bluuebunny/crossref_metadata_2025 huggingface dataset:
Second language speech comprehensibility
Authors: Crowther Dustin , Holden Daniel , Urada Kristen
Published: May 2022

Published in Language Learning in 1995, Munro and Derwing's* investigation of foreign accent, comprehensibility, and intelligibility in second language (L2) speech instigated significant change in L2 pronunciation research (Levis, 2020). A key finding was that despite the presence of a foreign accent, listeners could indeed comprehend L2 speech. Within their framework, comprehension of L2 speech was assessed along two dimensions. The first, intelligibility, was an assessment of actual listener comprehension, measured through listener transcriptions of a given utterance. The second, comprehensibility, was a scalar measure of how easy to understand listeners perceived an utterance to be. While these two measures of listener comprehension (i.e., understanding) have been shown to correlate, they have also been shown to measure different forms of understanding (Derwing & Munro, 2015). This means that while increased intelligibility can be associated with increased comprehensibility, it is still common for listeners to accurately transcribe nonnative speech while simultaneously indicating the speech to be hard to understand (i.e., evidence indicates that intelligibility outpaces comprehensibility in the development of L2 pronunciation). Research published in the 25 years since has repeatedly demonstrated that accentedness, comprehensibility, and intelligibility are partially independent dimensions of L2 speech (Munro & Derwing, 2020). Whereas Munro and Derwing's (2011) research timeline attended to the concepts of accent and broad intelligibility (i.e., inclusive of both actual and ease of understanding), the past decade has seen an increased scholarly emphasis specifically on the global speech dimension of comprehensibility. Given this increased scholarly interest, our timeline is presented with the goal of tracing the post-Munro and Derwing (1995) development of L2 speech comprehensibility research.
Random symmetric matrices: rank distribution and irreducibility of the characteristic polynomial
Authors: FERBER ASAF , JAIN VISHESH , SAH ASHWIN , SAWHNEY MEHTAAB
Published: May 2022

Conditional on the extended Riemann hypothesis, we show that with high probability, the characteristic polynomial of a random symmetric
$\{\pm 1\}$
-matrix is irreducible. This addresses a question raised by Eberhard in recent work. The main innovation in our work is establishing sharp estimates regarding the rank distribution of symmetric random
$\{\pm 1\}$
-matrices over
$\mathbb{F}_p$
for primes
$2 < p \leq \exp(O(n^{1/4}))$
. Previously, such estimates were available only for
$p = o(n^{1/8})$
. At the heart of our proof is a way to combine multiple inverse Littlewood–Offord-type results to control the contribution to singularity-type events of vectors in
$\mathbb{F}_p^{n}$
with anticoncentration at least
$1/p + \Omega(1/p^2)$
. Previously, inverse Littlewood–Offord-type results only allowed control over vectors with anticoncentration at least
$C/p$
for some large constant
$C > 1$
.
Hunting sustainability within two eastern Amazon Extractive Reserves
Authors: de Paula Milton José , Carvalho Elildo AR , Lopes Cintia Karoline Manos , Sousa Reysane de Alencar , Maciel Emerson Luiz Pereira , Wariss Manoela , Barboza Rafael Sá Leitão , Braga Francisco Chen de Araújo , Félix-Silva Daniely , Peres Carlos A , Pezzuti Juarez CB
Published: May 2022

Subsistence hunting provides an important food source for rural populations in tropical forests but can lead to wildlife depletion. Management of wildlife resources depends on assessments of hunting sustainability. We assessed the sustainability of subsistence hunting in two Amazonian Extractive Reserves. We examined hunting data from a community-based monitoring programme conducted in 30 communities during 63 consecutive months to address temporal trends in hunting yields in terms of catch per unit of effort of all game species and the six most hunted species. We also assessed the prey profiles across different communities. Game species composition did not differ between monitored communities, and the most hunted species were Tayassu pecari, large cracids, Cuniculus paca, Mazama spp., Tapirus terrestris and Pecari tajacu. Catch per unit of effort was stable for all game species and each of the most hunted species, indicating that hunting was generally sustainable. These findings reflect the exceptionally low human population density and continuous forest cover of the study landscape, and long-term hunting sustainability and local protein acquisition will depend on maintaining these social and environmental settings. The results also show that large Sustainable Use Protected Areas can help foster sustainable game management and should thus be included in public policies.
Workplace exposures associated with COVID-19: evidence from a case-control study with multiple sampling periods in England, August–October 2020
Authors: Hiironen Iina , Saavedra-Campos María , Panitz Jennifer , Ma Thomas , Nsonwu Olisaeloka , Charlett Andre , Hughes Gareth J. , Oliver Isabel
Published: May 2022

We investigated risk factors associated with COVID-19 by conducting a retrospective, frequency-matched case-control study, with three sampling periods (August–October 2020). We compared cases completing routine contact tracing to asymptomatic population controls. Multivariable analyses estimated adjusted odds ratios (aORs) for non-household community settings. Meta-analyses using random effects provided pooled odds ratios (pORs). Working in healthcare (pOR 2.87; aORs 2.72, 2.81, 3.08, for study periods 1–3 respectively), social care (pOR 4.15; aORs 2.46, 5.06, 5.41, for study periods 1–3 respectively) or hospitality (pOR 2.36; aORs 2.01, 2.54, 2.63, for study periods 1–3 respectively) were associated with increased odds of being a COVID-19 case. Additionally, working in bars, pubs and restaurants, warehouse settings, construction, educational settings were significantly associated. While definitively determining where transmission occurs is impossible, we provide evidence that in certain sectors, the impact of mitigation measures may only be partial and reinforcement of measures should be considered in these settings.
Behavioral, cognitive, and socioemotional pathways from early childhood adversity to BMI: Evidence from two prospective, longitudinal studies
Authors: Doom Jenalee R. , Young Ethan S. , Farrell Allison K. , Roisman Glenn I. , Simpson Jeffry A.
Published: May 2022

Childhood adversity is associated with higher adult weight, but few investigations prospectively test mechanisms accounting for this association. Using two socioeconomically high-risk prospective longitudinal investigations, the Minnesota Longitudinal Study of Risk and Adaptation (MLSRA; N = 267; 45.3% female) and the Fragile Families and Child Wellbeing Study (FFCWS; n = 2,587; 48.5% female), pathways between childhood adversity and later body mass index (BMI) were tested using impulsivity, emotion dysregulation, and overeating as mediators. Childhood adversity from 0 to 5 years included four types of adversities: greater unpredictability, threat/abuse, deprivation/neglect, and low socioeconomic status. Parents reported on child impulsivity, emotion dysregulation, and overeating. Height and weight were self-reported and measured at 32 and 37 years in MLSRA and at 15 years in FFCWS. FFCWS results indicated that threat, deprivation, and low socioeconomic status predicted greater impulsivity and emotion dysregulation at 5 years, which in turn predicted greater overeating at 9 years and higher BMI z-score at 15 years. Early unpredictability in FFCWS predicted higher BMI through greater impulsivity but not emotion dysregulation at age 5. MLSRA regression results replicated the threat/abuse → emotion dysregulation → overeating → higher BMI pathway. These findings suggest that different dimensions of early adversity may follow both similar and unique pathways to predict BMI.
Hom weak ω-categories of a weak ω-category
Authors: Cottrell Thomas , Fujii Soichiro
Published: May 2022

Classical definitions of weak higher-dimensional categories are given inductively, for example, a bicategory has a set of objects and hom categories, and a tricategory has a set of objects and hom bicategories. However, more recent definitions of weak n-categories for all natural numbers n, or of weak
$\omega$
-categories, take more sophisticated approaches, and the nature of the ‘hom is often not immediate from the definitions’. In this paper, we focus on Leinster’s definition of weak
$\omega$
-category based on an earlier definition by Batanin and construct, for each weak
$\omega$
-category
$\mathcal{A}$
, an underlying (weak
$\omega$
-category)-enriched graph consisting of the same objects and for each pair of objects x and y, a hom weak
$\omega$
-category
$\mathcal{A}(x,y)$
. We also show that our construction is functorial with respect to weak
$\omega$
-functors introduced by Garner.
Pupillary response in reward processing in adults with major depressive disorder in remission
Authors: Guath Mona , Willfors Charlotte , Björlin Avdic Hanna , Nordgren Ann , Kleberg Johan Lundin
Published: May 2022

Objective:

Major depressive disorder (MDD) is associated with impaired reward processing and reward learning. The literature is inconclusive regarding whether these impairments persist after remission. The current study examined reward processing during a probabilistic learning task in individuals in remission from MDD (n = 19) and never depressed healthy controls (n = 31) matched for age and sex. The outcome measures were pupil dilation (an indirect index of noradrenergic activity and arousal) and computational modeling parameters.

Method:

Participants completed two versions (facial/nonfacial feedback) of probabilistic reward learning task with changing contingencies. Pupil dilation was measured with a corneal reflection eye tracker. The hypotheses and analysis plan were preregistered.

Result:

Healthy controls had larger pupil dilation following losses than gains (p <.001), whereas no significant difference between outcomes was found in individuals with a history of MDD, resulting in an interaction between group and outcome (β = 0.81, SE = 0.34, t = 2.37, p = .018). The rMDD group also achieved lower mean score at the last trial (t[46.77] = 2.12, p = .040) as well as a smaller proportion of correct choices (t[46.70] = 2.09, p = .041) compared with healthy controls.

Conclusion:

Impaired reward processing may persist after remission from MDD and could constitute a latent risk factor for relapse. Measuring pupil dilation in a reward learning task is a promising method for identifying reward processing abnormalities linked to MDD. The task is simple and noninvasive, which makes it feasible for clinical research.
Differences in Collagen Fiber Diameter and Waviness between Healthy and Aneurysmal Abdominal Aortas
Authors: Niestrawska Justyna A , Pukaluk Anna , Babu Anju R , Holzapfel Gerhard A
Published: May 2022

Collagen plays a key role in the strength of aortic walls, so studying micro-structural changes during disease development is critical to better understand collagen reorganization. Second-harmonic generation microscopy is used to obtain images of human aortic collagen in both healthy and diseased states. Methods are being developed in order to efficiently determine the waviness, that is, tortuosity and amplitude, as well as the diameter, orientation, and dispersion of collagen fibers, and bundles in healthy and aneurysmal tissues. The results show layer-specific differences in the collagen of healthy tissues, which decrease in samples of aneurysmal aortic walls. In healthy tissues, the thick collagen bundles of the adventitia are characterized by greater waviness, both in the tortuosity and in the amplitude, compared to the relatively thin and straighter collagen fibers of the media. In contrast, most aneurysmal tissues tend to have a more uniform structure of the aortic wall with no significant difference in collagen diameter between the luminal and abluminal layers. An increase in collagen tortuosity compared to the healthy media is also observed in the aneurysmal luminal layer. The data set provided can help improve related material and multiscale models of aortic walls and aneurysm formation.
Characterization of novel low-molecular-weight glutenin subunit genes from the diploid wild wheat relative Aegilops umbellulata
Authors: Wang Wenyang , Ji Wenjun , Feng Lihua , Ning Shunzong , Yuan Zhongwei , Hao Ming , Zhang Lianquan , Yan Zehong , Wu Bihua , Liu Dengcai , Huang Lin
Published: May 2022

Low molecular weight glutenin subunits (LWM-GSs) play a crucial role in determining wheat flour processing quality. In this work, 35 novel LMW-GS genes (32 active and three pseudogenes) from three Aegilops umbellulata (2n = 2x = 14, UU) accessions were amplified by allelic-specific PCR. We found that all LMW-GS genes had the same primary structure shared by other known LMW-GSs. Thirty-two active genes encode 31 typical LMW-m-type subunits. The MZ424050 possessed nine cysteine residues with an extra cysteine residue located in the last amino acid residue of the conserved C-terminal III, which could benefit the formation of larger glutenin polymers, and therefore may have positive effects on dough properties. We have found extensive variations which were mainly resulted from single-nucleotide polymorphisms (SNPs) and insertions and deletions (InDels) among the LMW-GS genes in Ae. umbellulata. Our results demonstrated that Ae. umbellulata is an important source of LMW-GS variants and the potential value of the novel LMW-GS alleles for wheat quality improvement.
Delineation of Bangladeshi coastal rice germplasm based on qualitative phenotypic traits
Authors: Banik Susmita , Rasul Md. Golam , Ivy Nasrin Akter , Haque M. Moynul , Hasan Mehfuz
Published: May 2022

A detailed study of rice genetic resources in Bangladesh's coastal areas is necessary. This understanding is a necessary requirement for its utilization in selective breeding. The study reports on the qualitative morphological trait-based assessment of 150 local rice samples collected from Bangladesh's coastal zone, including 50 advanced lines developed from coastal germplasm. Six of the thirteen analysed characters had a substantial gene contribution, whereas the average was 0.694. The most impressive diversity was in leaf blade intensity of green colour (LBIGC: 0.705). The total morpho-qualitative diversity was calculated to be 0.412. The character efficiency content ranged from 0.655 (LBIGC) to 0.136 (Leaf Sheath: Anthocyanin colouration, Leaf Blade: Presence/Absence, and Leaf Blade: Anthocyanin. Colouration). As per the morphological variance study, 93% of morphological changes were detected within individuals, whereas 7% were found in populations. The 150 germplasm samples were divided into four subpopulations using STRUCTURE-based population analysis. A moderate genotypic difference was detected amongst all groups, with an Fst value of 0.111. The G statistic backed up the record as well. The Shannon mutual information index reached a value of 1.252 between populations 2 and 3. In terms of gene exchange, the highest value was found between populations 3 and 4. Our data indicate a high degree of diversity in Bangladesh's coastline rice germplasm. The findings will aid in conferring the farmers' Intellectual Property Rights on the investigated rice germplasm.
Work and Family Balance in Top Diplomacy: The Case of the Czech Republic
Authors: Fellegi Zuzana , Kočí Kateřina , Benešová Klára
Published: May 2022

While female representation in the top diplomatic circles was almost nonexistent during the Czechoslovak era, the number of female diplomats in the Czech Republic has steadily increased since the fall of the state-socialist regime. Women are currently solidly represented in the Czech Ministry of Foreign Affairs (MFA), but very few (14%) reach highest diplomatic positions. This study examines the main challenges that influence the careers of top diplomats using quantitative and qualitative data, including official statistics and documents of the Czech MFA and interviews with top diplomats and officials. The results indicate that work-family conflicts are the main challenge for all diplomats. However, women are apparently affected more disproportionately because of the existing “double burden” and a specific “concept of motherhood” vested in a deeply essentialist understanding of gender roles. These barriers have origins at the personal, institutional, and state levels that are strongly interrelated and historically and politically path dependent.
The Dynamic Relationship Between Social Capital and Suicide Rates
Authors: Han Sehee
Published: May 2022

Abstract. Background: Suicide is an important public health concern worldwide. Among various factors, social capital has been suggested to be an effective factor to prevent and reduce suicide. Aims: The purpose of this study was to investigate the association between social capital and suicide rates in Seoul, South Korea, using panel data from 2005 to 2018 at the administrative-district level. Methods: Data for the current study were obtained from Seoul Statistics. The within estimator and the system generalized methods of moments estimator were used. Results: The results showed that there was an inverse association between community facility and suicide rates. This result remained the same even after considering the dynamic relationship between social capital and suicide rates ( B = −0.57, 95% CI: −1.10, −0.04) while adjusting for dynamic panel bias. A 10% increase in community facility per 1,000 population was associated with 5.2% reduction in age-standardized suicide rates per 100,000 population. Limitations: In this study, only a structural dimension of social capital was utilized due to the lack of available data. Conclusion: The results indicate that facilitating opportunities for social interactions and community lives has a potential to prevent and reduce suicide.
Being Snoopy and Smart
Authors: Hartung Freda-Marie , Thieme Pia , Wild-Wall Nele , Hell Benedikt
Published: May 2022

Abstract. Curiosity is a basic driver for learning and development. It has been conceptualized as a desire for new information and knowledge that motivates people to explore their physical and social environment. This raises the question of whether curiosity facilitates the acquisition of knowledge. The present study ( N = 100) assessed epistemic curiosity and general knowledge as well as fluid intelligence (i.e., reasoning ability, processing speed, memory) in a student sample. The results indicate that epistemic curiosity is moderately related to knowledge ( r = .24) and reasoning ability ( r = .30). None of the fluid intelligence measures did moderate the relationship between curiosity and knowledge (interaction terms β < |.08|). Rather, reasoning ability mediated the relationship between epistemic curiosity and general knowledge (indirect effect: β = .10, p < .05). The findings suggest that epistemic curiosity facilitates the acquisition of knowledge by promoting reasoning. One might speculate that epistemically curious individuals enrich their environment, which in turn enhances their cognitive ability.
The Sources, Molecular Compositions, and Light Absorption Properties of Water‐Soluble Organic Carbon in Marine Aerosols From South China Sea to the Eastern Indian Ocean
Authors: Mo Yangzhi , Zhong Guangcai , Li Jun , Liu Xin , Jiang Hongxing , Tang Jiao , Jiang Bin , Liao Yuhong , Cheng Zhineng , Zhang Gan
Published: May 2022

Water‐soluble organic carbon (WSOC) is a substantial component of carbonaceous aerosols in South/East Asia. However, the poorly constrained sources, molecular compositions, and light absorption properties of WSOC over South/East Asian marine regions lead to large uncertainty in climate effects. Herein, we collected marine aerosol samples from South China Sea to the eastern Indian Ocean to investigate the sources, molecular compositions, and light absorption properties of WSOC. The δ13C of Marine‐influenced WSOC (−20.6 ± 1.4‰) was higher than those in Continent‐influenced (South Asia‐influenced: −24.4 ± 1.1‰ and Southeast Asia‐influenced: −22.7 ± 1.0‰, p < 0.01) regions. Additionally, combining with 5‐day back trajectories and the relationships of δ13C‐WSOC with chemical tracers (Cl−/Na+ and nonsea salt K+/K+), we found that the Marine‐influenced WSOC was mostly related to oceanic emissions, which was more enriched in saturated primary marine biological compounds with lower oxidation level. In contrast, the Continent‐influenced WSOC was significantly affected by C3 biomass burning and secondary organic aerosols formation, and it has a higher fraction of aromatic and highly oxidized compounds. Moreover, the high aromatic level of Continental‐influenced WSOC may result in high mass absorption efficiency at 365 nm (MAE365) but low absorption Ångström exponent (AAE) values. Taken together with previous WSOC light absorption properties studies, we found that the MAE365 of WSOC in urban, rural and background, and marine regions correlated well with AAE. However, the response and correlation coefficients of MAE365 to AAE were highest in urban regions, followed by rural and background and marine regions, which is likely associated with different aromatic compound contents. Therefore, in the future, more attention should be paid to the sources and atmospheric processes of condensed aromatic compounds.
The Study of Daytime Ionospheric E‐Region Radar Echoes Simultaneously Observed by Qujing VHF Radar and Multi‐Ionosondes
Authors: Zhu Yunzhou , Tang Qiong , Deng Zhongxin , Zhou Chen , Liu Yi , Xu Tong , Wang Zhuangkai , Zhao Zhengyu , Wei Fengsi , Feng Xueshang
Published: May 2022

In this work, the daytime E‐region field‐aligned irregularities (FAIs) observed by the Qujing (geographic 25.64°N, 103.70°E) Very High Frequency coherent backscatter radar was reported. The range spread and enhanced sporadic‐E layer (Es) during the same period of the unusual radar echoes were separately observed by two ionosondes located at the Huize and Qujing. The Huize (geographic 26.51°N, 103.61°E) ionosonde was roughly located underneath the radar scattering volume which measured enhanced and range spread Es layer during this period of the unusual radar echoes, indicating that the daytime E‐region FAIs were closely related to the localized density gradient that embedded within the coordinated Es layer. Fengyun‐4A (FY‐4A) satellite data show that a strong convective activity accompanied by gravity waves occurred near the radar scattering volume region. As a result, we proposed that the gravity waves driven by the convective activity in the lower atmosphere can modulate the Es layers and then generate the daytime FAIs through the polarization process.
Mapping a Magnetic Superstorm: March 1989 Geoelectric Hazards and Impacts on United States Power Systems
Authors: Love Jeffrey J. , Lucas Greg M. , Rigler E. Joshua , Murphy Benjamin S. , Kelbert Anna , Bedrosian Paul A.
Published: May 2022

A study is made of the relations between geomagnetic and geoelectric field variation, Earth‐surface impedance, and operational interference (“anomalies”) experienced on electric‐power systems across the contiguous United States during the 13–14 March, 1989, magnetic storm. For this, a 1‐min‐resolution sequence of geomagnetic field maps is constructed from magnetometer time series acquired at ground‐based observatories. Induced geoelectric field maps are calculated by convolving the geomagnetic maps with magnetotelluric impedance tensors. During the storm, anomalies were concentrated where the lithosphere is electrically resistive, and when and where geoelectric field amplitudes were high. This was particularly true in the Mid‐Atlantic, Northeast, and the upper Midwest. Few anomalies were experienced in other parts of the Midwest and across much of the West, where the lithosphere is more conductive, and when and where geoelectric field amplitudes were low. Peak 1‐min‐resolution geoelectric field amplitude ranged from 21.66 V/km in Maine and 19.02 V/km in Virginia to <0.02 V/km in Idaho. Latitude‐dependent organization of geoelectric hazards by auroral‐zone electrojet currents is detectable, but it is much weaker than geographic organization due to surface impedance. Hazardous geoelectric fields were induced during different storm phases, at different local times, and, by inference, by a variety of ionospheric currents. Compared to geoelectric field amplitudes realized across the United States during March 1989, hazard maps used by utility companies to estimate systems exposure have much less geographic detail and a much smaller maximum‐to‐minimum range in geoelectric field amplitude. Future research would benefit from denser geomagnetic monitoring, additional magnetotelluric surveying, and access to power‐system impact data.
The effect of perceived stress on cognition is mediated by personality and the underlying neural mechanism
Authors: Zhu Ximei , Yan Wei , Lin Xiao , Que Jianyu , Huang Yuetong , Zheng Haohao , Liu Lin , Deng Jiahui , Lu Lin , Chang Suhua
Published: May 2022

Perceived stress impairs cognitive function across the adult lifespan, but the extent to which cognition decline is variable across individuals. Individual differences in the stress response are described as personality traits. Substantial individual differences in the magnitude of cognitive impairment that is induced by short-term perceived stress are poorly understood. The present study tested the hypothesis that the relationship between short-term perceived stress and different aspects of cognition is mediated by personality traits. The study included 1066 participants with behavior and neuroimaging data from the Human Connectome Project after excluding individuals with missing variables. In the result, the parallel multiple mediation model demonstrated that the influence of perceived stress on the total and crystalized cognition is mainly mediated by neuroticism (indirect effect = −0.04, p < 0.05) and conscientiousness (indirect effect = 0.05, p < 0.05) in adults. Cortical thickness value (n = 1066) of the right superior frontal gyrus (SFG) showed not only positive correlations with short-term perceived stress and neuroticism, but negative associations with cognition. The chain mediation model found that the right SFG and neuroticism play a small but significant chain mediating effect between stress and total cognition. The strength of the resting-state functional connectivity (n = 968) between the left orbitofrontal cortex versus the left superior medial frontal cortex was positively correlated with crystallized cognition and negatively associated with conscientiousness. These results extend previous findings by the impacts of short-term perceived stress on cognitive function is mediated by neuroticism and the right SFG was the underlying neural mechanism.
Ferutinin induces osteoblast differentiation of DPSCs via induction of KLF2 and autophagy/mitophagy
Authors: Maity Jyotirindra , Barthels Derek , Sarkar Jaganmay , Prateeksha Prateeksha , Deb Moonmoon , Rolph Daniela , Das Hiranmoy
Published: May 2022

Osteoblast differentiation is critically reduced in various bone-related pathogenesis, including arthritis and osteoporosis. For future development of effective regenerative therapeutics, herein, we reveal the involved molecular mechanisms of a phytoestrogen, ferutinin-induced initiation of osteoblast differentiation from dental pulp-derived stem cell (DPSC). We demonstrate the significantly increased expression level of a transcription factor, Kruppel-like factor 2 (KLF2) along with autophagy-related molecules in DPSCs after induction with ferutinin. The loss-of-function and the gain-of-function approaches of KLF2 confirmed that the ferutinin-induced KLF2 modulated autophagic and OB differentiation-related molecules. Further, knockdown of the autophagic molecule (ATG7 or BECN1) from DPSC resulted not only in a decreased level of KLF2 but also in the reduced levels of OB differentiation-related molecules. Moreover, mitochondrial membrane potential-related molecules were increased and induction of mitophagy was observed in DPSCs after the addition of ferutinin. The reduction of mitochondrial as well as total ROS generations; and induction of intracellular Ca2+ production were also observed in ferutinin-treated DPSCs. To test the mitochondrial respiration in DPSCs, we found that the cells treated with ferutinin showed a reduced extracellular acidification rate (ECAR) than that of their vehicle-treated counterparts. Furthermore, mechanistically, chromatin immunoprecipitation (ChIP) analysis revealed that the addition of ferutinin in DPSCs not only induced the level of KLF2, but also induced the transcriptionally active epigenetic marks (H3K27Ac and H3K4me3) on the promoter region of the autophagic molecule ATG7. These results provide strong evidence that ferutinin stimulates OB differentiation via induction of KLF2-mediated autophagy/mitophagy.
Multimodal CEA-targeted fluorescence and radioguided cytoreductive surgery for peritoneal metastases of colorectal origin
Authors: de Gooyer Jan Marie , Elekonawo Fortuné M. K. , Bremers Andreas J. A. , Boerman Otto C. , Aarntzen Erik H. J. G. , de Reuver Philip R. , Nagtegaal Iris. D. , Rijpkema Mark , de Wilt Johannes H. W.
Published: May 2022

In patients with colorectal peritoneal metastases scheduled for cytoreductive surgery, accurate preoperative estimation of tumor burden and subsequent intraoperative detection of all tumor deposits remains challenging. In this study (ClinicalTrials.gov NCT03699332) we describe the results of a phase I clinical trial evaluating [111In]In-DOTA-labetuzumab-IRDye800CW, a dual-labeled anti-carcinoembryonic antigen (anti-CEA) antibody conjugate that enables both preoperative imaging and intraoperative radioguidance and fluorescence imaging. Primary study outcomes are safety and feasibility of this multimodal imaging approach. Secondary outcomes are determination of the optimal dose, correlation between tracer uptake and histopathology and effects on clinical strategy. Administration of [111In]In-DOTA-labetuzumab-IRDye800CW is well-tolerated and enables sensitive pre- and intraoperative imaging in patients who receive 10 or 50 mg of the tracer. Preoperative imaging revealed previously undetected lymph node metastases in one patient, and intraoperative fluorescence imaging revealed four previously undetected metastases in two patients. Alteration of clinical strategy based on multimodal imaging occurred in three patients. Thus, multimodal image-guided surgery after administration of this dual-labeled tracer is a promising approach that may aid in decision making before and during cytoreductive surgical procedures.
Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans
Authors: Maglioni Silvia , Schiavi Alfonso , Melcher Marlen , Brinkmann Vanessa , Luo Zhongrui , Laromaine Anna , Raimundo Nuno , Meyer Joel N. , Distelmaier Felix , Ventura Natascia
Published: May 2022

Complex-I-deficiency represents the most frequent pathogenetic cause of human mitochondriopathies. Therapeutic options for these neurodevelopmental life-threating disorders do not exist, partly due to the scarcity of appropriate model systems to study them.Caenorhabditis elegansis a genetically tractable model organism widely used to investigate neuronal pathologies. Here, we generateC. elegansmodels for mitochondriopathies and show that depletion of complex I subunits recapitulates biochemical, cellular and neurodevelopmental aspects of the human diseases. We exploit two models,nuo-5/NDUFS1- andlpd-5/NDUFS4-depleted animals, for a suppressor screening that identifies lutein for its ability to rescue animals’ neurodevelopmental deficits. We uncover overexpression of synaptic neuroligin as an evolutionarily conserved consequence of mitochondrial dysfunction, which we find to mediate an early cholinergic defect inC. elegans. We show lutein exerts its beneficial effects by restoring neuroligin expression independently from its antioxidant activity, thus pointing to a possible novel pathogenetic target for the human disease.
Next-generation biomonitoring of the early-life chemical exposome in neonatal and infant development
Authors: Jamnik Thomas , Flasch Mira , Braun Dominik , Fareed Yasmin , Wasinger Daniel , Seki David , Berry David , Berger Angelika , Wisgrill Lukas , Warth Benedikt
Published: May 2022

Exposure to synthetic and natural chemicals is a major environmental risk factor in the etiology of many chronic diseases. Investigating complex co-exposures is necessary for a holistic assessment in exposome-wide association studies. In this work, a sensitive liquid chromatography-tandem mass spectrometry approach was developed and validated. The assay enables the analysis of more than 80 highly-diverse xenobiotics in urine, serum/plasma, and breast milk; with detection limits generally in the pg-ng mL−1 range. In plasma of extremely-premature infants, 27 xenobiotics are identified; including contamination with plasticizers, perfluorinated alkylated substances and parabens. In breast milk samples collected longitudinally over the first 211 days post-partum, 29 analytes are detected, including pyrrolizidine- and tropane alkaloids which have not been identified in this matrix before. A preliminary estimation of daily toxicant intake via breast milk is conducted. In conclusion, we observe significant early-life co-exposure to multiple toxicants, and demonstrate the method’s applicability for large-scale exposomics-type cohort studies.
Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia
Authors: Bassal Mahmoud A. , Samaraweera Saumya E. , Lim Kelly , Benard Brooks A. , Bailey Sheree , Kaur Satinder , Leo Paul , Toubia John , Thompson-Peach Chloe , Nguyen Tran , Maung Kyaw Ze Ya , Casolari Debora A. , Iarossi Diana G. , Pagani Ilaria S. , Powell Jason , Pitson Stuart , Natera Siria , Roessner Ute , Lewis Ian D. , Brown Anna L. , Tenen Daniel G. , Robinson Nirmal , Ross David M. , Majeti Ravindra , Gonda Thomas J. , Thomas Daniel , D’Andrea Richard J.
Published: May 2022

The interaction of germline variation and somatic cancer driver mutations is under-investigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondrially-encoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.
Dissociable multi-scale patterns of development in personalized brain networks
Authors: Pines Adam R. , Larsen Bart , Cui Zaixu , Sydnor Valerie J. , Bertolero Maxwell A. , Adebimpe Azeez , Alexander-Bloch Aaron F. , Davatzikos Christos , Fair Damien A. , Gur Ruben C. , Gur Raquel E. , Li Hongming , Milham Michael P. , Moore Tyler M. , Murtha Kristin , Parkes Linden , Thompson-Schill Sharon L. , Shanmugan Sheila , Shinohara Russell T. , Weinstein Sarah M. , Bassett Danielle S. , Fan Yong , Satterthwaite Theodore D.
Published: May 2022

The brain is organized into networks at multiple resolutions, or scales, yet studies of functional network development typically focus on a single scale. Here, we derive personalized functional networks across 29 scales in a large sample of youths (n = 693, ages 8–23 years) to identify multi-scale patterns of network re-organization related to neurocognitive development. We found that developmental shifts in inter-network coupling reflect and strengthen a functional hierarchy of cortical organization. Furthermore, we observed that scale-dependent effects were present in lower-order, unimodal networks, but not higher-order, transmodal networks. Finally, we found that network maturation had clear behavioral relevance: the development of coupling in unimodal and transmodal networks are dissociably related to the emergence of executive function. These results suggest that the development of functional brain networks align with and refine a hierarchy linked to cognition.
Precisely translating computed tomography diagnosis accuracy into therapeutic intervention by a carbon-iodine conjugated polymer
Authors: Yin Mingming , Liu Xiaoming , Lei Ziqiao , Gao Yuting , Liu Jiacheng , Tian Sidan , Liang Zhiwen , Wang Ye , Meng Fanling , Luo Liang
Published: May 2022

X-ray computed tomography (CT) has an important role in precision medicine. However, CT contrast agents with high efficiency and the ability to translate diagnostic accuracy into therapeutic intervention are scarce. Here, poly(diiododiacetylene) (PIDA), a conjugated polymer composed of only carbon and iodine atoms, is reported as an efficient CT contrast agent to bridge CT diagnostic imaging with therapeutic intervention. PIDA has a high iodine payload (>84 wt%), and the aggregation of nanofibrous PIDA can further amplify CT intensity and has improved geometrical and positional stability in vivo. Moreover, with a conjugated backbone, PIDA is in deep blue color, making it dually visible by both CT imaging and the naked eyes. The performance of PIDA in CT-guided preoperative planning and visualization-guided surgery is validated using orthotopic xenograft rat models. In addition, PIDA excels clinical fiducial markers of imaging-guided radiotherapy in efficiency and biocompatibility, and exhibits successful guidance of robotic radiotherapy on Beagles, demonstrating clinical potential to translate CT diagnosis accuracy into therapeutic intervention for precision medicine.
Construction of boron-stereogenic compounds via enantioselective Cu-catalyzed desymmetric B–H bond insertion reaction
Authors: Zhang Guan , Zhang Zhihan , Hou Mengyuan , Cai Xinping , Yang Kai , Yu Peiyuan , Song Qiuling
Published: May 2022

Compared with the well-developed carbon-stereogenic chemistry, the construction of boron-stereogenic compounds remains undeveloped and challenging. Herein, the previously elusive catalytic enantioselective construction of boron-stereogenic compounds has been achieved through enantioselective desymmetric B–H bond insertion reaction. The B–H bond insertion reaction of 2-arylpyridine-boranes with versatile diazo compounds under chiral copper catalyst can afford boron-stereogenic compounds with good to excellent enantioselectivity. Moreover, the synthetic utility of this reaction is demonstrated by the scalability and downstream transformations. DFT calculations provide insights into the reaction mechanism and the origin of stereoselectivity.
Photo-thermo semi-hydrogenation of acetylene on Pd1/TiO2 single-atom catalyst
Authors: Guo Yalin , Huang Yike , Zeng Bin , Han Bing , AKRI Mohcin , Shi Ming , Zhao Yue , Li Qinghe , Su Yang , Li Lin , Jiang Qike , Cui Yi-Tao , Li Lei , Li Rengui , Qiao Botao , Zhang Tao
Published: May 2022

Semi-hydrogenation of acetylene in excess ethylene is a key industrial process for ethylene purification. Supported Pd catalysts have attracted most attention due to their superior intrinsic activity but often suffer from low selectivity. Pd single-atom catalysts (SACs) are promising to significantly improve the selectivity, but the activity needs to be improved and the feasible preparation of Pd SACs remains a grand challenge. Here, we report a simple strategy to construct Pd1/TiO2 SACs by selectively encapsulating the co-existed small amount of Pd nanoclusters/nanoparticles based on their different strong metal-support interaction (SMSI) occurrence conditions. In addition, photo-thermo catalysis has been applied to this process where a much-improved catalytic activity was obtained. Detailed characterization combined with DFT calculation suggests that photo-induced electrons transferred from TiO2 to the adjacent Pd atoms facilitate the activation of acetylene. This work offers an opportunity to develop highly stable Pd SACs for efficient catalytic semi-hydrogenation process.
MRNIP condensates promote DNA double-strand break sensing and end resection
Authors: Wang Yun-Long , Zhao Wan-Wen , Bai Shao-Mei , Feng Li-Li , Bie Shu-Ying , Gong Li , Wang Fang , Wei Ming-Biao , Feng Wei-Xing , Pang Xiao-Lin , Qin Cao-Litao , Yin Xin-Ke , Wang Ying-Nai , Zhou Weihua , Wahl Daniel R. , Liu Quentin , Chen Ming , Hung Mien-Chie , Wan Xiang-Bo
Published: May 2022

The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.
Sensory adaptation mediates efficient and unambiguous encoding of natural stimuli by vestibular thalamocortical pathways
Authors: Carriot Jerome , McAllister Graham , Hooshangnejad Hamed , Mackrous Isabelle , Cullen Kathleen E. , Chacron Maurice J.
Published: May 2022

Sensory systems must continuously adapt to optimally encode stimuli encountered within the natural environment. The prevailing view is that such optimal coding comes at the cost of increased ambiguity, yet to date, prior studies have focused on artificial stimuli. Accordingly, here we investigated whether such a trade-off between optimality and ambiguity exists in the encoding of natural stimuli in the vestibular system. We recorded vestibular nuclei and their target vestibular thalamocortical neurons during naturalistic and artificial self-motion stimulation. Surprisingly, we found no trade-off between optimality and ambiguity. Using computational methods, we demonstrate that thalamocortical neural adaptation in the form of contrast gain control actually reduces coding ambiguity without compromising the optimality of coding under naturalistic but not artificial stimulation. Thus, taken together, our results challenge the common wisdom that adaptation leads to ambiguity and instead suggest an essential role in underlying unambiguous optimized encoding of natural stimuli.
Tailored modular assembly derived self-healing polythioureas with largely tunable properties covering plastics, elastomers and fibers
Authors: Li Yan Mei , Zhang Ze Ping , Rong Min Zhi , Zhang Ming Qiu
Published: May 2022

To impart self-healing polymers largely adjustable dynamicity and mechanical performance, here we develop libraries of catalyst-free reversible polythioureas directly from commodity 1,4-phenylene diisothiocyanate and amines via facile click chemistry based modular assembly. By using the amine modules with various steric hindrances and flexibilities, the reversible thiourea units acquire triggering temperatures from room temperature to 120 °C. Accordingly, the derived self-healable, recyclable and controlled degradable dynamically crosslinked polythioureas can take effect within wide temperature range. Moreover, mechanical properties of the materials can be tuned covering plastics, elastomers and fibers using (i) different assemble modules or (ii) solid-state stretching. Particularly, unidirectional stretching leads to the record-high tensile strength of 266 MPa, while bidirectional stretching provides the materials with biaxial strengths up to over 120 MPa. The molecular mechanism and technological innovations discussed in this work may benefit promotion and application of self-healing polymers towards greatly diverse demands and scenarios.
Substrate recognition and cryo-EM structure of the ribosome-bound TAC toxin of Mycobacterium tuberculosis
Authors: Mansour Moise , Giudice Emmanuel , Xu Xibing , Akarsu Hatice , Bordes Patricia , Guillet Valérie , Bigot Donna-Joe , Slama Nawel , D’urso Gaetano , Chat Sophie , Redder Peter , Falquet Laurent , Mourey Lionel , Gillet Reynald , Genevaux Pierre
Published: May 2022

Toxins of toxin-antitoxin systems use diverse mechanisms to control bacterial growth. Here, we focus on the deleterious toxin of the atypical tripartite toxin-antitoxin-chaperone (TAC) system of Mycobacterium tuberculosis, whose inhibition requires the concerted action of the antitoxin and its dedicated SecB-like chaperone. We show that the TAC toxin is a bona fide ribonuclease and identify exact cleavage sites in mRNA targets on a transcriptome-wide scale in vivo. mRNA cleavage by the toxin occurs after the second nucleotide of the ribosomal A-site codon during translation, with a strong preference for CCA codons in vivo. Finally, we report the cryo-EM structure of the ribosome-bound TAC toxin in the presence of native M. tuberculosis cspA mRNA, revealing the specific mechanism by which the TAC toxin interacts with the ribosome and the tRNA in the P-site to cleave its mRNA target.
CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer
Authors: Filippone M. G. , Gaglio D. , Bonfanti R. , Tucci F. A. , Ceccacci E. , Pennisi R. , Bonanomi M. , Jodice G. , Tillhon M. , Montani F. , Bertalot G. , Freddi S. , Vecchi M. , Taglialatela A. , Romanenghi M. , Romeo F. , Bianco N. , Munzone E. , Sanguedolce F. , Vago G. , Viale G. , Di Fiore P. P. , Minucci S. , Alberghina L. , Colleoni M. , Veronesi P. , Tosoni D. , Pece S.
Published: May 2022

Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.