bluuebunny/crossref_metadata_2025 huggingface dataset:
Learning challenges of culturally and linguistically diverse students: A framework for psychological assessment
Authors: Khawaja Nigar G , Wotherspoon Jane
Published: March 2022

Australian schools are experiencing an increase in enrolments for students from culturally and linguistically diverse backgrounds. Many of these students, who are frequently from migrant, refugee or asylum-seeker backgrounds, progress academically, but a small number experience learning challenges. In these circumstances, practitioners (school psychologists and guidance counsellors) assess the students to determine underlying factors contributing to limited academic progress, and ways in which the student’s learning can be supported and enhanced. However, formal assessment can be challenging due to language and cultural barriers. Considering the gaps in the research and training, the present article proposes an assessment framework and highlights strategies that can be adopted by practitioners at schools to enrich their decision-making and assessment process. Two case studies are used to highlight factors that can impact students’ academic difficulties. Further interview protocols and assessment measures that can be used to assist these students and their families are discussed. Ways in which school authorities can guide and support these students in the classroom and in the school are examined.
“Cut it, woman”: Masculinity, Nectar, and the Orgasm in Charlotte Brontë'sShirley(1849)
Authors: Harrington Christopher
Published: March 2022

This paper identifies the theme of honey gathering in Charlotte Brontë's fiction and places it within the context of Romantic and early Victorian representations of the nectarium's role in insect-flower relationships. Brontë's novels often invert the conventional use of botany to represent female sexuality by representing men as flowers and endowing her protagonists with an ulterior form of entomological agency. These insects work to express Brontë's desire for greater economic and erotic mobility, but it is argued that this mobility is problematized by the self-absorbed nature of the masculine nectarium, a dulcet gland in flowers originally believed by botanists to ooze sugar to serve a plant's own needs. This is particularly evident in Brontë's industrial romanceShirley(1849), as the theme of honey gathering is pathologized to visualize a crisis in the plotting of Victorian femininity. This paper may be helpful to scholars interested in Brontë's fiction, representations of sexuality, botany, entomology, ecology, and early Victorian pest discourse.
Slutsk in 1920: Entangled Fighters, Locals, and Conflicts
Authors: Pomiecko Aleksandra
Published: March 2022

This article examines the armed fighting that took place in Slutsk, in present-day Belarus, in November and December of 1920, primarily between local forces and the Red Army. In contrast to existing understandings of the insurrection, this article situates the incident within more recent scholarship dedicated to better understanding the post-WWI period, the collapse of the Russian Empire, and experiences at the local level. In doing so, the goals are two-fold: to detangle the story of Slutsk from existing nationalist interpretations and to examine Slutsk as a site witnessing a series of clashes between centers of power and periphery, among different ethno-national groups, soldiers, and ideas. Ultimately, those participating in the Slutsk insurrection sought to resist any outside dominance and control. Though on the surface the insurrection in Slutsk has been interpreted as rather marginal in the longer history of Belarus and the region, the events that occurred manifested as a clash of some of the most critical processes underway in the early to mid-twentieth century. Through Slutsk, this article seeks to better understand the experience of the “periphery” during this time.
The Poetics of Shock: “The Pitiful Vice” in Khodasevich's “Under the Ground”
Authors: Waysband Edward
Published: March 2022

With its central image of the old masturbator in the Berlin “underground” restroom, Khodasevich's poem “Under the Ground” (1923) both shocked and fascinated its readers. Khodasevich's intervention into two taboo themes in turn-of-the-century European culture—masturbation and public restrooms—is primarily self-reflexive, indicating his anxieties about the ambiguous place and status of a modernist poet and exploring the norms of poetic representation. The essay proposes to read “Under the Ground” as a site of contested and mutually commenting meanings among concerns about taboo sites of urban modernity, a self-reflexive vision of autoerotism, and aesthetic modernism with an emphasis on the shock effect. In analyzing Khodasevich's radicalization of his modernist poetics through the re-appropriation of these taboo themes, I also examine how current theorizations in the developing subfields of sexuality and urban studies that deal with masturbation and restrooms can contribute to the ongoing research on modernist authorship as understood through the figure of the poet-flâneur.
Diversifying models for analysing global change scenarios and sustainability pathways
Authors: Moallemi Enayat A. , Gao Lei , Eker Sibel , Bryan Brett A.
Published: March 2022

Non-technical summary

Models are increasingly used to inform the transformation of human–Earth systems towards a sustainable future, aligned with the sustainable development goals (SDGs). We argue that a greater diversity of models ought to be used for sustainability analysis to better address complexity and uncertainty. We articulate the steps to model global change socioeconomic and climatic scenarios with new models. Through these steps, we generate new scenario projections using a human–Earth system dynamics model. Our modelling brings new insights about the sensitivity of sustainability trends to future uncertainty and their alignment with or divergence from previous model-based scenario projections.

Technical summary

The future uncertainty and complexity of alternative socioeconomic and climatic scenarios challenge the model-based analysis of sustainable development. Obtaining robust insights requires a systematic processing of uncertainty and complexity not only in input assumptions, but also in the diversity of model structures that simulates the multisectoral dynamics of human and Earth system interactions. Here, we implement the global change scenarios, that is, the shared socioeconomic pathways and the representative concentration pathways, in a feedback-rich, integrated assessment model (IAM) of human–Earth system dynamics, called FeliX, to serve two aims: (1) to provide modellers with well-defined steps for the adoption of established scenarios in new IAMs and (2) to explore the impacts of model uncertainty and its structural complexity on the projection of these scenarios for sustainable development. Our modelling shows internally consistent scenario storylines across sectors, yet with quantitatively different realisations of these scenarios compared to other IAMs due to the new model's structural complexity. The results highlight the importance of enumerating global change scenarios and their uncertainty exploration with a diversity of models of different input assumptions and structures to capture a wider variety of future possibilities and sustainability indicators.

Social media summary

New study highlights the importance of global change scenario analysis with new, SDG-focused IAMs.
Die Bedeutung von körperlicher Aktivität für die psychische Gesundheit
Authors: Imboden Christian , Claussen Malte Christian , Seifritz Erich , Gerber Markus
Published: March 2022

Zusammenfassung. Aufgrund der hohen weltweiten Prävalenz psychischer Erkrankungen und deren Assoziation mit inaktiven Verhaltensweisen und körperlichen Komorbiditäten kommt der Förderung körperlicher Aktivität bei psychisch erkrankten Menschen eine wichtige Bedeutung zu. Regelmässiges Training ist mit verbessertem psychischem Wohlbefinden assoziiert und hat eine präventive Wirkung bezüglich der Entwicklung verschiedener psychischer Erkrankungen wie Depressionen, Angststörungen und wahrscheinlich auch Schlafstörungen. Zudem fanden sich positive Effekte auf chronische körperliche Komorbiditäten. Regelmässiges Training über mehrere Wochen hat bei depressiven Erkrankungen einen nachweislichen antidepressiven Effekt. Ähnliche positive Effekte auf die Symptomatik konnten für Angsterkrankungen und Schizophrenie gezeigt werden. In der Praxis empfiehlt sich das strukturierte Erheben und Fördern körperlicher Aktivität psychiatrischer Patientinnen und Patienten mit dem Ziel, wöchentlich mindestens 150 Minuten moderate und/oder 75 Minuten intensive körperliche Aktivität zu erreichen. Der Aufbau und die Weiterentwicklung ambulanter Sport- und Bewegungsangebote für Menschen mit psychischer Erkrankung spielt für die Zukunft eine wichtige Rolle.
Sportpsychiatrie und -psychotherapie im Leistungssport
Authors: Claussen Malte Christian , Imboden Christian , Raas Marcel I. , Hemmeter Ulrich , Seifritz Erich , Hofmann Carlos Gonzalez
Published: March 2022

Zusammenfassung. Psychische Beschwerden und Erkrankungen sind häufige Gesundheitsprobleme im Leistungssport, und psychische Gesundheit ist wie körperliche Gesundheit und Leistung eine integrale Dimension im Leistungssport. Die Förderung der psychischen Gesundheit und ein sicherer Umgang mit psychischen Beschwerden und Erkrankungen im Leistungssport erfordern eine qualifizierte medizinische Fachdisziplin für die psychische Gesundheit: die Sportpsychiatrie und -psychotherapie sowie ein interdisziplinäres und interprofessionelles Verständnis der Versorgung und Zusammenarbeit. Im folgenden Artikel wird auf die Sportpsychiatrie und -psychotherapie im Leistungssport eingegangen und es werden (i) die Förderung der psychischen Gesundheit und Prävention, (ii) das Tandemkonzept der interprofessionellen Versorgung und Zusammenarbeit, (iii) Diagnostik, Therapie und Nachsorge psychischer Störungen und Erkrankungen und (iv) die Aus- und Weiterbildung in der Sportpsychiatrie und -psychotherapie vorgestellt und diskutiert.
Inundation of Stormwater Infrastructure Is Common and Increases Risk of Flooding in Coastal Urban Areas Along the US Atlantic Coast
Authors: Gold Adam C. , Brown Chelsea M. , Thompson Suzanne P. , Piehler Michael F.
Published: March 2022

Stormwater infrastructure can manage precipitation‐driven flooding when there are no obstructions to draining. Coastal areas increasingly experience recurrent flooding due to elevated water levels from storms or tides, but the inundation of coastal stormwater infrastructure by elevated water levels has not been broadly assessed. We conservatively estimated stormwater infrastructure inundation in municipalities along the Atlantic United States coast by using areas of high‐tide flooding (HTF) on roads as a proxy. We also modeled stormwater infrastructure inundation in four North Carolina municipalities and measured infrastructure inundation in one of the modeled municipalities. Combining methodologies at different scales provides context and allows the scope of stormwater infrastructure inundation to be broadly estimated. We found 137 census‐designated urban areas along the Atlantic coast with road area impacted by HTF, with a median percent of total road area subject to HTF of 0.16% (IQR: 0.02%–0.53%). Based on 2010 census block data, the median number of people per urban area that live in census blocks with HTF on roads was 1,622 (IQR: 366–5,779). In total, we estimate that over 2 million people live in census blocks where HTF occurs on roadways along the US Atlantic coast. Modeling results and water level measurements indicated that extensive inundation of underground stormwater infrastructure likely occurs at water levels within the mean tidal range. These results suggest that stormwater infrastructure inundation along the US Atlantic coast is likely widespread, affects a large number of people, occurs frequently, and increases the occurrence of urban flooding.
Impacts of Global Climate Warming on Meteorological and Hydrological Droughts and Their Propagations
Authors: Wu Guiyang , Chen Jie , Shi Xinyan , Kim Jong‐Suk , Xia Jun , Zhang Liping
Published: March 2022

Meteorological to hydrological drought propagation has been widely studied to reflect the relationship between these drought categories and better understand drought mechanisms. However, global warming may alter the drought propagation features, which are not fully understood. This study aims to investigate changes in meteorological and hydrological drought conditions, especially their propagation features in 1.5–3.0°C warmer climates for 8,655 watersheds globally. First, the three‐month scale standardized precipitation index and the standardized runoff index are calculated based on the precipitation simulated by the 15 global climate models and the runoff simulated by the four hydrological models, respectively. Drought events are then identified using the run theory, followed by the calculation of drought propagation features (i.e., pooling, lag, and lengthening) for matched meteorological and hydrological droughts. As a result, both meteorological and hydrological drought conditions (i.e., duration and severity) would relieve in warmer climates due to increased precipitation for regions excluding Western North America, South America, the Mediterranean, Southern Africa, East Asia, and Australia. However, the drought conditions would be more severe during drought propagation from meteorological to hydrological droughts over most regions. During drought propagation, the worsening drought conditions over half of the regions would be more serious first and then relieved with the rising temperature. These results indicate that efforts to slow down global warming can suppress the deterioration of drought conditions in the propagation.
The Role of River Discharge and Geometric Structure on Diurnal Tidal Dynamics, Alabama, USA
Authors: Dykstra Steven L. , Dzwonkowski Brian , Torres Raymond
Published: March 2022

As tides propagate inland, they become distorted by channel geometry and river discharge. Tidal dynamics in fluvial‐marine transitions are commonly observed in high‐energy tidal environments with relatively steady river conditions, leaving the effects of variable river discharge on tides and longitudinal changes poorly understood. To study the effects of variable river discharge on tide‐river interactions, we studied a low‐energy tidal environment where river discharge ranges several orders of magnitude, the diurnal microtidal Tombigbee River‐Mobile Bay fluvial‐marine transition, using water level and velocity observations from 21 stations. Results showed that diurnal tidal attenuation was reduced by the width convergence in seaward reaches and height convergence of the landward backwater reaches, with the channel convergence change location ∼40–50 km inland of the bayhead and seaward of the largest bifurcation. River events amplified tides in seaward regions and attenuated tides in landward regions. This created a region of river‐induced peak amplitude seaward of the flood limit (i.e., bidirectional‐unidirectional current transition), allowing more tidal energy to propagate inland. Tidal currents were attenuated and delayed more by river discharge than water levels, making the phase lag dynamic. The river impacts on the tides were delineated longitudinally and shifted seaward as river discharge increased, ranging up to ∼180 km. Results indicated the longitudinal shifts of river impacts on tides in alluvial systems can be estimated analytically using the ratio of river discharge to tidal discharge and the geometric convergence of the system. Our simple analytical theory provides a pathway for understanding the tide‐river‐geomorphic equilibrium along increasingly dynamic coasts.
MJO Phase Swings Modulate the Recurring Latitudinal Shifts of the 2020 Extreme Summer‐Monsoon Rainfall Around Yangtse
Authors: Wang Yuwen , Ren Hong‐Li , Wei Yuntao , Jin Fei‐Fei , Ren Pengfei , Gao Li , Wu Jie
Published: March 2022

Considering the unprecedented extremity of the Meiyu episodes in early summer of 2020, here the authors perform a comprehensive study of the intraseasonal evolution characteristics of the observed rainfall round Yangtse as well as the potential modulating effect of Madden‐Julian Oscillation (MJO). Results suggest that the Meiyu rainfall manifests as recurring latitudinal shifts around Yangtse during June–July of 2020, corresponding well to the continued swings of MJO circulation and convection between Phase 1 and Phase 2. The MJO affects the meridional migration of the 2020 Meiyu rainfall mainly through regulating the westward extended ridge line and southwesterly of the anomalous anticyclone over the western North Pacific (WNP). Specifically, the northeastward propagation of boreal summer MJO from Phase 1 to 2 shifts the ridge line of the anomalous WNP anticyclone northeastward. Consequently, the associated southwesterly anomaly over the southeastern China penetrates to the north of Yangtse and enhances the lower‐tropospheric moisture flux convergence, supporting heavy precipitation there. However, when the MJO swings back to Phase 1, the anomalous southwesterly and moisture flux convergence retreat southward, so does the Meiyu rain band. The present results advanced our understanding of the interactions between the latitudinal shifts of extreme Meiyu rainfall episodes and MJO Phase swings.
Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects
Authors: Qian Hong-jie , Wang Yu , Zhang Meng-qi , Xie Yuan-chao , Wu Qing-qing , Liang Li-yu , Cao Ye , Duan Hua-qing , Tian Guang-hui , Ma Juan , Zhang Zhuo-bing , Li Ning , Jia Jing-ying , Zhang Jing , Aisa Haji Akber , Shen Jing-shan , Yu Chen , Jiang Hua-liang , Zhang Wen-hong , Wang Zhen , Liu Gang-yi
Published: March 2022

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25–800 mg. T1/2 was within 4.80–6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.
Lon upregulation contributes to cisplatin resistance by triggering NCLX-mediated mitochondrial Ca2+ release in cancer cells
Authors: Tangeda Vidhya , Lo Yu Kang , Babuharisankar Ananth Ponneri , Chou Han-Yu , Kuo Cheng-Liang , Kao Yung-Hsi , Lee Alan Yueh-Luen , Chang Jang-Yang
Published: March 2022

Mitochondria are the major organelles in sensing cellular stress and inducing the response for cell survival. Mitochondrial Lon has been identified as an important stress protein involved in regulating proliferation, metastasis, and apoptosis in cancer cells. However, the mechanism of retrograde signaling by Lon on mitochondrial DNA (mtDNA) damage remains to be elucidated. Here we report the role of Lon in the response to cisplatin-induced mtDNA damage and oxidative stress, which confers cancer cells on cisplatin resistance via modulating calcium levels in mitochondria and cytosol. First, we found that cisplatin treatment on oral cancer cells caused oxidative damage of mtDNA and induced Lon expression. Lon overexpression in cancer cells decreased while Lon knockdown sensitized the cytotoxicity towards cisplatin treatment. We further identified that cisplatin-induced Lon activates the PYK2-SRC-STAT3 pathway to stimulate Bcl-2 and IL-6 expression, leading to the cytotoxicity resistance to cisplatin. Intriguingly, we found that activation of this pathway is through an increase of intracellular calcium (Ca2+) via NCLX, a mitochondrial Na+/Ca2+ exchanger. We then verified that NCLX expression is dependent on Lon levels; Lon interacts with and activates NCLX activity. NCLX inhibition increased the level of mitochondrial calcium and sensitized the cytotoxicity to cisplatin in vitro and in vivo. In summary, mitochondrial Lon-induced cisplatin resistance is mediated by calcium release into cytosol through NCLX, which activates calcium-dependent PYK2-SRC-STAT3-IL-6 pathway. Thus, our work uncovers the novel retrograde signaling by mitochondrial Lon on resistance to cisplatin-induced mtDNA stress, indicating the potential use of Lon and NCLX inhibitors for better clinical outcomes in chemoresistant cancer patients.
Erythropoietin promotes M2 macrophage phagocytosis of Schwann cells in peripheral nerve injury
Authors: Govindappa Prem Kumar , Elfar John C.
Published: March 2022

Following acute sciatic nerve crush injury (SNCI), inflammation and the improper phagocytic clearance of dying Schwann cells (SCs) has effects on remodeling that lead to morbidity and incomplete functional recovery. Therapeutic strategies like the use of erythropoietin (EPO) for peripheral nerve trauma may serve to bring immune cell phagocytotic clearance under control to support debris clearance. We evaluated EPO’s effect on SNCI and found EPO treatment increased myelination and sciatic functional index (SFI) and bolstered anti-apoptosis and phagocytosis of myelin debris via CD206+ macrophages when compared to saline treatment. EPO enhanced M2 phenotype activity, both in bone marrow-derived macrophages (BMMØs) and peritoneal-derived macrophages (PMØs) in vitro, as well as in PMØs in vivo. EPO increased efferocytosis of apoptotic sciatic nerve derived Schwann cells (SNSCs) in both settings as demonstrated using immunofluorescence (IF) and flow cytometry. EPO treatment significantly attenuated pro-inflammatory genes (IL1β, iNOS, and CD68) and augmented anti-inflammatory genes (IL10 and CD163) and the cell-surface marker CD206. EPO also increased anti-apoptotic (Annexin V/7AAD) effects after lipopolysaccharide (LPS) induction in macrophages. Our data demonstrate EPO promotes the M2 phenotype macrophages to ameliorate apoptosis and efferocytosis of dying SCs and myelin debris and improves SN functional recovery following SNCI.
Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma
Authors: Capparelli Claudia , Purwin Timothy J. , Glasheen McKenna , Caksa Signe , Tiago Manoela , Wilski Nicole , Pomante Danielle , Rosenbaum Sheera , Nguyen Mai Q. , Cai Weijia , Franco-Barraza Janusz , Zheng Richard , Kumar Gaurav , Chervoneva Inna , Shimada Ayako , Rebecca Vito W. , Snook Adam E. , Hookim Kim , Xu Xiaowei , Cukierman Edna , Herlyn Meenhard , Aplin Andrew E.
Published: March 2022

Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.
Nonlocal pseudopotential energy density functional for orbital-free density functional theory
Authors: Xu Qiang , Ma Cheng , Mi Wenhui , Wang Yanchao , Ma Yanming
Published: March 2022

Orbital-free density functional theory (OF-DFT) is an electronic structure method with a low computational cost that scales linearly with the number of simulated atoms, making it suitable for large-scale material simulations. It is generally considered that OF-DFT strictly requires the use of local pseudopotentials, rather than orbital-dependent nonlocal pseudopotentials, for the calculation of electron-ion interaction energies, as no orbitals are available. This is unfortunate situation since the nonlocal pseudopotentials are known to give much better transferability and calculation accuracy than local ones. We report here the development of a theoretical scheme that allows the direct use of nonlocal pseudopotentials in OF-DFT. In this scheme, a nonlocal pseudopotential energy density functional is derived by the projection of nonlocal pseudopotential onto the non-interacting density matrix (instead of “orbitals”) that can be approximated explicitly as a functional of electron density. Our development defies the belief that nonlocal pseudopotentials are not applicable to OF-DFT, leading to the creation for an alternate theoretical framework of OF-DFT that works superior to the traditional approach.
Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma
Authors: Zakeri Nekisa , Hall Andrew , Swadling Leo , Pallett Laura J. , Schmidt Nathalie M. , Diniz Mariana O. , Kucykowicz Stephanie , Amin Oliver E. , Gander Amir , Pinzani Massimo , Davidson Brian R. , Quaglia Alberto , Maini Mala K.
Published: March 2022

Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (TRM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδTRM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a TRM phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2TRM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2TRM-based targeting.
The aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma
Authors: Chang Cunjie , Rajasekaran Muthukumar , Qiao Yiting , Dong Heng , Wang Yu , Xia Hongping , Deivasigamani Amudha , Wu Minjie , Sekar Karthik , Gao Hengjun , Sun Mengqing , Niu Yuqin , Li Qian , Tao Lin , Yan Zhen , Wang Menglan , Chen Shasha , Zhao Shujuan , Chen Dajing , Li Lina , Yang Fan , Gao Haojin , Chen Baodong , Su Ling , Xu Liang , Chen Ye , Seshachalam Veerabrahma Pratap , Chen Gongxing , Gunaratne Jayantha , Hong Wanjin , Shi Junping , Chen Gongying , Grierson David S. , Chabot Benoit , Xie Tian , Hui Kam Man , Chen Jianxiang
Published: March 2022

Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of a Splicing Regulatory Glutamine/Lysine-Rich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). HCC patients with poor prognosis express higher levels of exon 10-inclusive SREK1 (SREK1L). SREK1L can sustain BLOC1S5-TXNDC5 (B-T) expression, a targeted gene of nonsense-mediated mRNA decay through inhibiting exon-exon junction complex binding with B-T to exert its oncogenic role. B-T plays its competing endogenous RNA role by inhibiting miR-30c-5p and miR-30e-5p, and further promoting the expression of downstream oncogenic targets SRSF10 and TXNDC5. Interestingly, SRSF10 can act as a splicing regulator for SREK1L to promote hepatocarcinogenesis via the formation of a SRSF10-associated complex. In summary, we demonstrate a SRSF10/SREK1L/B-T signalling loop to accelerate the hepatocarcinogenesis.
Intralocus conflicts associated with a supergene
Authors: Giraldo-Deck Lina M. , Loveland Jasmine L. , Goymann Wolfgang , Tschirren Barbara , Burke Terry , Kempenaers Bart , Lank David B. , Küpper Clemens
Published: March 2022

Chromosomal inversions frequently underlie major phenotypic variation maintained by divergent selection within and between sexes. Here we examine whether and how intralocus conflicts contribute to balancing selection stabilizing an autosomal inversion polymorphism in the ruff Calidris pugnax. In this lekking shorebird, three male mating morphs (Independents, Satellites and Faeders) are controlled by an inversion-based supergene. We show that in a captive population, Faeder females, who are smaller and whose inversion haplotype has not undergone recombination, have lower average reproductive success in terms of laying rate, egg size, and offspring survival than Independent females, who lack the inversion. Satellite females, who carry a recombined inversion haplotype and have intermediate body size, more closely resemble Independent than Faeder females in reproductive performance. We inferred that the lower reproductive output of Faeder females is most likely balanced by higher than average reproductive success of individual Faeder males. These findings suggest that intralocus conflicts may play a major role in the evolution and maintenance of supergene variants.
Tertiary lymphoid structures critical for prognosis in endometrial cancer patients
Authors: Horeweg Nanda , Workel Hagma H. , Loiero Dominik , Church David N. , Vermij Lisa , Léon-Castillo Alicia , Krog Ricki T. , de Boer Stephanie M. , Nout Remi A. , Powell Melanie E. , Mileshkin Linda R. , MacKay Helen , Leary Alexandra , Singh Naveena , Jürgenliemk-Schulz Ina M. , Smit Vincent T. H. B. M. , Creutzberg Carien L. , Koelzer Viktor H. , Nijman Hans W. , Bosse Tjalling , de Bruyn Marco ,   TransPORTEC consortium, Horeweg Nanda , Church David N. , de Boer Stephanie M. , Nout Remi A. , Powell Melanie E. , Mileshkin Linda R. , MacKay Helen , Leary Alexandra , Singh Naveena , Creutzberg Carien L. , Nijman Hans W. , Bosse Tjalling , de Bruyn Marco
Published: March 2022

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.
Spinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control
Authors: Fossey Mary P. M. , Balthazaar Shane J. T. , Squair Jordan W. , Williams Alexandra M. , Poormasjedi-Meibod Malihe-Sadat , Nightingale Tom E. , Erskine Erin , Hayes Brian , Ahmadian Mehdi , Jackson Garett S. , Hunter Diana V. , Currie Katharine D. , Tsang Teresa S. M. , Walter Matthias , Little Jonathan P. , Ramer Matt S. , Krassioukov Andrei V. , West Christopher R.
Published: March 2022

Spinal cord injury chronically alters cardiac structure and function and is associated with increased odds for cardiovascular disease. Here, we investigate the cardiac consequences of spinal cord injury on the acute-to-chronic continuum, and the contribution of altered bulbospinal sympathetic control to the decline in cardiac function following spinal cord injury. By combining experimental rat models of spinal cord injury with prospective clinical studies, we demonstrate that spinal cord injury causes a rapid and sustained reduction in left ventricular contractile function that precedes structural changes. In rodents, we experimentally demonstrate that this decline in left ventricular contractile function following spinal cord injury is underpinned by interrupted bulbospinal sympathetic control. In humans, we find that activation of the sympathetic circuitry below the level of spinal cord injury causes an immediate increase in systolic function. Our findings highlight the importance for early interventions to mitigate the cardiac functional decline following spinal cord injury.
Magnetically tightened form-stable phase change materials with modular assembly and geometric conformality features
Authors: Lu Yongyu , Yu Dehai , Dong Haoxuan , Lv Jinran , Wang Lichen , Zhou He , Li Zhen , Liu Jing , He Zhizhu
Published: March 2022

Phase change materials have attracted significant attention due to their promising applications in many fields like solar energy and chip cooling. However, they suffer leakage during the phase transition process and have relatively low thermal conductivity. Here, through introducing hard magnetic particles, we synthesize a kind of magnetically tightened form-stable phase change materials. They achieve multifunctions such as leakage-proof, dynamic assembly, and morphological reconfiguration, presenting superior high thermal (increasing of 1400–1600%) and electrical (>104 S/m) conductivity, and prominent compressive strength, respectively. Furthermore, free-standing temperature control and high-performance thermal and electric conversion systems based on these materials are developed. This work suggests an efficient way toward exploiting a smart phase change material for thermal management of electronics and low-grade waste heat utilization.
CEP128 is involved in spermatogenesis in humans and mice
Authors: Zhang Xueguang , Wang Lingbo , Ma Yongyi , Wang Yan , Liu Hongqian , Liu Mohan , Qin Lang , Li Jinghong , Jiang Chuan , Zhang Xiaojian , Shan Xudong , Liu Yuliang , Li Jinsong , Li Yaqian , Zheng Rui , Sun Yongkang , Sun Jianfeng , Leng Xiangyou , Liang Yan , Zhang Feng , Jiang Xiaohui , Yang Yihong , Shen Ying
Published: March 2022

Centrosomal proteins are necessary components of the centrosome, a conserved eukaryotic organelle essential to the reproductive process. However, few centrosomal proteins have been genetically linked to fertility. Herein we identify a homozygous missense variant of CEP128 (c.665 G > A [p.R222Q]) in two infertile males. Remarkably, male homozygous knock-in mice harboring the orthologous CEP128R222Q variant show anomalies in sperm morphology, count, and motility. Moreover, Cep128 knock-out mice manifest male infertility associated with disrupted sperm quality. We observe defective sperm flagella in both homozygous Cep128 KO and KI mice; the cilia development in other organs is normal—suggesting that CEP128 variants predominantly affected the ciliogenesis in the testes. Mechanistically, CEP128 is involved in male reproduction via regulating the expression of genes and/or the phosphorylation of TGF-β/BMP-signalling members during spermatogenesis. Altogether, our findings unveil a crucial role for CEP128 in male fertility and provide important insights into the functions of centrosomal proteins in reproductive biology.
Mechanically interlocked networks cross-linked by a molecular necklace
Authors: Zhang Zhaoming , Zhao Jun , Guo Zhewen , Zhang Hao , Pan Hui , Wu Qian , You Wei , Yu Wei , Yan Xuzhou
Published: March 2022

Molecular necklaces have attracted much research attention due to their unique topological structures. Although numerous molecular necklaces with exquisite structures have been constructed, it remains a major challenge to exploit the functions and applications associated with their fascinating architectural and dynamic characteristics. Herein, we report a class of mechanically interlocked networks (MINs) cross-linked by a molecular necklace, in which multiple crown ethers are threaded on a hexagonal metallacyclic framework to furnish a cross-linker with delicate interlocked structures. The molecular necklace cross-linker possesses multiple peculiar advantages: multivalent interactions and rigid metallacycle framework guarantee robust features of MINs while the motion and dissociation of the interlocked structures bring in notable mechanical adaptivity. Moreover, the MINs could respond to the stimuli of K+and Br−, which lead to the dethreading of crown ether and even the complete decomposition of molecular necklace, respectively, showing abundant active properties. These findings demonstrate the untapped potential of molecular necklaces as cross-linkers and open the door to extend their advanced applications in intelligent supramolecular materials.
Precision drugging of the MAPK pathway in head and neck cancer
Authors: Ngan Hoi-Lam , Law Chun-Ho , Choi Yannie Chung Yan , Chan Jenny Yu-Sum , Lui Vivian Wai Yan
Published: March 2022

The mitogen-activating protein kinase (MAPK) pathway is central for cell proliferation, differentiation, and senescence. In human, germline defects of the pathway contribute to developmental and congenital head and neck disorders. Nearly 1/5 of head and neck squamous cell carcinoma (HNSCC) harbors MAPK pathway mutations, which are largely activating mutations. Yet, previous approaches targeting the MAPK pathway in HNSCC were futile. Most recent clinical evidences reveal remarkable, or even exceptional pharmacologic vulnerabilities of MAPK1-mutated, HRAS-mutated, KRAS-germline altered, as well as BRAF-mutated HNSCC patients with various targeted therapies, uncovering diverse opportunities for precision drugging this pathway at multiple “genetically condemned” nodes. Further, recent patient tumor omics unveil novel effects of MAPK aberrations on direct induction of CD8+ T cell recruitment into the HNSCC microenvironment, providing evidences for future investigation of precision immunotherapy for this large subset of patients. MAPK pathway-mutated HNSCC should warrant precision therapy assessments in vigorous manners.
Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics
Authors: Correll Christoph U. , Martin Amber , Patel Charmi , Benson Carmela , Goulding Rebecca , Kern-Sliwa Jennifer , Joshi Kruti , Schiller Emma , Kim Edward
Published: March 2022

Clinical practice guidelines (CPGs) translate evidence into recommendations to improve patient care and outcomes. To provide an overview of schizophrenia CPGs, we conducted a systematic literature review of English-language CPGs and synthesized current recommendations for the acute and maintenance management with antipsychotics. Searches for schizophrenia CPGs were conducted in MEDLINE/Embase from 1/1/2004–12/19/2019 and in guideline websites until 06/01/2020. Of 19 CPGs, 17 (89.5%) commented on first-episode schizophrenia (FES), with all recommending antipsychotic monotherapy, but without agreement on preferred antipsychotic. Of 18 CPGs commenting on maintenance therapy, 10 (55.6%) made no recommendations on the appropriate maximum duration of maintenance therapy, noting instead individualization of care. Eighteen (94.7%) CPGs commented on long-acting injectable antipsychotics (LAIs), mainly in cases of nonadherence (77.8%), maintenance care (72.2%), or patient preference (66.7%), with 5 (27.8%) CPGs recommending LAIs for FES. For treatment-resistant schizophrenia, 15/15 CPGs recommended clozapine. Only 7/19 (38.8%) CPGs included a treatment algorithm.
Deep rTMS of the insula and prefrontal cortex in smokers with schizophrenia: Proof-of-concept study
Authors: Moeller Scott J. , Gil Roberto , Weinstein Jodi J. , Baumvoll Topaz , Wengler Kenneth , Fallon Natalka , Van Snellenberg Jared X. , Abeykoon Sameera , Perlman Greg , Williams John , Manu Lucian , Slifstein Mark , Cassidy Clifford M. , Martinez Diana M. , Abi-Dargham Anissa
Published: March 2022

Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia.
Machine Learning algorithm unveils glutamatergic alterations in the post-mortem schizophrenia brain
Authors: De Rosa Arianna , Fontana Andrea , Nuzzo Tommaso , Garofalo Martina , Di Maio Anna , Punzo Daniela , Copetti Massimiliano , Bertolino Alessandro , Errico Francesco , Rampino Antonio , de Bartolomeis Andrea , Usiello Alessandro
Published: March 2022

Schizophrenia is a disorder of synaptic plasticity and aberrant connectivity in which a major dysfunction in glutamate synapse has been suggested. However, a multi-level approach tackling diverse clusters of interacting molecules of the glutamate signaling in schizophrenia is still lacking. We investigated in the post-mortem dorsolateral prefrontal cortex (DLPFC) and hippocampus of schizophrenia patients and non-psychiatric controls, the levels of neuroactive d- and l-amino acids (l-glutamate, d-serine, glycine, l-aspartate, d-aspartate) by HPLC. Moreover, by quantitative RT-PCR and western blotting we analyzed, respectively, the mRNA and protein levels of pre- and post-synaptic key molecules involved in the glutamatergic synapse functioning, including glutamate receptors (NMDA, AMPA, metabotropic), their interacting scaffolding proteins (PSD-95, Homer1b/c), plasma membrane and vesicular glutamate transporters (EAAT1, EAAT2, VGluT1, VGluT2), enzymes involved either in glutamate-dependent GABA neurotransmitter synthesis (GAD65 and 67), or in post-synaptic NMDA receptor-mediated signaling (CAMKIIα) and the pre-synaptic marker Synapsin-1. Univariable analyses revealed that none of the investigated molecules was differently represented in the post-mortem DLPFC and hippocampus of schizophrenia patients, compared with controls. Nonetheless, multivariable hypothesis-driven analyses revealed that the presence of schizophrenia was significantly affected by variations in neuroactive amino acid levels and glutamate-related synaptic elements. Furthermore, a Machine Learning hypothesis-free unveiled other discriminative clusters of molecules, one in the DLPFC and another in the hippocampus. Overall, while confirming a key role of glutamatergic synapse in the molecular pathophysiology of schizophrenia, we reported molecular signatures encompassing elements of the glutamate synapse able to discriminate patients with schizophrenia and normal individuals.
Flat-surface-assisted and self-regulated oxidation resistance of Cu(111)
Authors: Kim Su Jae , Kim Yong In , Lamichhane Bipin , Kim Young-Hoon , Lee Yousil , Cho Chae Ryong , Cheon Miyeon , Kim Jong Chan , Jeong Hu Young , Ha Taewoo , Kim Jungdae , Lee Young Hee , Kim Seong-Gon , Kim Young-Min , Jeong Se-Young
Published: March 2022

Oxidation can deteriorate the properties of copper that are critical for its use, particularly in the semiconductor industry and electro-optics applications1–7. This has prompted numerous studies exploring copper oxidation and possible passivation strategies8. In situ observations have, for example, shown that oxidation involves stepped surfaces: Cu2O growth occurs on flat surfaces as a result of Cu adatoms detaching from steps and diffusing across terraces9–11. But even though this mechanism explains why single-crystalline copper is more resistant to oxidation than polycrystalline copper, the fact that flat copper surfaces can be free of oxidation has not been explored further. Here we report the fabrication of copper thin films that are semi-permanently oxidation resistant because they consist of flat surfaces with only occasional mono-atomic steps. First-principles calculations confirm that mono-atomic step edges are as impervious to oxygen as flat surfaces and that surface adsorption of O atoms is suppressed once an oxygen face-centred cubic (fcc) surface site coverage of 50% has been reached. These combined effects explain the exceptional oxidation resistance of ultraflat Cu surfaces.
The Carbon Catalogue, carbon footprints of 866 commercial products from 8 industry sectors and 5 continents
Authors: Meinrenken Christoph J. , Chen Daniel , Esparza Ricardo A. , Iyer Venkat , Paridis Sally P. , Prasad Aruna , Whillas Erika
Published: March 2022

Product carbon footprints (PCFs) are playing an increasing role in decisions around sustainability for companies and consumers. Using data reported to CDP, we have previously built a dataset of 866 PCFs, from 145 companies, 30 industry groups, and 28 countries, showing trends of how upstream and downstream emissions vary by industry and how life cycle assessment (LCA) appears to aid companies in achieving steeper carbon reductions through improvements throughout a product’s value chain. Here, we present the greenhouse gas emissions and respective meta data for every product in this dataset. The Carbon Catalogue provides each product with name and description, PCF (in kg CO2e) and the respective LCA protocol/standard, product weight, as well as the name, industry, and country of incorporation of its manufacturer. For a subset of 421 products, the Carbon Catalogue further includes the PCF’s reported breakdown into two to nine separate stages of the product’s life cycle. For another subset of 250 products, the Carbon Catalogue includes how the respective PCFs changed and why the changes occurred.