bluuebunny/crossref_metadata_2025 huggingface dataset:
Adolescent gaming and social media usage before and during the COVID-19 pandemic
Authors: Paschke Kerstin , Austermann Maria Isabella , Simon-Kutscher Kathrin , Thomasius Rainer
Published: February 2021

Abstract. Background: The COVID-19 pandemic has raised concerns about a potential increase of addictive behaviors. Adolescents are considered particularly vulnerable to a problematic usage of digital applications. For the first systematic investigation of screen time and problematic usage patterns over the course of the pandemic, a pre-pandemic survey on adolescent social media (SM) and gaming use was extended to a longitudinal study. Here we present the results of the first two measurements points (pre-pandemic/under lockdown). Methods: A representative sample of 1,221 adolescents (10–17 years) participated in an online survey in 09/2019, 824 of them in 04/2020. Prevalence rates were measured at baseline with standardized scales covering ICD-11 criteria for problematic usage patterns. These were statistically compared and related to pre- and under-lockdown screen time. Results: Pre-pandemic prevalence rates for pathological SM/gaming were about 3 % each, for at-risk usage 8–10 % including more boys than girls. Usage frequencies and screen times significantly increased under the lockdown. The predictive value of usage patterns for screen time decreased from before to during the lockdown. Changes in screen time could not be predicted by the usage pattern. Discussion: The stability of the observed rates and effects should be further examined over the course of the pandemic. This will lead to relevant implications for prevention measures and the allocation of intervention resources.
Massacre, Earthquake, Flood
Authors: Rucklidge Julia J. , Afzali M. Usman , Kaplan Bonnie J. , Bhattacharya Oindrila , Blampied F. Meredith , Mulder Roger T. , Blampied Neville M.
Published: February 2021

Abstract. Natural (e.g., earthquake, flood, wildfires) and human-made (e.g., terrorism, civil strife) disasters are inevitable, can cause extensive disruption, and produce chronic and disabling psychological injuries leading to formal diagnoses (e.g., post-traumatic stress disorder [PTSD]). Following natural disasters of earthquake (Christchurch, Aotearoa/New Zealand, 2010–11) and flood (Calgary, Canada, 2013), controlled research showed statistically and clinically significant reductions in psychological distress for survivors who consumed minerals and vitamins (micronutrients) in the following months. Following a mass shooting in Christchurch (March 15, 2019), where a gunman entered mosques during Friday prayers and killed and injured many people, micronutrients were offered to survivors as a clinical service based on translational science principles and adapted to be culturally appropriate. In this first translational science study in the area of nutrition and disasters, clinical results were reported for 24 clients who completed the Impact of Event Scale – Revised (IES-R), the Depression Anxiety Stress Scales (DASS), and the Modified-Clinical Global Impression (M-CGI-I). The findings clearly replicated prior controlled research. The IES-R Cohen’s d ESs were 1.1 (earthquake), 1.2 (flood), and 1.13 (massacre). Effect sizes (ESs) for the DASS subscales were also consistently positive across all three events. The M-CGI-I identified 58% of the survivors as “responders” (i.e., self-reported as “much” to “very much” improved), in line with those reported in the earthquake (42%) and flood (57%) randomized controlled trials, and PTSD risk reduced from 75% to 17%. Given ease of use and large ESs, this evidence supports the routine use of micronutrients by disaster survivors as part of governmental response.
Syrian Refugee Access to and Quality of Healthcare in Turkey
Authors: Chen En Chi
Published: February 2021

Abstract. Although Turkey affirms the right to health regardless of citizenship status, as defined by the Declaration of Human Rights, there are gaps in the legislation and administration regarding the conditions for which an individual must fulfill as a Syrian refugee to access healthcare in Turkey ( Mardin, 2017 ). One of the greatest healthcare access barriers is not gaining status under the temporary protection regulation (TPR) as a Syrian refugee ( Mardin, 2017 ). Even after gaining status under the TPR, individuals are bound to the city in which they have registered and are designated, outside of which they are ineligible for healthcare ( Mardin, 2017 ). This limits the autonomy of the individual when making appropriate resettlement decisions within Turkey. This process also poses an additional burden on healthcare professionals to act as healthcare access “gatekeeper” ( Mardin, 2017 ). This policy brief seeks to outline both the challenges Syrian refugees face in accessing quality healthcare in Turkey and provide reformation suggestions to allow for a more streamlined approach. Furthermore, suggestions are made with consideration of lessening the burden of Turkey’s healthcare system as the host country.
Lithospheric Formation and Evolution of Eastern North American Continent
Authors: Gao Haiying , Li Cong
Published: February 2021

Lithospheric layering contains critical information about continental formation and evolution. However, discrepancies on the depth distributions of lithospheric layers have significantly limited our understanding of possible tectonic connections among the layers. Here, we construct a high‐resolution shear velocity model of eastern North America using full‐wave ambient noise simulation and inversion by integrating onshore and offshore seismic datasets. Our new model reveals large lateral variations of lithosphere thickness approximately across the major tectonic boundaries, strong low‐velocity anomalies underlying the thinner lithosphere, and multiple low‐velocity layers within the continental lithosphere. We suggest that the present mantle lithosphere beneath eastern North America was formed and modified through multiple stages of tectonic processes, among which metasomatism may have significantly contributed to the observed intralithospheric low‐velocity layers. The sharp thickness variation of lithosphere promoted edge‐driven mantle convection, which has been consequently modifying the overlying mantle lithosphere and further sharpening the gradient of lithosphere thickness
Frequent Polarity Reversals in the Cretaceous Normal Superchron
Authors: Zhang Dawen , Yan Maodu , Song Chunhui , Zhang Weilin , Fang Xiaomin , Li Bingshuai
Published: February 2021

The Cretaceous Normal Superchron (CNS), defined as a magnetic quiet zone spanning from ∼126 to ∼84 Myr, is often used to understand the Earth’s geodynamo processes. However, whether there were polarity reversals within the CNS remains contentious. This paper presents the youngest detrital zircon U‐Pb age‐constrained magnetostratigraphic study of the Cretaceous Khorat Group for two sections (i.e., Ban Phonngam (BP) and Ban Nongpen (BN)) in Vientiane, Laos. Both sections are characterized by the prominent long normal‐polarity zones that are correlated to the CNS. Interestingly, six (four) short primary reversed horizons were identified within the BP (BN) section. Integrated with other reported reversed events, there likely at least five globally and two single reported reversed‐polarity events or clusters of events have happened within the CNS. The confirmation of frequent reversed polarities within the two parallel sections will provide a new comprehensive understanding of the Earth’s geodynamic behavior during the CNS.
Direct Observational Evidence of the Simultaneous Excitation of Electromagnetic Ion Cyclotron Waves and Magnetosonic Waves by an Anisotropic Proton Ring Distribution
Authors: Teng S. , Liu N. , Ma Q. , Tao X. , Li W.
Published: February 2021

Magnetosonic (MS) waves and electromagnetic ion cyclotron (EMIC) waves are two important plasma wave modes in the magnetosphere. Previous simulations have shown that both waves could be generated by a ring‐like proton distribution, while direct observational evidence has yet to be reported. Here, we present simultaneous observations of MS and EMIC waves and a detailed case analysis. The linear growth rates estimated for both waves are in good agreement with the observed wave frequency spectra. The measured proton distribution evolution is also compared with the simulation results, providing direct observational evidence for the previous theoretical prediction that anisotropic ring‐like proton distributions could excite MS and EMIC waves simultaneously. Our findings are crucial for understanding the generation mechanisms of and relation between MS and EMIC waves and for evaluating their combined effects on energetic electron and ion dynamics.
The Importance of Scale‐Dependent Groundwater Processes in Land‐Atmosphere Interactions Over the Central United States
Authors: Barlage Michael , Chen Fei , Rasmussen Roy , Zhang Zhe , Miguez‐Macho Gonzalo
Published: February 2021

This study explores the impacts of groundwater processes on the simulated land‐surface water balance and hydrometeorology. Observations are compared to multiscale Weather Research and Forecasting (WRF) simulations of three summer seasons: 2012, 2013, and 2014. Results show that a grid spacing of 3 km or smaller is necessary to capture small‐scale river and stream networks and associated shallow water tables, which supplies additional root‐zone water double that of simulations with 9‐km and 27‐km grid spacing and is critical to replenishing the depleted vegetation root zones and leads to 150 mm more evapotranspiration. Including groundwater processes in convection‐permitting models is effective to reduce: (1) 2‐m temperature warm biases from 5–6 to 2–3 °C and (2) the low precipitation bias by half. The additional groundwater supply to active soil flux in convection‐permitting simulations with groundwater for June‐August is nearly translated into the same amount of increased precipitation in the domain investigated.
Regional Drought Risk in the Contiguous United States
Authors: Apurv Tushar , Cai Ximing
Published: February 2021

In this study, we provide an outlook for regional drought risk in the contiguous US (CONUS) in the near future based on ongoing drought trends, and assess its impacts on soil moisture, streamflow, and water supply in different regions. It is found that the meteorological drought risk has been decreasing in northern parts of the CONUS and increasing in the Southwest and Southeast United States (US). In the Southwest US, droughts are associated with severe deficits in soil moisture and streamflow, which can adversely affect ecosystems in the region. Meanwhile, droughts are expected to have severe impacts on water supply and agriculture in the Southeast US due to increasing water demand, limited storage capacity, and predominantly rainfed agriculture in the region. The study shows that the impacts of droughts on natural and human systems are influenced by nonlinearity of the drought propagation process and vary significantly across regions in the CONUS.
Source Apportionment of Regional Ozone Pollution Observed at Mount Tai, North China: Application of Lagrangian Photochemical Trajectory Model and Implications for Control Policy
Authors: Zhang Yingnan , Xue Likun , Li Hongyong , Chen Tianshu , Mu Jiangshan , Dong Can , Sun Lei , Liu Hengde , Zhao Yong , Wu Di , Wang Xinfeng , Wang Wenxing
Published: February 2021

To better understand the characteristics and trace the sources of regional ozone (O3) in the North China Plain (NCP), we analyzed 1‐year continuous observations obtained at Mount Tai in 2018 and compared with previous data from 2006–2009. In the warm seasons (April–September), O3 pollution (defined as a maximum daily 8‐h average O3 mixing ratio that exceeds 75 ppbv) occurred frequently (59%–92% of days) and O3 concentrations significantly increased (especially in July–September) from 2006–2009 to 2018. We applied the Lagrangian photochemical trajectory model, built on the coupling of the Lagrangian backward trajectory model and Master Chemical Mechanism box model, to identify the source regions, key precursors, and emission sectors. The NCP was identified as the major source region with an average contribution of 74% ± 27% to the regional O3 concentrations during the O3 episodes in April–September. Regional O3 formation was highly NOx‐sensitive in air masses traveling from the southern part of the NCP but limited by anthropogenic hydrocarbons (especially alkenes) in air masses from the northern part of the NCP. The reduction of emissions from transportation and industry sectors would significantly reduce the regional O3 concentrations. Biomass burning also exerts a significant influence on regional O3 concentrations under certain circumstances. This study demonstrates that the regional background O3 at mountaintop levels is a good indicator of surface O3 pollution over a wide spatial coverage, and provides guidance for regional collaboration on emission control to mitigate photochemical air pollution over the NCP.
Home blood pressure monitors owned by participants in a large decentralised clinical trial in hypertension: the Treatment In Morning versus Evening (TIME) study
Authors: Anbarasan Thineskrishna , Rogers Amy , Rorie David A. , Kerr Grieve J. W. , MacDonald Thomas M. , Mackenzie Isla S.
Published: February 2021

Various home blood pressure monitors (HBPMs) are available to the public for purchase but only some are validated against standardised protocols. This study aimed to assess whether HBPMs owned by participants taking part in a clinical trial were validated models. The TIME study is a decentralised randomised trial investigating the effect of antihypertensive medication dosing time on cardiovascular outcomes in adults with hypertension. No HBPMs were provided to participants in this trial but patients were asked to report if they already owned one. We identified the model of HBPM reported by participants, then cross-referenced this against lists of validated HBPMs produced by dabl Educational Trust and the British and Irish Hypertension Society (BIHS). Of 21,104 participants, 10,464 (49.6%) reported their model of HBPM. 7464 (71.3%) of these participants owned a monitor that could be identified from the participants’ entry. Of these, 6066 (81.3%) participants owned a monitor listed as validated by either dabl (n = 5903) or BIHS (n = 5491). Some were listed as validated by both. 1398 (18.7%) participants owned an identifiable HBPM that lacked clear evidence of validation. 6963 (93.3%) participants owned an upper arm HBPM and 501 (6.7%) owned a wrist HBPM. Validated HBPMs had a higher median online retail price of £45.00 compared to £20.00 for HBPMs lacking clear evidence of validation. A significant number of participants own HBPMs lacking evidence of validation.
Latent brain state dynamics distinguish behavioral variability, impaired decision-making, and inattention
Authors: Cai Weidong , Warren Stacie L. , Duberg Katherine , Pennington Bruce , Hinshaw Stephen P. , Menon Vinod
Published: February 2021

Children with Attention Deficit Hyperactivity Disorder (ADHD) have prominent deficits in sustained attention that manifest as elevated intra-individual response variability and poor decision-making. Influential neurocognitive models have linked attentional fluctuations to aberrant brain dynamics, but these models have not been tested with computationally rigorous procedures. Here we use a Research Domain Criteria approach, drift-diffusion modeling of behavior, and a novel Bayesian Switching Dynamic System unsupervised learning algorithm, with ultrafast temporal resolution (490 ms) whole-brain task-fMRI data, to investigate latent brain state dynamics of salience, frontoparietal, and default mode networks and their relation to response variability, latent decision-making processes, and inattention. Our analyses revealed that occurrence of a task-optimal latent brain state predicted decreased intra-individual response variability and increased evidence accumulation related to decision-making. In contrast, occurrence and dwell time of a non-optimal latent brain state predicted inattention symptoms and furthermore, in a categorical analysis, distinguished children with ADHD from controls. Importantly, functional connectivity between salience and frontoparietal networks predicted rate of evidence accumulation to a decision threshold, whereas functional connectivity between salience and default mode networks predicted inattention. Taken together, our computational modeling reveals dissociable latent brain state features underlying response variability, impaired decision-making, and inattentional symptoms common to ADHD. Our findings provide novel insights into the neurobiology of attention deficits in children.
Clinical significance of STEAP1 extracellular vesicles in prostate cancer
Authors: Khanna Karan , Salmond Nikki , Lynn Kalan S. , Leong Hon S. , Williams Karla C.
Published: February 2021

Background

Extracellular vesicles (EVs) are cell-derived lipid bilayer enclosed structures shed from the plasma membrane by all cell types. Evidence of EV presence in biological fluids has led to considerable efforts focused on identifying their cargo and determining their utility as a non-invasive diagnostic platform for cancer. In this study, we identify circulating STEAP1 (six-transmembrane epithelial antigen of the prostate 1)-positive EVs in the plasma of healthy males and prostate cancer patients and evaluate its diagnostic and prognostic significance.

Methods

STEAP1 was identified on EVs in prostate cancer patient plasma. EVs were validated using electron microscopy, Western blot, nanoparticle tracking analysis, and nanoscale flow cytometry. STEAP1-positive EVs were quantified for 121 males with prostate cancer and 55 healthy age-matched control males. An evaluation of STEAP1 in prostate cancer tissue was also performed using established prostate cancer cohort data (TCGA, MSKCC, and SU2C/PCF Dream Team).

Results

Evaluation of STEAP1-positive EVs by nanoscale flow cytometry identified a significant increase in prostate cancer patient plasma compared to healthy males. However, no association was found between total STEAP1 EV levels and disease recurrence or overall survival. Cohort data from prostate cancer tissue also found STEAP1 to be elevated in prostate cancer while no significant association with recurrence or overall survival was identified.

Conclusions

STEAP1 is known to be enriched on the cells of the prostate with potential clinical significance in prostate cancer. Our results identify and quantitate STEAP1-positive EVs in plasma and provide rationale for a STEAP1 EV-based liquid biopsy as a diagnostic strategy in prostate cancer.
Impact of family history on oncological outcomes in primary therapy for localized prostate cancer patients: a systematic review and meta-analysis
Authors: Urabe Fumihiko , Kimura Shoji , Yamamoto Shutaro , Tashiro Kojiro , Kimura Takahiro , Egawa Shin
Published: February 2021

Background

The influence of family history on oncological outcomes of prostate cancer remains controversial. We conducted a systematic literature review and meta-analysis to investigate the impact of family history of localized prostate cancer on oncological outcomes.

Methods

On May 2020, we systematically searched MEDLINE, the Cochrane library, and Scopus for studies that compared patients who had localized prostate cancer with or without a positive family history of prostate cancer. Our aim was to evaluate the association of family history with biochemical recurrence-free survival, cancer-specific survival, and overall survival by means of a multivariate Cox regression analysis.

Results

Eleven studies with 39,716 patients were included in the systematic review, and eight studies with 33,027 patients for the meta-analysis. A positive family history was not associated with worse biochemical recurrence-free survival (pooled HR: 0.96; 95% CI: 0.79–1.17) or cancer-specific survival (pooled HR: 1.1; 95% CI: 0.52–2.35). Subgroup analyses showed no association between positive family history and poor biochemical recurrence-free survival in prostate cancer patients treated with radical prostatectomy (pooled HR: 0.99; 95% CI: 0.76–1.31) or radiation therapy (pooled HR: 0.93; 95% CI: 0.67–1.30).

Conclusions

This meta-analysis indicated that family history of prostate cancer does not increase the risk of biochemical recurrence or cancer-specific mortality in localized prostate cancer patients.
Resolving cryptic species complexes in marine protists: phylogenetic haplotype networks meet global DNA metabarcoding datasets
Authors: De Luca Daniele , Piredda Roberta , Sarno Diana , Kooistra Wiebe H C F
Published: February 2021

Marine protists have traditionally been assumed to be lowly diverse and cosmopolitan. Yet, several recent studies have shown that many protist species actually consist of cryptic complexes of species whose members are often restricted to particular biogeographic regions. Nonetheless, detection of cryptic species is usually hampered by sampling coverage and application of methods (e.g. phylogenetic trees) that are not well suited to identify relatively recent divergence and ongoing gene flow. In this paper, we show how these issues can be overcome by inferring phylogenetic haplotype networks from global metabarcoding datasets. We use the Chaetoceros curvisetus (Bacillariophyta) species complex as study case. Using two complementary metabarcoding datasets (Ocean Sampling Day and Tara Oceans), we equally resolve the cryptic complex in terms of number of inferred species. We detect new hypothetical species in both datasets. Gene flow between most of species is absent, but no barcoding gap exists. Some species have restricted distribution patterns whereas others are widely distributed. Closely related taxa occupy contrasting biogeographic regions, suggesting that geographic and ecological differentiation drive speciation. In conclusion, we show the potential of the analysis of metabarcoding data with evolutionary approaches for systematic and phylogeographic studies of marine protists.
Interspecies bacterial competition regulates community assembly in the C. elegans intestine
Authors: Ortiz Anthony , Vega Nicole M , Ratzke Christoph , Gore Jeff
Published: February 2021

From insects to mammals, a large variety of animals hold in their intestines complex bacterial communities that play an important role in health and disease. To further our understanding of how intestinal bacterial communities assemble and function, we study the C. elegans microbiota with a bottom-up approach by feeding this nematode with bacterial monocultures as well as mixtures of two to eight bacterial species. We find that bacteria colonizing well in monoculture do not always do well in co-cultures due to interspecies bacterial interactions. Moreover, as community diversity increases, the ability to colonize the worm gut in monoculture becomes less important than interspecies interactions for determining community assembly. To explore the role of host–microbe adaptation, we compare bacteria isolated from C. elegans intestines and non-native isolates, and we find that the success of colonization is determined more by a species’ taxonomy than by the isolation source. Lastly, by comparing the assembled microbiotas in two C. elegans mutants, we find that innate immunity via the p38 MAPK pathway decreases bacterial abundances yet has little influence on microbiota composition. These results highlight that bacterial interspecies interactions, more so than host–microbe adaptation or gut environmental filtering, play a dominant role in the assembly of the C. elegans microbiota.
Balance between promiscuity and specificity in phage λ host range
Authors: Andrews Bryan , Fields Stanley
Published: February 2021

As hosts acquire resistance to viruses, viruses must overcome that resistance to re-establish infectivity, or go extinct. Despite the significant hurdles associated with adapting to a resistant host, viruses are evolutionarily successful and maintain stable coevolutionary relationships with their hosts. To investigate the factors underlying how pathogens adapt to their hosts, we performed a deep mutational scan of the region of the λ tail fiber tip protein that mediates contact with the receptor on λ’s host, Escherichia coli. Phages harboring amino acid substitutions were subjected to selection for infectivity on wild type E. coli, revealing a highly restrictive fitness landscape, in which most substitutions completely abrogate function. A subset of positions that are tolerant of mutation in this assay, but diverse over evolutionary time, are associated with host range expansion. Imposing selection for phage infectivity on three λ-resistant hosts, each harboring a different missense mutation in the λ receptor, reveals hundreds of adaptive variants in λ. We distinguish λ variants that confer promiscuity, a general ability to overcome host resistance, from those that drive host-specific infectivity. Both processes may be important in driving adaptation to a novel host.
Identification of a long non-coding RNA regulator of liver carcinoma cell survival
Authors: Rybakova Yulia , Gonzalez John T. , Bogorad Roman , Chauhan Vikash P. , Dong Yize L. , Whittaker Charles A. , Zatsepin Timofei , Koteliansky Victor , Anderson Daniel G.
Published: February 2021

Genomic studies have significantly improved our understanding of hepatocellular carcinoma (HCC) biology and have led to the discovery of multiple protein-coding genes driving hepatocarcinogenesis. In addition, these studies have identified thousands of new non-coding transcripts deregulated in HCC. We hypothesize that some of these transcripts may be involved in disease progression. Long non-coding RNAs are a large class of non-coding transcripts which participate in the regulation of virtually all cellular functions. However, a majority of lncRNAs remain dramatically understudied. Here, we applied a pooled shRNA-based screen to identify lncRNAs essential for HCC cell survival. We validated our screening results using RNAi, CRISPRi, and antisense oligonucleotides. We found a lncRNA, termed ASTILCS, that is critical for HCC cell growth and is overexpressed in tumors from HCC patients. We demonstrated that HCC cell death upon ASTILCS knockdown is associated with apoptosis induction and downregulation of a neighboring gene, protein tyrosine kinase 2 (PTK2), a crucial protein for HCC cell survival. Taken together, our study describes a new, non-coding RNA regulator of HCC.
SChLAP1 promotes prostate cancer development through interacting with EZH2 to mediate promoter methylation modification of multiple miRNAs of chromosome 5 with a DNMT3a-feedback loop
Authors: Huang Kai , Tang Yuxin
Published: February 2021

This study aimed to investigate the mechanism of SChLAP1 (second chromosome locus associated with prostate-1) on microRNA expression in prostate cancer. Differential expression of lncRNAs and microRNA prostate cancer cells were predicted by informatics and confirmed by qRT-PCR. SChLAP1-interacting proteins were characterized by RNA pull-down combined with western blotting, which was verified using RIP and qPCR analysis. Then ChIP assay and DNA pull-down were used to validate the binding of DNMT3a and HEK27me3 with miRNA gene promoters. Target genes of miRNAs were bioinformatically predicted and validated by dual-luciferase reporter assays. The tumorigenicity of prostate cancer cells was assessed using the cancer cell line-based xenograft (CDX) model. We found that SChLAP1 expression was significantly elevated in prostate cancer tissues and cell lines, which was negatively correlated with miR-340 expression. SChLAP1 directly binds with EZH2 and repressed multiple miRNA expression on chromosome 5 including the miR-340-3p in prostate cancer cells through recruiting H3K27me3 to mediate promoter methylation modification of miR-340-5p/miR-143-3p/miR-145-5p to suppress gene transcription. Moreover, DNMT3a was one of the common target genes of miR-340-5p/miR-143-3p/miR-145-5p in prostate cancer cells. And SChLAP1/EZH2 could also promote prostate cancer tumor development via the interaction of microRNA-DNMT3a signaling pathways in xenograft nude mice. Altogether, our results suggest that SChLAP1 enhanced the proliferation, migration, and tumorigenicity of prostate cancer cells through interacting with EZH2 to recruit H2K27me3 and mediate promoter methylation modification of miR-340-5p/miR-143-3p/miR-145-5p with a DNMT3a-feedback loop.
TOM20-mediated transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis
Authors: Lalier Lisenn , Mignard Vincent , Joalland Marie-Pierre , Lanoé Didier , Cartron Pierre-François , Manon Stéphen , Vallette François M.
Published: February 2021

In this work, we have explored the subcellular localization of Bcl2, a major antiapoptotic protein. In U251 glioma cells, we found that Bcl2 is localized mainly in the ER and is translocated to MAM and mitochondria upon induction of apoptosis; this mitochondrial transfer was not restricted to the demonstrator cell line, even if cell-specific modulations exist. We found that the Bcl2/mitochondria interaction is controlled by TOM20, a protein that belongs to the protein import machinery of the mitochondrial outer membrane. The expression of a small domain of interaction of TOM20 with Bcl2 potentiates its anti-apoptotic properties, which suggests that the Bcl2–TOM20 interaction is proapoptotic. The role of MAM and TOM20 in Bcl2 apoptotic mitochondrial localization and function has been confirmed in a yeast model in which the ER–mitochondria encounter structure (ERMES) complex (required for MAM stability in yeast) has been disrupted. Bcl2–TOM20 interaction is thus an additional player in the control of apoptosis.
Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer
Authors: Zhang Ning , Tian Yu-Nan , Zhou Li-Na , Li Meng-Zhu , Chen Hua-Dong , Song Shan-Shan , Huan Xia-Juan , Bao Xu-Bin , Zhang Ao , Miao Ze-Hong , He Jin-Xue
Published: February 2021

Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3β and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3β was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.
MCT8 deficiency in a patient with a novel frameshift variant in the SLC16A2 gene
Authors: Wakabayashi Kei , Osaka Hitoshi , Kojima Karin , Imaizumi Taichi , Yamamoto Toshiyuki , Yamagata Takanori
Published: February 2021

MCT8 deficiency is an X-linked recessive disorder. We report the case of a 2-year-old Japanese boy with MCT8 deficiency caused by a novel frameshift variant, NM_006517.5(SLC16A2_v001):c.966dup [p.(Ile323Hisfs*57)]. He presented no head control and spoke no meaningful words, indicating severe developmental delay. Although missense or in-frame mutations of SLC16A2 are usually related to milder phenotypes and later-onset pyramidal signs, loss-of-function mutations are expected to cause severe clinical symptoms.
Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers
Authors: Zhang Yingyi , Dijkman Patricia M. , Zou Rongfeng , Zandl-Lang Martina , Sanchez Ricardo M. , Eckhardt-Strelau Luise , Köfeler Harald , Vogel Horst , Yuan Shuguang , Kudryashev Mikhail
Published: February 2021

Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A serotonin receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the receptor in a more tightly packed, ‘coupled’ state, involving a cluster of highly conserved residues. In consequence, the agonist-bound receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the receptor.
Author Correction: A brain-wide functional map of the serotonergic responses to acute stress and fluoxetine
Authors: Grandjean Joanes , Corcoba Alberto , Kahn Martin C. , Upton A. Louise , Deneris Evan S. , Seifritz Erich , Helmchen Fritjof , Mansuy Isabelle M. , Mann Edward O. , Rudin Markus , Saab Bechara J.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21192-6
Climate change, not human population growth, correlates with Late Quaternary megafauna declines in North America
Authors: Stewart Mathew , Carleton W. Christopher , Groucutt Huw S.
Published: February 2021

The disappearance of many North American megafauna at the end of the Pleistocene is a contentious topic. While the proposed causes for megafaunal extinction are varied, most researchers fall into three broad camps emphasizing human overhunting, climate change, or some combination of the two. Understanding the cause of megafaunal extinctions requires the analysis of through-time relationships between climate change and megafauna and human population dynamics. To do so, many researchers have used summed probability density functions (SPDFs) as a proxy for through-time fluctuations in human and megafauna population sizes. SPDFs, however, conflate process variation with the chronological uncertainty inherent in radiocarbon dates. Recently, a new Bayesian regression technique was developed that overcomes this problem—Radiocarbon-dated Event-Count (REC) Modelling. Here we employ REC models to test whether declines in North American megafauna species could be best explained by climate changes, increases in human population densities, or both, using the largest available database of megafauna and human radiocarbon dates. Our results suggest that there is currently no evidence for a persistent through-time relationship between human and megafauna population levels in North America. There is, however, evidence that decreases in global temperature correlated with megafauna population declines.
Biological and therapeutic implications of a unique subtype of NPM1 mutated AML
Authors: Mer Arvind Singh , Heath Emily M. , Madani Tonekaboni Seyed Ali , Dogan-Artun Nergiz , Nair Sisira Kadambat , Murison Alex , Garcia-Prat Laura , Shlush Liran , Hurren Rose , Voisin Veronique , Bader Gary D. , Nislow Corey , Rantalainen Mattias , Lehmann Soren , Gower Mark , Guidos Cynthia J. , Lupien Mathieu , Dick John E. , Minden Mark D. , Schimmer Aaron D. , Haibe-Kains Benjamin
Published: February 2021

In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit.
Bridging scales in disordered porous media by mapping molecular dynamics onto intermittent Brownian motion
Authors: Bousige Colin , Levitz Pierre , Coasne Benoit
Published: February 2021

Owing to their complex morphology and surface, disordered nanoporous media possess a rich diffusion landscape leading to specific transport phenomena. The unique diffusion mechanisms in such solids stem from restricted pore relocation and ill-defined surface boundaries. While diffusion fundamentals in simple geometries are well-established, fluids in complex materials challenge existing frameworks. Here, we invoke the intermittent surface/pore diffusion formalism to map molecular dynamics onto random walk in disordered media. Our hierarchical strategy allows bridging microscopic/mesoscopic dynamics with parameters obtained from simple laws. The residence and relocation times – tA, tB – are shown to derive from pore size d and temperature-rescaled surface interaction ε/kBT. tA obeys a transition state theory with a barrier ~ε/kBT and a prefactor ~10−12 s corrected for pore diameter d. tB scales with d which is rationalized through a cutoff in the relocation first passage distribution. This approach provides a formalism to predict any fluid diffusion in complex media using parameters available to simple experiments.
Bistability and time crystals in long-ranged directed percolation
Authors: Pizzi Andrea , Nunnenkamp Andreas , Knolle Johannes
Published: February 2021

Stochastic processes govern the time evolution of a huge variety of realistic systems throughout the sciences. A minimal description of noisy many-particle systems within a Markovian picture and with a notion of spatial dimension is given by probabilistic cellular automata, which typically feature time-independent and short-ranged update rules. Here, we propose a simple cellular automaton with power-law interactions that gives rise to a bistable phase of long-ranged directed percolation whose long-time behaviour is not only dictated by the system dynamics, but also by the initial conditions. In the presence of a periodic modulation of the update rules, we find that the system responds with a period larger than that of the modulation for an exponentially (in system size) long time. This breaking of discrete time translation symmetry of the underlying dynamics is enabled by a self-correcting mechanism of the long-ranged interactions which compensates noise-induced imperfections. Our work thus provides a firm example of a classical discrete time crystal phase of matter and paves the way for the study of novel non-equilibrium phases in the unexplored field of driven probabilistic cellular automata.
Optoelectronic frequency-modulated continuous-wave terahertz spectroscopy with 4 THz bandwidth
Authors: Liebermeister Lars , Nellen Simon , Kohlhaas Robert B. , Lauck Sebastian , Deumer Milan , Breuer Steffen , Schell Martin , Globisch Björn
Published: February 2021

Broadband terahertz spectroscopy enables many promising applications in science and industry alike. However, the complexity of existing terahertz systems has as yet prevented the breakthrough of this technology. In particular, established terahertz time-domain spectroscopy (TDS) schemes rely on complex femtosecond lasers and optical delay lines. Here, we present a method for optoelectronic, frequency-modulated continuous-wave (FMCW) terahertz sensing, which is a powerful tool for broadband spectroscopy and industrial non-destructive testing. In our method, a frequency-swept optical beat signal generates the terahertz field, which is then coherently detected by photomixing, employing a time-delayed copy of the same beat signal. Consequently, the receiver current is inherently phase-modulated without additional modulator. Owing to this technique, our broadband terahertz spectrometer performs (200 Hz measurement rate, or 4 THz bandwidth and 117 dB peak dynamic range with averaging) comparably to state-of-the-art terahertz-TDS systems, yet with significantly reduced complexity. Thickness measurements of multilayer dielectric samples with layer-thicknesses down to 23 µm show its potential for real-world applications. Within only 0.2 s measurement time, an uncertainty of less than 2 % is achieved, the highest accuracy reported with continuous-wave terahertz spectroscopy. Hence, the optoelectronic FMCW approach paves the way towards broadband and compact terahertz spectrometers that combine fiber optics and photonic integration technologies.
Implications of the 2019–2020 megafires for the biogeography and conservation of Australian vegetation
Authors: Godfree Robert C. , Knerr Nunzio , Encinas-Viso Francisco , Albrecht David , Bush David , Christine Cargill D. , Clements Mark , Gueidan Cécile , Guja Lydia K. , Harwood Tom , Joseph Leo , Lepschi Brendan , Nargar Katharina , Schmidt-Lebuhn Alexander , Broadhurst Linda M.
Published: February 2021

Australia’s 2019–2020 ‘Black Summer’ bushfires burnt more than 8 million hectares of vegetation across the south-east of the continent, an event unprecedented in the last 200 years. Here we report the impacts of these fires on vascular plant species and communities. Using a map of the fires generated from remotely sensed hotspot data we show that, across 11 Australian bioregions, 17 major native vegetation groups were severely burnt, and up to 67–83% of globally significant rainforests and eucalypt forests and woodlands. Based on geocoded species occurrence data we estimate that >50% of known populations or ranges of 816 native vascular plant species were burnt during the fires, including more than 100 species with geographic ranges more than 500 km across. Habitat and fire response data show that most affected species are resilient to fire. However, the massive biogeographic, demographic and taxonomic breadth of impacts of the 2019–2020 fires may leave some ecosystems, particularly relictual Gondwanan rainforests, susceptible to regeneration failure and landscape-scale decline.
Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice
Authors: McNae Iain W. , Kinkead James , Malik Divya , Yen Li-Hsuan , Walker Martin K. , Swain Chris , Webster Scott P. , Gray Nick , Fernandes Peter M. , Myburgh Elmarie , Blackburn Elizabeth A. , Ritchie Ryan , Austin Carol , Wear Martin A. , Highton Adrian J. , Keats Andrew J. , Vong Antonio , Dornan Jacqueline , Mottram Jeremy C. , Michels Paul A. M. , Pettit Simon , Walkinshaw Malcolm D.
Published: February 2021

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.
Phenotypic covariance across the entire spectrum of relatedness for 86 billion pairs of individuals
Authors: Kemper Kathryn E. , Yengo Loic , Zheng Zhili , Abdellaoui Abdel , Keller Matthew C. , Goddard Michael E. , Wray Naomi R. , Yang Jian , Visscher Peter M.
Published: February 2021

Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship ($$\pi$$π) among 417,060 individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and$$\pi$$πthat agree with the SNP-based heritability ($$\hat h_{SNP}^2$$ĥSNP2) in unrelated pairs ($$\pi \, < \, 0.02$$π<0.02), and with pedigree-estimated heritability in close relatives ($$\pi \, > \, 0.05$$π>0.05). The covariance increases faster than$$\pi \hat h_{SNP}^2$$πĥSNP2in distant relatives ($$0.02 \, > \, \pi \, > \, 0.05$$0.02>π>0.05), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct$$\pi$$π. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.
A scalable physician-level deep learning algorithm detects universal trauma on pelvic radiographs
Authors: Cheng Chi-Tung , Wang Yirui , Chen Huan-Wu , Hsiao Po-Meng , Yeh Chun-Nan , Hsieh Chi-Hsun , Miao Shun , Xiao Jing , Liao Chien-Hung , Lu Le
Published: February 2021

Pelvic radiograph (PXR) is essential for detecting proximal femur and pelvis injuries in trauma patients, which is also the key component for trauma survey. None of the currently available algorithms can accurately detect all kinds of trauma-related radiographic findings on PXRs. Here, we show a universal algorithm can detect most types of trauma-related radiographic findings on PXRs. We develop a multiscale deep learning algorithm called PelviXNet trained with 5204 PXRs with weakly supervised point annotation. PelviXNet yields an area under the receiver operating characteristic curve (AUROC) of 0.973 (95% CI, 0.960–0.983) and an area under the precision-recall curve (AUPRC) of 0.963 (95% CI, 0.948–0.974) in the clinical population test set of 1888 PXRs. The accuracy, sensitivity, and specificity at the cutoff value are 0.924 (95% CI, 0.912–0.936), 0.908 (95% CI, 0.885–0.908), and 0.932 (95% CI, 0.919–0.946), respectively. PelviXNet demonstrates comparable performance with radiologists and orthopedics in detecting pelvic and hip fractures.