. Oxidative stress (OxS) damage, including inflammation and the impairment of fast-spiking gamma-aminobutyric acid neurons have been hypothesized as a potential mechanism responsible for the onset and development of schizophrenia. Yet, the link between OxS and perturbation of thalamocortical dynamics and sleep remains unclear. Here, we sought to investigate the effects of OxS on sleep regulation by characterizing the dynamics of thalamocortical networks across sleep-wake states in a mouse model with a genetic deletion of the modifier subunit of glutamate-cysteine ligase (Gclm knockout, KO) using high-density electrophysiology in freely-moving mice. We found that Gcml KO mice exhibited a fragmented sleep architecture and impaired sleep homeostasis responses as revealed by the increased NREM sleep latencies, decreased slow-wave activities and spindle rate after sleep deprivation. These changes were associated with altered bursting activity and firing dynamics of neurons from the thalamic reticularis nucleus, anterior cingulate and anterodorsal thalamus. Administration of N-acetylcysteine (NAC), a clinically relevant antioxidant, rescued the sleep fragmentation and spindle rate through a renormalization of local neuronal dynamics in Gclm KO mice. Collectively, these findings provide novel evidence for a link between OxS and the deficits of frontal TC network dynamics as a possible mechanism underlying sleep abnormalities and impaired homeostatic responses observed in schizophrenia.
Altered brain activation during reward anticipation in bipolar disorder
Authors: Long Xipeng , Wang Xiuli , Tian Fangfang , Cao Yuan , Xie Hongsheng , Jia Zhiyun
Published: July 2022

Although altered reward sensitivity has been observed in individuals with bipolar disorder (BD), the brain function findings related to reward processing remain unexplored and inconsistent. This meta-analysis aimed to identify brain activation alterations underlying reward anticipation in BD. A systematic literature research was conducted to identify fMRI studies of reward-relevant tasks performed by BD individuals. Using Anisotropic Effect Size Signed Differential Mapping, whole-brain and ROI of the ventral striatum (VS) coordinate-based meta-analyses were performed to explore brain regions showing anomalous activation in individuals with BD compared to healthy controls (HC), respectively. A total of 21 studies were identified in the meta-analysis, 15 of which were included in the whole-brain meta-analysis and 17 in the ROI meta-analysis. The whole-brain meta-analysis revealed hypoactivation in the bilateral angular gyrus and right inferior frontal gyrus during reward anticipation in individuals with BD compared to HC. No significant activation differences were observed in bilateral VS between two groups by whole-brain or ROI-based meta-analysis. Individuals with BD type I and individuals with euthymic BD showed altered activation in prefrontal, angular, fusiform, middle occipital gyrus, and striatum. Hypoactivation in the right angular gyrus was positively correlated with the illness duration of BD. The present study reveals the potential neural mechanism underlying impairment in reward anticipation in BD. Some clinical features such as clinical subtype, mood state, and duration of illness confound the underlying neurobiological abnormality reward anticipation in BD. These findings may have implications for identifying clinically relevant biomarkers to guide intervention strategies for BD.
Plasma Amyloid-β dynamics in late-life major depression: a longitudinal study
Authors: Pomara Nunzio , Bruno Davide , Plaska Chelsea Reichert , Ramos-Cejudo Jaime , Osorio Ricardo S. , Pillai Anilkumar , Imbimbo Bruno P. , Zetterberg Henrik , Blennow Kaj
Published: July 2022

Depressed individuals are twice as likely to develop Alzheimer’s disease (AD) as compared to controls. Brain amyloid-β (Aβ) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aβ dynamics and depression. The aim of this study was to test if plasma Aβ levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-β1-40 (Aβ40) and amyloid-β1-42 (Aβ42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aβ42/Aβ40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (p < 0.001). At screening, Aβ42/Aβ40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma Aβ42/Aβ40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low Aβ42/Aβ40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma Aβ42/Aβ40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD.
Tumor-promoting properties of karyopherin β1 in melanoma by stabilizing Ras-GTPase-activating protein SH3 domain-binding protein 1
Authors: Yang Fan , Li Lin , Mu Zhenzhen , Liu Pengyue , Wang Ying , Zhang Yue , Han Xiuping
Published: July 2022

The nuclear import receptor karyopherin β1 (KPNB1), a member of the Karyopherin protein family, is reported to be overexpressed in various cancers and promote carcinogenesis. By analyzing the correlation between the expression of KPNB1 and the overall survival rate of melanoma patients, we found that melanoma patients with higher expression of KPNB1 had worse survival. Furthermore, the database analyzed that the KPNB1 mRNA level was higher in melanoma samples than that in skin nevus tissues. We thus proposed that KPNB1 played a role in promoting melanoma development, and conducted gain-of- and loss-of-function experiments to test our hypothesis. We found that KPNB1 knockdown significantly retarded the growth and metastasis of melanoma cells in vitro and in vivo, and increased their sensitivity towards the anti-tumor drug cisplatin. KPNB1 overexpression had opposite effects. Notably, in melanoma cells, KPNB1 overexpression significantly decreased Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) protein level, which was also overexpressed in melanoma samples and enhanced malignant behaviors of melanoma cells. We further demonstrated that KPNB1 overexpression induced deubiquitination of G3BP1, and prevented its degradation. However, KPNB1 overexpression hardly affected the nuclear translocation of G3BP1. Additionally, alterations induced by KPNB1 overexpression were partly reversed by G3BP1 inhibition. Therefore, the results suggest that KPNB1 may promote melanoma progression by stabilizing the G3BP1 protein. KPNB1-G3BP1 axis represents a potential therapeutic targetable node for melanoma.
Epigenetically silenced apoptosis-associated tyrosine kinase (AATK) facilitates a decreased expression of Cyclin D1 and WEE1, phosphorylates TP53 and reduces cell proliferation in a kinase-dependent manner
Authors: Woods Michelle L. , Weiss Astrid , Sokol Anna M. , Graumann Johannes , Boettger Thomas , Richter Antje M. , Schermuly Ralph T. , Dammann Reinhard H.
Published: July 2022

Silencing of the Apoptosis associated Tyrosine Kinase gene (AATK) has been described in cancer. In our study, we specifically investigated the epigenetic inactivation of AATK in pancreatic adenocarcinoma, lower grade glioma, lung, breast, head, and neck cancer. The resulting loss of AATK correlates with impaired patient survival. Inhibition of DNA methyltransferases (DNMTs) reactivated AATK in glioblastoma and pancreatic cancer. In contrast, epigenetic targeting via the CRISPR/dCas9 system with either EZH2 or DNMT3A inhibited the expression of AATK. Via large-scale kinomic profiling and kinase assays, we demonstrate that AATK acts a Ser/Thr kinase that phosphorylates TP53 at Ser366. Furthermore, whole transcriptome analyses and mass spectrometry associate AATK expression with the GO term ‘regulation of cell proliferation’. The kinase activity of AATK in comparison to the kinase-dead mutant mediates a decreased expression of the key cell cycle regulators Cyclin D1 and WEE1. Moreover, growth suppression through AATK relies on its kinase activity. In conclusion, the Ser/Thr kinase AATK represses growth and phosphorylates TP53. Furthermore, expression of AATK was correlated with a better patient survival for different cancer entities. This data suggests that AATK acts as an epigenetically inactivated tumor suppressor gene.
XAF1 drives apoptotic switch of endoplasmic reticulum stress response through destabilization of GRP78 and CHIP
Authors: Lee Kyung-Woo , Hong Hui-Ra , Lim Ji-Sun , Ko Kyung-Phil , Lee Min-Goo , Chi Sung-Gil
Published: July 2022

X-linked inhibitor of apoptosis-associated factor-1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in many human cancers. Despite accumulating evidence for the pro-apoptotic role for XAF1 under various stressful conditions, its involvement in endoplasmic reticulum (ER) stress response remains undefined. Here, we report that XAF1 increases cell sensitivity to ER stress and acts as a molecular switch in unfolded protein response (UPR)-mediated cell-fate decisions favoring apoptosis over adaptive autophagy. Mechanistically, XAF1 interacts with and destabilizes ER stress sensor GRP78 through the assembly of zinc finger protein 313 (ZNF313)-mediated destruction complex. Moreover, XAF1 expression is activated through PERK-Nrf2 signaling and destabilizes C-terminus of Hsc70-interacting protein (CHIP) ubiquitin E3 ligase, thereby blocking CHIP-mediated K63-linked ubiquitination and subsequent phosphorylation of inositol-required enzyme-1α (IRE1α) that is involved in in the adaptive ER stress response. In tumor xenograft assays, XAF1−/− tumors display substantially lower regression compared to XAF1+/+ tumors in response to cytotoxic dose of ER stress inducer. XAF1 and GRP78 expression show an inverse correlation in human cancer cell lines and primary breast carcinomas. Collectively this study uncovers an important role for XAF1 as a linchpin to govern the sensitivity to ER stress and the outcomes of UPR signaling, illuminating the mechanistic consequence of XAF1 inactivation in tumorigenesis.
Topological digestion drives time-varying rheology of entangled DNA fluids
Authors: Michieletto D. , Neill P. , Weir S. , Evans D. , Crist N. , Martinez V. A. , Robertson-Anderson R. M.
Published: July 2022

Understanding and controlling the rheology of polymeric complex fluids that are pushed out-of-equilibrium is a fundamental problem in both industry and biology. For example, to package, repair, and replicate DNA, cells use enzymes to constantly manipulate DNA topology, length, and structure. Inspired by this feat, here we engineer and study DNA-based complex fluids that undergo enzymatically-driven topological and architectural alterations via restriction endonuclease (RE) reactions. We show that these systems display time-dependent rheological properties that depend on the concentrations and properties of the comprising DNA and REs. Through time-resolved microrheology experiments and Brownian Dynamics simulations, we show that conversion of supercoiled to linear DNA topology leads to a monotonic increase in viscosity. On the other hand, the viscosity of entangled linear DNA undergoing fragmentation displays a universal decrease that we rationalise using living polymer theory. Finally, to showcase the tunability of these behaviours, we design a DNA fluid that exhibits a time-dependent increase, followed by a temporally-gated decrease, of its viscosity. Our results present a class of polymeric fluids that leverage naturally occurring enzymes to drive diverse time-varying rheology by performing architectural alterations to the constituents.
Sustainable environmental remediation via biomimetic multifunctional lignocellulosic nano-framework
Authors: Li Jinghao , Li Xiaohan , Da Yabin , Yu Jiali , Long Bin , Zhang Peng , Bakker Christopher , McCarl Bruce A. , Yuan Joshua S. , Dai Susie Y.
Published: July 2022

Chemical pollution threatens human health and ecosystem sustainability. Persistent organic pollutants (POPs) like per- and polyfluoroalkyl substances (PFAS) are expensive to clean up once emitted. Innovative and synergistic strategies are urgently needed, yet process integration and cost-effectiveness remain challenging. An in-situ PFAS remediation system is developed to employ a plant-derived biomimetic nano-framework to achieve highly efficient adsorption and subsequent fungal biotransformation synergistically. The multiple component framework is presented as Renewable Artificial Plant for In-situ Microbial Environmental Remediation (RAPIMER). RAPIMER exhibits high adsorption capacity for the PFAS compounds and diverse adsorption capability toward co-contaminants. Subsequently, RAPIMER provides the substrates and contaminants for in situ bioremediation via fungus Irpex lacteus and promotes PFAS detoxification. RAPIMER arises from cheap lignocellulosic sources, enabling a broader impact on sustainability and a means for low-cost pollutant remediation.
High-temperature flexible WSe2 photodetectors with ultrahigh photoresponsivity
Authors: Zou Yixuan , Zhang Zekun , Yan Jiawen , Lin Linhan , Huang Guanyao , Tan Yidong , You Zheng , Li Peng
Published: July 2022

The development of high-temperature photodetectors can be beneficial for numerous applications, such as aerospace engineering, military defence and harsh-environments robotics. However, current high-temperature photodetectors are characterized by low photoresponsivity (<10 A/W) due to the poor optical sensitivity of commonly used heat-resistant materials. Here, we report the realization of h-BN-encapsulated graphite/WSe2 photodetectors which can endure temperatures up to 700 °C in air (1000 °C in vacuum) and exhibit unconventional negative photoconductivity (NPC) at high temperatures. Operated in NPC mode, the devices show a photoresponsivity up to 2.2 × 106 A/W, which is ~5 orders of magnitude higher than that of state-of-the-art high-temperature photodetectors. Furthermore, our devices demonstrate good flexibility, making it highly adaptive to various shaped surfaces. Our approach can be extended to other 2D materials and may stimulate further developments of 2D optoelectronic devices operating in harsh environments.
Pressure-induced monotonic enhancement of Tc to over 30 K in superconducting Pr0.82Sr0.18NiO2 thin films
Authors: Wang N. N. , Yang M. W. , Yang Z. , Chen K. Y. , Zhang H. , Zhang Q. H. , Zhu Z. H. , Uwatoko Y. , Gu L. , Dong X. L. , Sun J. P. , Jin K. J. , Cheng J.-G.
Published: July 2022

The successful synthesis of superconducting infinite-layer nickelate thin films with the highest Tc ≈ 15 K has ignited great enthusiasm for this material class as potential analogs of the high-Tc cuprates. Pursuing a higher Tc is always an imperative task in studying a new superconducting material system. Here we report high-quality Pr0.82Sr0.18NiO2 thin films with Tconset ≈ 17 K synthesized by carefully tuning the amount of CaH2 in the topotactic chemical reduction and the effect of pressure on its superconducting properties by measuring electrical resistivity under various pressures in a cubic anvil cell apparatus. We find that the onset temperature of the superconductivity, Tconset, can be enhanced monotonically from ~17 K at ambient pressure to ~31 K at 12.1 GPa without showing signatures of saturation upon increasing pressure. This encouraging result indicates that the Tc of infinite-layer nickelates superconductors still has room to go higher and it can be further boosted by applying higher pressures or strain engineering in the heterostructure films.
Metaplastic and energy-efficient biocompatible graphene artificial synaptic transistors for enhanced accuracy neuromorphic computing
Authors: Kireev Dmitry , Liu Samuel , Jin Harrison , Patrick Xiao T. , Bennett Christopher H. , Akinwande Deji , Incorvia Jean Anne C.
Published: July 2022

CMOS-based computing systems that employ the von Neumann architecture are relatively limited when it comes to parallel data storage and processing. In contrast, the human brain is a living computational signal processing unit that operates with extreme parallelism and energy efficiency. Although numerous neuromorphic electronic devices have emerged in the last decade, most of them are rigid or contain materials that are toxic to biological systems. In this work, we report on biocompatible bilayer graphene-based artificial synaptic transistors (BLAST) capable of mimicking synaptic behavior. The BLAST devices leverage a dry ion-selective membrane, enabling long-term potentiation, with ~50 aJ/µm2 switching energy efficiency, at least an order of magnitude lower than previous reports on two-dimensional material-based artificial synapses. The devices show unique metaplasticity, a useful feature for generalizable deep neural networks, and we demonstrate that metaplastic BLASTs outperform ideal linear synapses in classic image classification tasks. With switching energy well below the 1 fJ energy estimated per biological synapse, the proposed devices are powerful candidates for bio-interfaced online learning, bridging the gap between artificial and biological neural networks.
A unique class of Zn2+-binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile
Authors: Sacco Michael D. , Wang Shaohui , Adapa Swamy R. , Zhang Xiujun , Lewandowski Eric M. , Gongora Maura V. , Keramisanou Dimitra , Atlas Zachary D. , Townsend Julia A. , Gatdula Jean R. , Morgan Ryan T. , Hammond Lauren R. , Marty Michael T. , Wang Jun , Eswara Prahathees J. , Gelis Ioannis , Jiang Rays H. Y. , Sun Xingmin , Chen Yu
Published: July 2022

Treatment with β-lactam antibiotics, particularly cephalosporins, is a major risk factor forClostridioides difficileinfection. These broad-spectrum antibiotics irreversibly inhibit penicillin-binding proteins (PBPs), which are serine-based enzymes that assemble the bacterial cell wall. However,C. difficilehas four different PBPs (PBP1-3 and SpoVD) with various roles in growth and spore formation, and their specific links to β-lactam resistance in this pathogen are underexplored. Here, we show that PBP2 (known to be essential for vegetative growth) is the primary bactericidal target for β-lactams inC. difficile. PBP2 is insensitive to cephalosporin inhibition, and this appears to be the main basis for cephalosporin resistance in this organism. We determine crystal structures ofC. difficilePBP2, alone and in complex with β-lactams, revealing unique features including ligand-induced conformational changes and an active site Zn2+-binding motif that influences β-lactam binding and protein stability. The Zn2+-binding motif is also present inC. difficilePBP3 and SpoVD (which are known to be essential for sporulation), as well as in other bacterial taxa including species living in extreme environments and the human gut. We speculate that this thiol-containing motif and its cognate Zn2+might function as a redox sensor to regulate cell wall synthesis for survival in adverse or anaerobic environments.
TidyMass an object-oriented reproducible analysis framework for LC–MS data
Authors: Shen Xiaotao , Yan Hong , Wang Chuchu , Gao Peng , Johnson Caroline H. , Snyder Michael P.
Published: July 2022

Reproducibility, traceability, and transparency have been long-standing issues for metabolomics data analysis. Multiple tools have been developed, but limitations still exist. Here, we present the tidyMass project (https://www.tidymass.org/), a comprehensive R-based computational framework that can achieve the traceable, shareable, and reproducible workflow needs of data processing and analysis for LC-MS-based untargeted metabolomics. TidyMass is an ecosystem of R packages that share an underlying design philosophy, grammar, and data structure, which provides a comprehensive, reproducible, and object-oriented computational framework. The modular architecture makes tidyMass a highly flexible and extensible tool, which other users can improve and integrate with other tools to customize their own pipeline.
Mesoderm-derived PDGFRA+ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta
Authors: Chandrakanthan Vashe , Rorimpandey Prunella , Zanini Fabio , Chacon Diego , Olivier Jake , Joshi Swapna , Kang Young Chan , Knezevic Kathy , Huang Yizhou , Qiao Qiao , Oliver Rema A. , Unnikrishnan Ashwin , Carter Daniel R. , Lee Brendan , Brownlee Chris , Power Carl , Brink Robert , Mendez-Ferrer Simon , Enikolopov Grigori , Walsh William , Göttgens Berthold , Taoudi Samir , Beck Dominik , Pimanda John E.
Published: July 2022

Mouse haematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5), on the ventral surface of the dorsal aorta, by endothelial-to-haematopoietic transition. We investigated whether mesenchymal stem cells, which provide an essential niche for long-term HSCs (LT-HSCs) in the bone marrow, reside in the aorta–gonad–mesonephros and contribute to the development of the dorsal aorta and endothelial-to-haematopoietic transition. Here we show that mesoderm-derived PDGFRA+stromal cells (Mesp1derPSCs) contribute to the haemogenic endothelium of the dorsal aorta and populate the E10.5–E11.5 aorta–gonad–mesonephros but by E13.5 were replaced by neural-crest-derived PSCs (Wnt1derPSCs). Co-aggregating non-haemogenic endothelial cells withMesp1derPSCs but notWnt1derPSCs resulted in activation of a haematopoietic transcriptional programme in endothelial cells and generation of LT-HSCs. Dose-dependent inhibition of PDGFRA or BMP, WNT and NOTCH signalling interrupted this reprogramming event. Together, aorta–gonad–mesonephrosMesp1derPSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.
Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells
Authors: Csomos Krisztian , Ujhazi Boglarka , Blazso Peter , Herrera Jose L. , Tipton Christopher M. , Kawai Tomoki , Gordon Sumai , Ellison Maryssa , Wu Kevin , Stowell Matthew , Haynes Lauren , Cruz Rachel , Zakota Bence , Nguyen Johnny , Altrich Michelle , Geier Christoph B. , Sharapova Svetlana , Dasso Joseph F. , Leiding Jennifer W. , Smith Grace , Al-Herz Waleed , de Barros Dorna Mayra , Fadugba Olajumoke , Fronkova Eva , Kanderova Veronika , Svaton Michael , Henrickson Sarah E. , Hernandez Joseph D. , Kuijpers Taco , Kandilarova Snezhina Mihailova , Naumova Elizaveta , Milota Tomas , Sediva Anna , Moshous Despina , Neven Benedicte , Saco Tara , Sargur Ravishankar , Savic Sinisa , Sleasman John , Sunkersett Gauri , Ward Brant R. , Komatsu Masanobu , Pittaluga Stefania , Kumanovics Attila , Butte Manish J. , Cancro Michael P. , Pillai Shiv , Meffre Eric , Notarangelo Luigi D. , Walter Jolan E.
Published: July 2022

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact ofRAG1/RAG2on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an ‘experiment of nature’ to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal aRAG-dependent ‘domino effect’ that impacts stringency of tolerance and B cell fate in the periphery.