bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrinsic Social Incentives in State and Non-State Armed Groups
Authors: GILLIGAN MICHAEL J. , KHADKA PRABIN , SAMII CYRUS
Published: April 2022

How do non-state armed groups (NSAGs) survive and even thrive in situations where state armed groups (SAGs) collapse, despite the former’s often greater material adversity? We argue that, optimizing under their different constraints, SAGs invest more in technical military training and NSAGs invest more in enhancing soldiers’ intrinsic payoffs from serving their group. Therefore, willingness to contribute to the group should be more positively correlated with years of service in NSAGs than in SAGs. We confirm this hypothesis with lab-in-the-field and qualitative evidence from SAG and NSAG soldiers in Nepal, Ivory Coast, and Kurdistan. Each field study addresses specific inferential weaknesses in the others. Assembled together, these cases reduce concerns about external validity or replicability. Our findings reveal how the basis of NSAG cohesion differs from that of SAGs, with implications for strategies to counter NSAG mobilization.
‘Once a combatant, always a combatant’? Revisiting assumptions about Liberian former combatant networks
Authors: Käihkö Ilmari
Published: April 2022

Building on 15 months of ethnographic fieldwork, this article draws from military sociology to revisit past portrayals of Liberian former combatant networks and assesses four central assumptions connected to them: that formal wartime command structures continue as informal networks long after the end of the war; that former combatants are united by a wartime identity and form a community to an extent separated from the surrounding society; that wartime experiences have had a major disciplining effect on former combatants; and that former combatants are both good mobilisers and easy to mobilise in elections and armed conflict alike. Finding limited evidence close to two decades after the end of war to support these assumptions, I ultimately ask whether it would be more productive to both theory and Liberians alike to widen investigation from former combatants to structural issues that affect many more in the country.
Empowering Civil Society: The Theatricality of Protest in Malta
Authors: Cremona Vicki Ann
Published: April 2022

The recent barbaric murder of an investigative journalist in Malta who was looking into corruption at the top echelons of power sparked off a civil society movement, Repubblika, spurring ordinary citizens into participating in collective protest action. The movement also incorporated a loose grouping of women calling themselves ‘Occupy Justice’. Different forms of protest against government corruption have resulted in the resignation of various senior politicians and high-ranking officials, including the Prime Minister. Taking as a point of departure the struggle against the unequal distribution of power as defined by Michel Foucault and Jacques Rancière, the empowering force of civil protest is here examined in relation to how power is appropriated and how institutional power is resisted. Micromobilization and mesomobilization are seen as two means of staging protest and creating a common force with which to confront corrupt power structures. Protest, power, and resistance are viewed in the light of theatrical events; the creative means deployed to stage protests are discussed. The aesthetic qualities meant to transform perception and move people to action for bringing about political change are highlighted in relation to both sensory and symbolic dynamics. Vicki Ann Cremona is Professor of Theatre Studies at the University of Malta and the author of Carnival and Power: Play and Politics in a Crown Colony (Palgrave Macmillan, 2018), as well as a co-editor of Theatre Scandals: Social Dynamics of Turbulent Theatrical Events (Brill-Rodopi, 2020).
Changes in expeditioners' personality measures during 1 year Antarctic expeditions
Authors: Kokun Oleg , Bakhmutova Larysa
Published: April 2022

The extreme working and living conditions at Antarctic stations cause numerous psychological changes in expeditioners. However, research on the changes in expeditioners' personality traits is virtually non-existent. Therefore, the present study aims to determine the changes in expeditioners' personality measures during 1 year Antarctic expeditions. This study examined 56 expeditioners working at the Ukrainian Antarctic Akademik Vernadsky station (52 men, 4 women; ages 20–63 years, M = 38.12, SD = 10.01) who participated in five annual expeditions between 2016 and 2021. The Ukrainian adaptations of four measures were used: the Thomas-Kilmann Conflict Mode Instrument, the Eysenck Personality Questionnaire, the Leonhard-Schmieschek Questionnaire and the Leary Interpersonal Checklist. During 1 year Antarctic expeditions, 8 of the 26 indicators used to describe expeditioners' personality measures changed significantly (P < 0.001–0.1). These indicators belonged to three of the four measures used in the study and were assessed as personally unfavourable. They included increased psychoticism and competing, managerial-autocratic, aggressive-sadistic, responsible-hypernormal, competitive-narcissistic and self-effacing-masochistic styles and a decreased accommodating style. Based on these results, promising areas for further research that could improve psychological selection, training and work for Antarctic expedition personnel are outlined.
State of the Art Diagnostik des Ösophagus
Authors: Gerdes Christoph , Reinecke Johanna , Neesse Albrecht , Borggrefe Jan , Kröger Jan Robert
Published: April 2022

Zusammenfassung. Die moderne Diagnostik des Ösophagus ist hochgradig technisiert. Sie schliesst schwerpunktmässig endoskopische, radiologische, nuklearmedizinische, funktionelle und elektrochemische Untersuchungen ein. So kommen je nach Fragestellung Ösophagogastroduodenoskopie mit Chromoendoskopie, Endosonographie, Mano- und pH-Metrie oder radiologische Untersuchungen, wie Röntgenbreischluck, CT, MRT oder PET-CT, zur Anwendung. Die Anamnese und die körperliche Untersuchung stehen vor Beginn der Diagnostik und sind für die Indikationsstellung der anschliessenden Untersuchungen wichtig. Die Ösophagogastroduodenoskopie hat einen hohen Stellenwert in der Standarddiagnostik und die Indikation kann aufgrund der geringen Komplikationsrate grosszügig gestellt werden. Zusätzlich zu makroskopischen Beurteilung, Abstrich und Biopsie bietet sie die Möglichkeit, therapeutische Interventionen anzuschliessen. Zur Verbesserung der Diagnostik von Dysplasien können die klassische und virtuelle Chromoendoskopie eingesetzt werden. Die Endosonographie ist für das Staging von Ösophaguskarzinomen zwingend erforderlich, zusätzlich können endosonographisch gesteuerte Biopsien erfolgen. Eine CT ergänzt das Staging und ist notwendig zur Metastasendiagnostik. Für Motilitätsstörungen ist die HR-Manometrie heutzutage Goldstandard, welche um Bariumbreischluckuntersuchungen erweitert werden kann. Die pH-Metrie-Impedanz-Messung wird für die Diagnostik von Refluxerkrankungen eingesetzt. MRT-Schluckuntersuchungen sind klinisch noch kein Standard, werden aber im Rahmen von klinischen Studien bereits durchgeführt.
Collective Punishment and Cheating in the Die-Under-the-Cup Task
Authors: Siniver Erez , Tobol Yossef , Yaniv Gideon
Published: April 2022

Abstract: A popular tool in the experimental research on dishonest behavior is the die-under-the-cup (DUTC) task in which subjects roll a die in private and report the outcome to the experimenter after being promised a payoff which increases with the die’s outcome. The present paper reports the results of incorporating collective punishment into the DUTC task. We ran two experiments, each involving two rounds of the task performed in a computer lab. Despite being asked not to cheat, the average reported outcome in the first round exceeded the statistical expectancy of 3.5. The second round of the first experiment involved the threat that if this happened again, each subject would be fined by the difference between the average reported outcome and 3.5. Nevertheless, the average reported outcome in the second round significantly exceeded that of the first round. Running a second experiment, this time without the punishment threat, we ruled out the possibility that the increased cheating in the second round of the first experiment was due to a feedback effect, concluding that the threat of collective punishment acted to encourage cheating rather than helped deterring it.
Earth System's Gatekeeping of “One Health” Approach to Manage Climate‐Sensitive Infectious Diseases
Authors: Dovie Delali B. K. , Miyittah Michael K. , Dodor Daniel E. , Dzodzomenyo Mawuli , Christian Aaron K. , Tete‐Larbi Reuben , Codjoe Samuel N. A. , Bawah Ayaga A.
Published: April 2022

Global response to climate‐sensitive infectious diseases has been uncertain and slow. The understanding of the underlying vulnerabilities which forms part of changes created by forces within the Earth system has never before been critical until the coronavirus disease 2019, “COVID‐19” pandemic with the initial developmental phase linked to weather elements and climate change. Hence, the heightened interest in climate‐sensitive infectious diseases and GeoHealth, evident in the renewed calls for “One Health” approach to disease management. “One Health” explains the commonality of human and animal medicine, and links to the bio‐geophysical environment, yet are at crossroads with how forces within the Earth system shape etiologies, incidences, and transmission dynamics of infectious diseases. Hence, the paper explores how these forces, which are multistage and driven by climate change impacts on ecosystems affect emerging infectious diseases, leading to the question “what drive the drivers of diseases?” Three questions that challenge broad theories of Earth system science on boundaries and connectivity emerged to guide study designs to further interrogating disease surveillance and health early warning systems. This is because, climate change (a) drives prevailing biological health hazards as part of forces within the Earth system, (b) shifts disease control services of ecosystems and functioning to effectively regulate disease incidence, and (c) modifies pathogen—species hosts relationships. Hence, the need to rethink pluralistic concepts of climate‐sensitive diseases in their infection and management from a GeoHealth perspective, which “One Health” potentially conveys, and to also maintain ecosystem health.
Rock Magnetic Signatures of Hydrothermal Mineralization in the Trans‐Atlantic Geotraverse (TAG) Hydrothermal Field
Authors: Wang Shishun , Chang Liao
Published: April 2022

The Ocean Drilling Program Leg 158 drill holes from the Trans‐Atlantic Geotraverse hydrothermal field are investigated to understand the rock magnetic signatures of hydrothermal mineralization. A composite columnar section has been constructed through hole correlation to understand the stratigraphic variation of magnetomineralogy within the stockwork. Isothermal remanent magnetization components unmixing, first‐order reversal curve diagrams, low‐temperature magnetic signatures, and electron microscopic analyses disclose magnetic minerals of disparate occurrences related to predominating hydrothermal mineralization reactions in three broad zones: For basaltic basements, serpentinization of olivine phenocrysts during preliminary hydrothermal alteration produces magnetite, in addition to primary titanomagnetite; Chloritized and silicified zone samples contain relict titanomagnetite and exsolved magnetite that survived hydrothermal dissolution; Anhydrite and sulfide zone samples are dominated by magnetite and hematite, likely from oxidation of polymetallic sulfides due to exposure in oxidative seafloor environments during drilling. Our findings suggest that seafloor oxidation potentially modifies the magnetic properties of polymetallic sulfides in hydrothermal deposits, which applies to magnetic tomography of sophisticated subseafloor vent structures and prospecting seafloor massive sulfides (SMS) deposits therein. Meanwhile, we alert future deep‐sea mining that drilling may promote physicochemical alteration of SMS deposits, causing environmental risks. The established magnetic signatures ultimately contribute to understanding the in situ geological preservation of SMS deposits and optimizing exploitation procedures in the future.
In Situ and Orbital Stratigraphic Characterization of the InSight Landing Site—A Type Example of a Regolith‐Covered Lava Plain on Mars
Authors: Warner N. H. , Golombek M. P. , Ansan V. , Marteau E. , Williams N. , Grant J. A. , Hauber E. , Weitz C. , Wilson S. , Piqueux S. , Mueller N. , Grott M. , Spohn T. , Pan L. , Schmelzbach C. , Daubar I. J. , Garvin J. , Charalambous C. , Baker M. , Banks M.
Published: April 2022

The InSight lander rests on a regolith‐covered, Hesperian to Early Amazonian lava plain in Elysium Planitia within a ∼27‐m‐diameter, degraded impact crater called Homestead hollow. The km to cm‐scale stratigraphy beneath the lander is relevant to the mission's geophysical investigations. Geologic mapping and crater statistics indicate that ∼170 m of mostly Hesperian to Early Amazonian basaltic lavas are underlain by Noachian to Early Hesperian (∼3.6 Ga) materials of possible sedimentary origin. Up to ∼140 m of this volcanic resurfacing occurred in the Early Amazonian at 1.7 Ga, accounting for removal of craters ≤700 m in diameter. Seismic data however, suggest a clastic horizon that interrupts the volcanic sequence between depths of ∼30 and ∼75 m. Meter‐scale stratigraphy beneath the lander is constrained by local and regional regolith thickness estimates that indicate up to 10–30 m of coarse‐grained, brecciated regolith that fines upwards to a ∼3 m thick loosely‐consolidated, sand‐dominated unit. The maximum depth of Homestead hollow, at ∼3 m, indicates that the crater is entirely embedded in regolith. The hollow is filled by sand‐size eolian sediments, with contributions from sand to cobble‐size slope debris, and sand to cobble‐size ejecta. Lander‐based observations indicate that the fill at Homestead hollow contains a cohesive layer down to ∼10–20 cm depth that is visible in lander rocket‐excavated pits and the HP3 mole hole. The surface of the landing site is capped by a ∼1 to 2 cm‐thick loosely granular, sand‐sized layer with a microns‐thick surficial dust horizon.
Rural-urban difference in the prevalence of hypertension in West Africa: a systematic review and meta-analysis
Authors: Sani Ruqayya Nasir , Connelly Paul J. , Toft Mette , Rowa-Dewar Neneh , Delles Christian , Gasevic Danijela , Karaye Kamilu Musa
Published: April 2022

Urbanisation is considered a major contributor to the rising prevalence of hypertension in West Africa, yet the evidence regarding rural-urban differences in the prevalence of hypertension in the region has been mixed. A systematic literature search of four electronic databases: PubMed, Embase, African Journals Online, and WHO’s African Index Medicus; and reference lists of eligible studies was carried out. Original quantitative studies describing the rural-urban difference in the prevalence of hypertension in one or more countries in West Africa, and published in English language from the year 2000 to 2021 were included. A random effects meta-analysis model was used to estimate the odds ratio of hypertension in rural compared to urban locations. A limited sex-based random effects meta-analysis was conducted with 16 studies that provided sex-disaggregated data. Of the 377 studies screened, 22 met the inclusion criteria (n = 62,907). The prevalence of hypertension was high in both rural, and urban areas, ranging from 9.7% to 60% in the rural areas with a pooled prevalence of 27.4%; and 15.5% to 59.2% in the urban areas with a pooled prevalence of 33.9%. The odd of hypertension were lower in rural compared to urban dwellers [OR 0.74, 95% CI: 0.66-0.83; p < 0.001]. The pooled prevalence of hypertension was 32.6% in males, and 30.0% in females, with no significant difference in the odds of hypertension between the sexes [OR 0.91, 95% CI: 0.8-1.05, p = 0.196]. Comprehensive hypertension control policies are needed for both rural, and urban areas in West Africa, and for both sexes.
Chip-integrated van der Waals PN heterojunction photodetector with low dark current and high responsivity
Authors: Tian Ruijuan , Gan Xuetao , Li Chen , Chen Xiaoqing , Hu Siqi , Gu Linpeng , Van Thourhout Dries , Castellanos-Gomez Andres , Sun Zhipei , Zhao Jianlin
Published: April 2022

Two-dimensional materials are attractive for constructing high-performance photonic chip-integrated photodetectors because of their remarkable electronic and optical properties and dangling-bond-free surfaces. However, the reported chip-integrated two-dimensional material photodetectors were mainly implemented with the configuration of metal-semiconductor-metal, suffering from high dark currents and low responsivities at high operation speed. Here, we report a van der Waals PN heterojunction photodetector, composed of p-type black phosphorous and n-type molybdenum telluride, integrated on a silicon nitride waveguide. The built-in electric field of the PN heterojunction significantly suppresses the dark current and improves the responsivity. Under a bias of 1 V pointing from n-type molybdenum telluride to p-type black phosphorous, the dark current is lower than 7 nA, which is more than two orders of magnitude lower than those reported in other waveguide-integrated black phosphorus photodetectors. An intrinsic responsivity up to 577 mA W−1 is obtained. Remarkably, the van der Waals PN heterojunction is tunable by the electrostatic doping to further engineer its rectification and improve the photodetection, enabling an increased responsivity of 709 mA W−1. Besides, the heterojunction photodetector exhibits a response bandwidth of ~1.0 GHz and a uniform photodetection over a wide spectral range, as experimentally measured from 1500 to 1630 nm. The demonstrated chip-integrated van der Waals PN heterojunction photodetector with low dark current, high responsivity and fast response has great potentials to develop high-performance on-chip photodetectors for various photonic integrated circuits based on silicon, lithium niobate, polymer, etc.
Influence of resistant starch resulting from the cooling of rice on postprandial glycemia in type 1 diabetes
Authors: Strozyk Sylwia , Rogowicz-Frontczak Anita , Pilacinski Stanislaw , LeThanh-Blicharz Joanna , Koperska Anna , Zozulinska-Ziolkiewicz Dorota
Published: April 2022

Introduction

Carbohydrates are one of the macronutrients which have the most substantial influence on glycemic response. The cooling of rice after cooking causes retrogradation of starch, which becomes a non-absorbable product in the human digestive tract.

Aim of the study

This study aimed to assess whether cooling of rice affects postprandial glycemia in subjects with type 1 diabetes.

Materials and methods

The study included 32 patients with type 1 diabetes. Each participant of the study consumed two standardized test meals consisting of long-grain white rice. One of the test meals was served immediately after preparation, and another was cooled for 24 h at 4 °C after preparation and reheated before being served. Postprandial glycemia was measured for 3 h using the FreeStyle Libre flash glucose monitoring system for each patient.

Results

After consumption of the test meal containing rice subjected to the cooling process when compared to fresh rice, a significantly lower value of maximum glycemia (11 vs. 9.9 mmol/L,p = 0.0056), maximum glycemic increase (2.7 vs. 3.9 mmol/L,p < 0.0001), areas under the glycemic curve (135 vs. 336 mmol/L * 180 min,p < 0.0001) and significantly shorter time to peak (35 vs. 45 min,p = 0.031) was observed. There was a significantly higher number of hypoglycemic episodes among the patients after consuming test meals with cooled rice compared to fresh ones during 180 min of observation (12(38) vs. 3(9),p = 0.0039).

Conclusions

Consumption of rice subjected to the cooling process results in a lower increase of postprandial blood glucose in subjects with type 1 diabetes. At the same time it increases the risk of postprandial hypoglycemia using a standard insulin dose.
Differential routing and disposition of the long-chain saturated fatty acid palmitate in rodent vs human beta-cells
Authors: Thomas Patricia , Arden Catherine , Corcoran Jenna , Hacker Christian , Welters Hannah J. , Morgan Noel G.
Published: April 2022

Background

Rodent and human β-cells are differentially susceptible to the “lipotoxic” effects of long-chain saturated fatty acids (LC-SFA) but the factors accounting for this are unclear. Here, we have studied the intracellular disposition of the LC-SFA palmitate in human vs rodent β–cells and present data that reveal new insights into the factors regulating β-cell lipotoxicity.

Methods

The subcellular distribution of the LC-SFA palmitate was studied in rodent (INS-1E and INS-1 823/13 cells) and human (EndoC-βH1) β-cells using confocal fluorescence and electron microscopy (EM). Protein expression was assessed by Western blotting and cell viability, by vital dye staining.

Results

Exposure of INS-1 cells to palmitate for 24 h led to loss of viability, whereas EndoC-βH1 cells remained viable even after 72 h of treatment with a high concentration (1 mM) of palmitate. Use of the fluorescent palmitate analogue BODIPY FL C16 revealed an early localisation of the LC-SFA to the Golgi apparatus in INS-1 cells and this correlated with distention of intracellular membranes, visualised under the EM. Despite this, the PERK-dependent ER stress pathway was not activated under these conditions. By contrast, BODIPY FL C16 did not accumulate in the Golgi apparatus in EndoC-βH1 cells but, rather, co-localised with the lipid droplet-associated protein, PLIN2, suggesting preferential routing into lipid droplets. When INS-1 cells were treated with a combination of palmitate plus oleate, the toxic effects of palmitate were attenuated and BODIPY FL C16 localised primarily with PLIN2 but not with a Golgi marker.

Conclusion

In rodent β-cells, palmitate accumulates in the Golgi apparatus at early time points whereas, in EndoC- βH1 cells, it is routed preferentially into lipid droplets. This may account for the differential sensitivity of rodent vs human β-cells to “lipotoxicity” since manoeuvres leading to the incorporation of palmitate into lipid droplets is associated with the maintenance of cell viability in both cell types.
Venetoclax combinations delay the time to deterioration of HRQoL in unfit patients with acute myeloid leukemia
Authors: Pratz Keith W. , Panayiotidis Panayiotis , Recher Christian , Wei Xudong , Jonas Brian A. , Montesinos Pau , Ivanov Vladimir , Schuh Andre C. , DiNardo Courtney D. , Novak Jan , Pejsa Vlatko , Stevens Don , Yeh Su-Peng , Kim Inho , Turgut Mehmet , Fracchiolla Nicola , Yamamoto Kazuhito , Ofran Yishai , Wei Andrew H. , Bui Cat N. , Benjamin Katy , Kamalakar Rajesh , Potluri Jalaja , Mendes Wellington , Devine Jacob , Fiedler Walter
Published: April 2022

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P < 0.001). VEN + LDAC vs PBO + LDAC patients had significantly longer TTD in GHS/QoL (P = 0.011), PF (P = 0.020), and fatigue (P = 0.004), and a trend in HS-VAS (P = 0.057). Approximately 43%, 35%, 32%, and 18% of patients treated with VEN + AZA, AZA + PBO, VEN + LDAC, or LDAC + PBO, respectively, saw improvements >MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status.
p53 at the crossroad of DNA replication and ribosome biogenesis stress pathways
Authors: Lindström Mikael S. , Bartek Jiri , Maya-Mendoza Apolinar
Published: April 2022

Despite several decades of intense research focused on understanding function(s) and disease-associated malfunction of p53, there is no sign of any “mid-life crisis” in this rapidly advancing area of biomedicine. Firmly established as the hub of cellular stress responses and tumor suppressor targeted in most malignancies, p53’s many talents continue to surprise us, providing not only fresh insights into cell and organismal biology, but also new avenues to cancer treatment. Among the most fruitful lines of p53 research in recent years have been the discoveries revealing the multifaceted roles of p53-centered pathways in the fundamental processes of DNA replication and ribosome biogenesis (RiBi), along with cellular responses to replication and RiBi stresses, two intertwined areas of cell (patho)physiology that we discuss in this review. Here, we first provide concise introductory notes on the canonical roles of p53, the key interacting proteins, downstream targets and post-translational modifications involved in p53 regulation. We then highlight the emerging involvement of p53 as a key component of the DNA replication Fork Speed Regulatory Network and the mechanistic links of p53 with cellular checkpoint responses to replication stress (RS), the driving force of cancer-associated genomic instability. Next, the tantalizing, yet still rather foggy functional crosstalk between replication and RiBi (nucleolar) stresses is considered, followed by the more defined involvement of p53-mediated monitoring of the multistep process of RiBi, including the latest updates on the RPL5/RPL11/5 S rRNA-MDM2-p53-mediated Impaired Ribosome Biogenesis Checkpoint (IRBC) pathway and its involvement in tumorigenesis. The diverse defects of RiBi and IRBC that predispose and/or contribute to severe human pathologies including developmental syndromes and cancer are then outlined, along with examples of promising small-molecule-based strategies to therapeutically target the RS- and particularly RiBi- stress-tolerance mechanisms to which cancer cells are addicted due to their aberrant DNA replication, repair, and proteo-synthesis demands.
Artesunate improves venetoclax plus cytarabine AML cell targeting by regulating the Noxa/Bim/Mcl-1/p-Chk1 axis
Authors: Zhang Jingyi , Wang Yuetong , Yin Chujie , Gong Ping , Zhang Zhenwei , Zhao Linxiang , Waxman Samuel , Jing Yongkui
Published: April 2022

Venetoclax plus cytarabine therapy is approved for elderly acute myeloid leukemia (AML) patients and needs further improvement. We studied the mechanisms of venetoclax plus cytarabine treatment and searched for a third agent to enhance their effects. Cytarabine induces S phase arrest-mediated DNA damage with activation of DNA replication checkpoint kinase 1 (Chk1) through phosphorylation, while venetoclax induces B cell lymphoma 2 (Bcl-2)-interacting mediator of cell death (Bim)-mediated apoptotic DNA damage. Myeloid cell leukemia-1 (Mcl-1) plays negative roles in both events by sequestering Bim and accelerating Chk1 phosphorylation. Venetoclax releases Bim from Bcl-2 with increased Bim binding to Mcl-1. Artesunate, an antimalaria drug, induces Noxa to replace Bim from Mcl-1 and induces synergistic apoptosis with venetoclax accompanied with Mcl-1 reduction. Silencing Mcl-1 or adding venetoclax/artesunate diminishes the cytarabine resistance pathway p-Chk1. The triple combination exhibits S phase arrest with enhanced DNA damage, improves AML colony formation inhibition, and prolongs survival of two mice xenograft models compared to the venetoclax/cytarabine dual combination. Artesunate serves as a bridge for venetoclax and cytarabine combination by Noxa and Bim-mediated apoptosis and Mcl-1 reduction. We provide a new triple combination for AML treatment by targeting the Noxa/Mcl-1/Bim axis to reverse Mcl-1/p-Chk1 resistance of cytarabine therapy.
Mitochondrial oxidative phosphorylation is dispensable for survival of CD34+ chronic myeloid leukemia stem and progenitor cells
Authors: Yan Jin-Song , Yang Meng-Ying , Zhang Xue-Hong , Luo Chen-Hui , Du Cheng-Kan , Jiang Yue , Dong Xuan-Jia , Wang Zhang-Man , Yang Li-Xue , Li Yi-Dong , Xia Li , Lu Ying
Published: April 2022

Chronic myeloid leukemia (CML) are initiated and sustained by self-renewing malignant CD34+ stem cells. Extensive efforts have been made to reveal the metabolic signature of the leukemia stem/progenitor cells in genomic, transcriptomic, and metabolomic studies. However, very little proteomic investigation has been conducted and the mechanism regarding at what level the metabolic program was rewired remains poorly understood. Here, using label-free quantitative proteomic profiling, we compared the signature of CD34+ stem/progenitor cells collected from CML individuals with that of healthy donors and observed significant changes in the abundance of enzymes associated with aerobic central carbonate metabolic pathways. Specifically, CML stem/progenitor cells expressed increased tricarboxylic acid cycle (TCA) with decreased glycolytic proteins, accompanying by increased oxidative phosphorylation (OXPHOS) and decreased glycolysis activity. Administration of the well-known OXPHOS inhibitor metformin eradicated CML stem/progenitor cells and re-sensitized CD34+ CML cells to imatinib in vitro and in patient-derived tumor xenograft murine model. However, different from normal CD34+ cells, the abundance and activity of OXPHOS protein were both unexpectedly elevated with endoplasmic reticulum stress induced by metformin in CML CD34+ cells. The four major aberrantly expressed protein sets, in contrast, were downregulated by metformin in CML CD34+ cells. These data challenged the dependency of OXPHOS for CML CD34+ cell survival and underlined the novel mechanism of metformin. More importantly, it suggested a strong rationale for the use of tyrosine kinase inhibitors in combination with metformin in treating CML.
Vascular derived endothelin receptor A controls endothelin-induced retinal ganglion cell death
Authors: Marola Olivia J. , Howell Gareth R. , Libby Richard T.
Published: April 2022

Endothelin (EDN, also known as ET) signaling has been suggested to be an important mediator of retinal ganglion cell (RGC) death in glaucoma. Antagonism of EDN receptors (EDNRA and EDNRB, also known as ET-A and ET-B) prevented RGC death in mouse models of chronic ocular hypertension, and intravitreal injection of EDN ligand was sufficient to drive RGC death. However, it remains unclear which cell types EDN ligands directly affect to elicit RGC death. Multiple cell types in the retina and optic nerve express EDNRA and EDNRB and thus could respond to EDN ligands in the context of glaucoma. Here, we systematically deleted Edn receptors from specific cell types to identify the critical EDN receptor mediating RGC death in vivo. Deletion of both Ednra and Ednrb from retinal neurons (including RGCs) and macroglia did not prevent RGC loss after exposure to EDN1 ligands, suggesting EDN1 ligands cause RGC death via an indirect mechanism involving a secondary cell type. Deletion of Ednra from the full body, and then specifically from vascular mural cells, prevented EDN1-induced vasoconstriction and RGC death. Together, these data suggest EDN ligands cause RGC death via a mechanism initiated by vascular mural cells. It is possible RGC death is a consequence of vascular mural cell-induced vasoconstriction and its pathological sequelae. These results highlight the potential importance of neurovascular dysfunction in glaucoma.
Modulation of energy metabolism to overcome drug resistance in chronic myeloid leukemia cells through induction of autophagy
Authors: Li Yiqing , Zeng Peiting , Xiao Jie , Huang Peng , Liu Panpan
Published: April 2022

Tyrosine kinase inhibitors (TKIs) such as imatinib (IM) are key drugs for treatment of chronic myeloid leukemia (CML). Development of drug resistance to TKIs due to BCR-ABL mutation, especially T315I mutation, poses a major challenge in the clinical treatment of CML. The purpose of this study was to test metabolic modulation as a potential strategy to overcome imatinib resistance based on the possible crosstalk between BCR-ABL signaling and metabolic changes in CML. 2-deoxy-d-glucose (2-DG) was used to modulate the glucose metabolism in CML cells sensitive to IM (KBM5 cell line) and resistant to imatinib with BCR-ABL T315I mutation (KBM5-T315I cell line). Seahorse XFe24 extracellular flux analyzer to quantify oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was used to measure cellular energy metabolism. Cell proliferation was analyzed by CCK-8 assay and MTS assay. Annexin V/PI staining was used to evaluate cell apoptosis. Autophagy-related proteins and enzyme/proteins were detected by Western blotting. Cellular ATP concentration was detected using an ATP-based Cell Titer Kit. The combined action of 2-DG and IM was evaluated by calculating the drug combination index. Our results found that inhibition of glucose metabolism by 2-DG significantly impaired the viability of CML cells and co-treatment with 2-DG and imatinib induced a synergistic inhibition of KBM5 and KBM5-T315I cells. 2-DG induced cell death by autophagy, not by apoptosis, as evidenced by increased expression of Beclin1 and LC3AII and lack of annexin V/PI-positive cells. At the biochemical level, 2-DG inhibited glycolysis and mitochondrial oxygen consumption manifested by a significant decrease in ECAR and OCR, and a depletion of ATP. The severe metabolic stress induced by 2-DG in CML cells led to autophagic cell death. Our results suggested a metabolic vulnerability of CML cells that could be targeted by a combination of 2-DG and imatinib as an alternative treatment for imatinib-resistant CML.
RETRACTED ARTICLE: MIR600HG sponges miR-125a-5p to regulate glycometabolism and cisplatin resistance of oral squamous cell carcinoma cells via mediating RNF44
Authors: Liu Xingguang , Zhao Tengda , Yuan Zhe , Ge Shaohua
Published: April 2022

There is increasing evidence that dysregulated long non-coding RNA (lncRNA) is implicated in tumorigenesis and progression. We aim to explore the role of lncRNA MIR600HG in glycometabolism and cisplatin (DDP) resistance of oral squamous cell carcinoma (OSCC) cells via regulating microRNA-125a-5p (miR-125a-5p) and RING finger 44 (RNF44). Expression of MIR600HG, miR-125a-5p, and RNF44 in OSCC clinical samples, cell lines, and DDP-resistant OSCC cells (SCC-9/DDP) was determined. In SCC-9 cells, proliferation, IC50 value of DDP, migration, invasion, and apoptosis were detected; in SCC-9/DDP cells, proliferation, IC50 value of DDP, apoptosis, glucose consumption, and production of lactic acid and ATP were evaluated. The interaction of MR600HG, miR-125a-5p, and RNF44 was verified. MIR600HG and RNF44 were upregulated while miR-125a-5p was downregulated in OSCC tissues and cell lines, and also in SCC-9/DDP cells. In SCC-9 cells, MIR600HG overexpression improved cell growth, metastasis, and inhibited cell susceptibility to DDP; in SCC-9/DDP cells, silencing of MIR600HG promoted apoptosis, improved DDP sensitivity, and inhibited cell glycolysis. Downregulation of miR-125a-5p showed the opposite effect to downregulation of MIR600HG. MIR600HG bound to miR-125a-5p and miR-125a-5p targeted RNF44. Downregulation of miR-125a-5p reversed the improvement of DDP sensitivity and the inhibition of cell glycolysis by downregulated MIR600HG on SCC-9/DDP cells. Downregulating RNF44 reversed the promotion of DDP resistance and cell glycolysis of SCC-9/DDP cells mediated by downregulation of miR-125a-5p. Collectively, our study addresses that MIR600HG downregulation elevates miR-125a-5p and reduces RNF44 expression, thereby improving DDP sensitivity and inhibiting glycolysis in DDP-resistant OSCC cells.
The BCL-2 inhibitor ABT-199/venetoclax synergizes with proteasome inhibition via transactivation of the MCL-1 antagonist NOXA
Authors: Weller Sandra , Toennießen Astrid , Schaefer Benjamin , Beigl Tobias , Muenchow Alina , Böpple Kathrin , Hofmann Ute , Gillissen Bernhard F. , Aulitzky Walter E. , Kopp Hans-Georg , Essmann Frank
Published: April 2022

Enhanced expression of anti-apoptotic B-cell lymphoma 2 (BCL-2) protein is frequent in cancer. Targeting of BCL-2 with the specific inhibitor ABT-199 (Venetoclax) has significant clinical activity in malignant diseases such as chronic lymphocytic leukemia and multiple myeloma. The small molecule drug ABT-199 mimics the pro-apoptotic BCL-2 homology domain 3 of BH3-only proteins and blocks the hydrophobic BC-groove in BCL-2. We have previously shown that ABT-199 synergizes with the proteasome inhibitor (PI) bortezomib in soft tissue sarcoma derived cells and cell lines to induce apoptosis. Synergistic apoptosis induction relies on the pore-forming effector BAX and expression of the pro-apoptotic BH3-only protein NOXA. Bortezomib augments expression of NOXA by blocking its proteasomal degradation. Interestingly, shown here for the first time, expression of NOXA is strongly enhanced by ABT-199 induced integrated stress response (ISR). ISR transcription factors ATF3 & ATF4 mediate transactivation of the BH3-only protein NOXA which specifically inhibits the anti-apoptotic MCL-1. Thus, NOXA potentiates the efficacy of the BCL-2 inhibitor ABT-199 by simultaneous inhibition of MCL-1. Hence, ABT-199 has a double impact by directly blocking anti-apoptotic BCL-2 and inhibiting MCL-1 via transactivated NOXA. By preventing degradation of NOXA PIs synergize with ABT-199. Synergism of ABT-199 and PIs therefore occurs on several, previously unexpected levels. This finding should prompt clinical evaluation of combinatorial regimens in further malignancies.
Hippo signaling pathway and respiratory diseases
Authors: Tang Weifeng , Li Min , Yangzhong Xiaoting , Zhang Xifeng , Zu Anju , Hou Yunjiao , Li Lin , Sun Shibo
Published: April 2022

The hippo signaling pathway is a highly conserved evolutionary signaling pathway that plays an important role in regulating cell proliferation, organ size, tissue development, and regeneration. Increasing evidences consider that the hippo signaling pathway is involved in the process of respiratory diseases. Hippo signaling pathway is mainly composed of mammalian STE20-like kinase 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), WW domain of the Sav family containing protein 1 (SAV1), MOB kinase activator 1 (MOB1), Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ), and members of the TEA domain (TEAD) family. YAP is the cascade effector of the hippo signaling pathway. The activation of YAP promotes pulmonary arterial vascular smooth muscle cells (PAVSMCs) proliferation, which leads to pulmonary vascular remodeling; thereby the pulmonary arterial hypertension (PAH) is aggravated. While the loss of YAP leads to high expression of inflammatory genes and the accumulation of inflammatory cells, the pneumonia is consequently exacerbated. In addition, overexpressed YAP promotes the proliferation of lung fibroblasts and collagen deposition; thereby the idiopathic pulmonary fibrosis (IPF) is promoted. Moreover, YAP knockout reduces collagen deposition and the senescence of adult alveolar epithelial cells (AECs); hence the IPF is slowed. In addition, hippo signaling pathway may be involved in the repair of acute lung injury (ALI) by promoting the proliferation and differentiation of lung epithelial progenitor cells and intervening in the repair of pulmonary capillary endothelium. Moreover, the hippo signaling pathway is involved in asthma. In conclusion, the hippo signaling pathway is involved in respiratory diseases. More researches are needed to focus on the molecular mechanisms by which the hippo signaling pathway participates in respiratory diseases.
Tension can directly suppress Aurora B kinase-triggered release of kinetochore-microtubule attachments
Authors: de Regt Anna K. , Clark Cordell J. , Asbury Charles L. , Biggins Sue
Published: April 2022

Chromosome segregation requires sister kinetochores to attach microtubules emanating from opposite spindle poles. Proper attachments come under tension and are stabilized, but defective attachments lacking tension are released, giving another chance for correct attachments to form. This error correction process depends on Aurora B kinase, which phosphorylates kinetochores to destabilize their microtubule attachments. However, the mechanism by which Aurora B distinguishes tense versus relaxed kinetochores remains unclear because it is difficult to detect kinase-triggered detachment and to manipulate kinetochore tension in vivo. To address these challenges, we apply an optical trapping-based assay using soluble Aurora B and reconstituted kinetochore-microtubule attachments. Strikingly, the tension on these attachments suppresses their Aurora B-triggered release, suggesting that tension-dependent changes in the conformation of kinetochores can regulate Aurora B activity or its outcome. Our work uncovers the basis for a key mechano-regulatory event that ensures accurate segregation and may inform studies of other mechanically regulated enzymes.
High-throughput production of functional prototissues capable of producing NO for vasodilation
Authors: Zhang Xiangxiang , Li Chao , Liu Fukai , Mu Wei , Ren Yongshuo , Yang Boyu , Han Xiaojun
Published: April 2022

Bottom-up synthesis of prototissues helps us to understand the internal cellular communications in the natural tissues and their functions, as well as to improve or repair the damaged tissues. The existed prototissues are rarely used to improve the function of living tissues. We demonstrate a methodology to produce spatially programmable prototissues based on the magneto-Archimedes effect in a high-throughput manner. More than 2000 prototissues are produced once within 2 h. Two-component and three-component spatial coded prototissues are fabricated by varying the addition giant unilamellar vesicles order/number, and the magnetic field distributions. Two-step and three-step signal communications in the prototissues are realized using cascade enzyme reactions. More importantly, the two-component prototissues capable of producing nitric oxide cause vasodilation of rat blood vessels in the presence of glucose and hydroxyurea. The tension force decreases 2.59 g, meanwhile the blood vessel relaxation is of 31.2%. Our works pave the path to fabricate complicated programmable prototissues, and hold great potential in the biomedical field.
Symmetry collapse due to the presence of multiple local aromaticity in Ge244−
Authors: Xu Hong-Lei , Tkachenko Nikolay V. , Szczepanik Dariusz W. , Popov Ivan A. , Muñoz-Castro Alvaro , Boldyrev Alexander I. , Sun Zhong-Ming
Published: April 2022

Understanding the structural changes taking place during the assembly of single atoms leading to the formation of atomic clusters and bulk materials remains challenging. The isolation and theoretical characterization of medium-sized clusters can shed light on the processes that occur during the transition to a solid-state structure. In this work, we synthesize and isolate a continuous 24-atom cluster Ge244−, which is characterized by X-ray diffraction analysis and Energy-dispersive X-ray spectroscopy, showing an elongated structural characteristic. Theoretical analysis reveals that electron delocalization plays a vital role in the formation and stabilization of the prolate cluster. In contrast with carbon atoms, 4 s orbitals of Ge-atoms do not easily hybridize with 4p orbitals and s-type lone-pairs can be localized with high occupancy. Thus, there are not enough electrons to form a stable symmetrical fullerene-like structure such as C24 fullerene. Three aromatic units with two [Ge9] and one [Ge6] species, connected by classical 2c-2e Ge-Ge σ-bonds, are aligned together forming three independent shielding cones and eventually causing a collapse of the global symmetry of the Ge244− cluster.
Unlocking bimetallic active sites via a desalination strategy for photocatalytic reduction of atmospheric carbon dioxide
Authors: Feng Xuezhen , Zheng Renji , Gao Caiyan , Wei Wenfei , Peng Jiangguli , Wang Ranhao , Yang Songhe , Zou Wensong , Wu Xiaoyong , Ji Yongfei , Chen Hong
Published: April 2022

Ultrathin two-dimensional (2D) metal oxyhalides exhibit outstanding photocatalytic properties with unique electronic and interfacial structures. Compared with monometallic oxyhalides, bimetallic oxyhalides are less explored. In this work, we have developed a novel top-down wet-chemistry desalination approach to remove the alkali-halide salt layer within the complicated precursor bulk structural matrix Pb0.6Bi1.4Cs0.6O2Cl2, and successfully fabricate a new 2D ultrathin bimetallic oxyhalide Pb0.6Bi1.4O2Cl1.4. The unlocked larger surface area, rich bimetallic active sites, and faster carrier dynamics within Pb0.6Bi1.4O2Cl1.4 layers significantly enhance the photocatalytic efficiency for atmospheric CO2 reduction. It outperforms the corresponding parental matrix phase and other state-of-the-art bismuth-based monometallic oxyhalides photocatalysts. This work reports a top-down desalination strategy to engineering ultrathin bimetallic 2D material for photocatalytic atmospheric CO2 reduction, which sheds light on further constructing other ultrathin 2D catalysts for environmental and energy applications from similar complicate structure matrixes.
Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183
Authors: de Vries Laura E. , Jansen Patrick A. M. , Barcelo Catalina , Munro Justin , Verhoef Julie M. J. , Pasaje Charisse Flerida A. , Rubiano Kelly , Striepen Josefine , Abla Nada , Berning Luuk , Bolscher Judith M. , Demarta-Gatsi Claudia , Henderson Rob W. M. , Huijs Tonnie , Koolen Karin M. J. , Tumwebaze Patrick K. , Yeo Tomas , Aguiar Anna C. C. , Angulo-Barturen Iñigo , Churchyard Alisje , Baum Jake , Fernández Benigno Crespo , Fuchs Aline , Gamo Francisco-Javier , Guido Rafael V. C. , Jiménez-Diaz María Belén , Pereira Dhelio B. , Rochford Rosemary , Roesch Camille , Sanz Laura M. , Trevitt Graham , Witkowski Benoit , Wittlin Sergio , Cooper Roland A. , Rosenthal Philip J. , Sauerwein Robert W. , Schalkwijk Joost , Hermkens Pedro H. H. , Bonnert Roger V. , Campo Brice , Fidock David A. , Llinás Manuel , Niles Jacquin C. , Kooij Taco W. A. , Dechering Koen J.
Published: April 2022

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.