bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental inflection point for the effect of maternal childhood adversity on children’s mental health from childhood to adolescence: Time-varying effect of gender differences
Authors: Lee Jungeun Olivia , Duan Lei , Lee Woo Jung , Rose Jennifer , Oxford Monica L. , Cederbaum Julie A.
Published: March 2022

Childhood adversities have a well-established dose–response relationship with later mental health. However, less attention has been given to intergenerational influences. Further, it is unknown how intergenerational influences intersect with children’s developmental stages and gender. The current study examined whether a developmental inflection point exists when the intergenerational influences of childhood adversities gain salience and explored differences by children’s gender. Data were from the Young Women and Child Development Study (n = 361). Time-varying effect models (TVEMs) and moderation TVEMs by child’s gender were evaluated. Our findings reveal that ages 5–8, the period of transition into primary schools, may represent a developmental inflection point when the intergenerational influences of maternal childhood adversity start emerging substantially. The results from gender interaction TVEMs reveal that maternal childhood adversity was a statistically significant predictor of internalizing problems until age 11, regardless of child’s gender, and remained statistically significant for girls’ internalizing problems until age 16.7. For externalizing problems, maternal childhood adversity was a statistically significant predictor until age 13, regardless of gender.
Left ventricular-infundibular apical septal defect: a rare entity revisited
Authors: Kakarla Saikiran , Sasikumar Deepa , Kurup Harikrishnan K. N.
Published: March 2022

Apical ventricular septal defects are a heterogeneous group of septal defects that need accurate anatomic characterisation for planning appropriate management. Left ventricular-infundibular apical septal defects are defects between the left ventricular septum and the infundibular apex of the right ventricle with distinctive morphological features. We describe two illustrative examples of this septal defect with focus on their therapeutic implications and long-term outcome.
How the ARCH Project has Contributed to the Development of the ASEAN Regional Collaboration Mechanism on Disaster Health Management
Authors: Silapunt Phumin , Fernando Ferdinal , Catampongan Jim , Limpaporn Sansana , Yuddhasaraprasiddhi Kittima , Promkhum Dangfun , Tianwibool Parinya , Sairai Phatsawan , Rungsansarit Hathairat , Wuthisuthimethawee Prasit , Keeratipongpaiboon Kanin , Tantivesruangdet Nopmanee , Chantaratin Kanungnij , Tiyawat Gawin , Takada Yosuke , Kita Taro , Kai Soichiro , Ikeda Shuichi
Published: March 2022

Objective:

This paper aims to clarify how the Project for Strengthening the ASEAN Regional Capacity on Disaster Health Management (ARCH Project) strengthened regional collaboration mechanisms on disaster health management (DHM) in ASEAN.

Methods:

The political process and the relevant documents of the ARCH Project were reviewed.

Results:

The ARCH Project established the Regional Coordination Committee as a coordination platform for providing strategic direction to the project and strengthening the regional coordination of DHM. Also, the Project Working Groups and Sub-Working Groups were set up as implementation bodies for the project activities with representatives of ASEAN Member States (AMS). With support from DHM experts of Japan and Thailand, a series of discussions were conducted for the development of a Standard Operating Procedure (SOP) for the Coordination of International Emergency Medical Teams (I-EMTs), regional tools, and collective measures supporting AMS to overcome challenges, and thereby meeting the minimum requirements set by the WHO EMT Initiative. The progress and outputs of the ARCH Project are subsequently elevated to the ASEAN Health Sector for endorsement, the updates are further shared to the Joint Task Force to Promote Synergy with Other Relevant ASEAN Bodies on Humanitarian Assistance and Disaster Relief (JTF-HADR) for the implementation of the ASEAN Declaration on One ASEAN One Response. The initiation of the ARCH Project in July 2016 has resulted in the development of the ASEAN regional collaboration framework, including the establishment of the Regional Coordination Committee on Disaster Health Management (RCCDHM), the SOP for ASEAN I-EMT coordination, and regional tools, such as forms for Medical Record for Emergency and Disaster and Health Needs Assessment. Moreover, further discussions on ASEAN Collective Measures that aim to support AMS to meet the WHO EMT minimum standards and strengthening I-EMT coordination capacity were also conducted. As adopted by the ASEAN Health Ministers Meeting (AHMM) in 2019, the RCCDHM was established as one of the mechanisms to operationalize the Plan of Action to implement the ASEAN Leaders’ Declaration on DHM.

Conclusion:

The contribution of the ARCH Project to strengthen the ASEAN regional capacity in DHM has enhanced the regional coordination platform, with a formalization of RCCDHM as ASEAN’s official regional mechanism, and of the on-going integration process of the SOP for EMT coordination into the ASEAN SASOP.
Design of monopole antennas based on progressive Gaussian process
Authors: Zheng Xie , Meng Fei , Tian Yubo , Zhang Xinyu
Published: March 2022

Electromagnetic simulation software has become an important tool for antenna design. However, high-fidelity simulation of wideband or ultra-wideband antennas is very expensive. Therefore, antenna optimization design by using an electromagnetic solver may be limited due to its high computational cost. This problem can be alleviated by the utilization of fast and accurate surrogate models. Unfortunately, conventional surrogate models for antenna design are usually prohibitive because training data acquisition is time-consuming. In order to solve the problem, a modeling method named progressive Gaussian process (PGP) is proposed in this study. Specially, when a Gaussian process (GP) is trained, test sample with the largest predictive variance is inputted into an electromagnetic solver to simulate its results. After that, the test sample is added to the training set to train the GP progressively. The process can incrementally increase some important trusted training data and improve the model generalization performance. Based on the proposed PGP, two monopole antennas are optimized. The optimization results show effectiveness and efficiency of the method.
A Single Dras‐Kohistan‐Ladakh Arc Revealed by Volcaniclastic Records
Authors: Andjić Goran , Zhou Renjie , Jonell Tara N. , Aitchison Jonathan C.
Published: March 2022

Tectonic interpretations of arc remnants in the Himalayan orogen remain uncertain, despite their important implications for the overall convergence history between India and Eurasia. Provenance results from deep‐water volcaniclastic rocks of the Indus Suture Zone in Ladakh provide new constraints on the Mesozoic tectonic evolution of the Dras and Kohistan‐Ladakh arcs. Detrital zircon (DZ) U‐Pb ages and whole‐rock geochemistry of the fault‐bounded Upper Cretaceous Nindam and Paleocene Jurutze formations present age patterns and compositions that are consistent with those of the Dras and Kohistan‐Ladakh arcs, respectively. The combination of DZs of the Nindam and Jurutze formations with the igneous zircons of the Dras and Kohistan‐Ladakh arcs shows similar age distributions that support a Late Jurassic to Paleocene tectonic connection between all these units. We argue that the secular trends in geochemical composition of DZs and volcaniclastic material are consistent with the magmatic evolution of one convergent margin, which shifted from a primitive to a mature stage during the Late Cretaceous. The recognition of a single Dras‐Kohistan‐Ladakh arc sets the stage for reevaluating competing scenarios of the Mesozoic evolution of the India–Eurasia convergent system. We find that the most likely scenario is that of a Jurassic arc formed above a south‐dipping intraoceanic subduction zone and accreted to Eurasia during the Early Cretaceous, after which it evolved above a north‐dipping subduction zone.
Increasing Functional Diversity in a Global Land Surface Model Illustrates Uncertainties Related to Parameter Simplification
Authors: Butler Ethan E. , Wythers Kirk R. , Flores‐Moreno Habacuc , Ricciuto Daniel M. , Datta Abhirup , Banerjee Arindam , Atkin Owen K. , Kattge Jens , Thornton Peter E. , Anand Madhur , Burrascano Sabina , Byun Chaeho , Cornelissen J. H. C. , Forey Estelle , Jansen Steven , Kramer Koen , Minden Vanessa , Reich Peter B.
Published: March 2022

Simulations of the land surface carbon cycle typically compress functional diversity into a small set of plant functional types (PFT), with parameters defined by the average value of measurements of functional traits. In most earth system models, all wild plant life is represented by between five and 14 PFTs and a typical grid cell (≈100 × 100 km) may contain a single PFT. Model logic applied to this coarse representation of ecological functional diversity provides a reasonable proxy for the carbon cycle, but does not capture the non‐linear influence of functional traits on productivity. Here we show through simulations using the Energy Exascale Land Surface Model in 15 diverse terrestrial landscapes, that better accounting for functional diversity markedly alters predicted total carbon uptake. The shift in carbon uptake is as great as 30% and 10% in boreal and tropical regions, respectively, when compared to a single PFT parameterized with the trait means. The traits that best predict gross primary production vary based on vegetation phenology, which broadly determines where traits fall within the global distribution. Carbon uptake is more closely associated with specific leaf area for evergreen PFTs and the leaf carbon to nitrogen ratio in deciduous PFTs.
Size‐Dependent Characteristics of Surface‐Rooted Three‐Dimensional Convective Objects in Continental Shallow Cumulus Simulations
Authors: Griewank Philipp J. , Heus Thijs , Neggers Roel A. J.
Published: March 2022

A segmentation algorithm is applied to high resolution simulations of shallow continental convection to identify individual convective 3D objects within the convective boundary layer, in order to investigate which properties of the objects vary with the object width. The study analyses the geometry of the objects, along with their profiles of vertical velocity and total water, to assess various assumptions often used in spectral mass‐flux convection schemes. The methodology of this paper is unique in that we use (a) a novel application of the watershed algorithm to detect individual objects in the constantly evolving continental boundary layer efficiently, and (b) an unprecedentedly large number of simulations being analyzed. In total, 26 days of LASSO simulations at the Atmospheric Radiation Measurement Southern Great Plains site are analyzed, yielding roughly one million objects. Plume‐like surface‐rooted objects are found to be omnipresent, the vertical extent of which is strongly dependent on the object width. The vertical velocity and moisture anomaly profiles of the widest objects are roughly consistent with the classic buoyancy‐driven rising plume model. The kinematic and thermodynamic properties of the objects vary with object width. This width dependence is strongest above cloud base, but much weaker below. Finally the impact of neglecting the contribution of covariances to the vertical moisture flux, which is commonly used in mass‐flux parameterizations, is investigated. The average effect of neglecting covariances increases linearly with object width, leading to a 20% flux underestimation for 2 km wide objects. Implications of the results for spectral convection scheme development are briefly discussed.
Modeling and Validating a SuperDARN Radar's Poynting Flux Profile
Authors: Perry G. W. , Ruzic K. D. , Sterne K. , Howarth A. D. , Yau A. W.
Published: March 2022

We have developed a model that simulates the Poynting flux profile of the Saskatoon Super Dual Auroral Radar Network (SuperDARN) radar at ionospheric altitudes. The model uses ray tracing software to project the radar system's vacuum Poynting flux profile through the ionosphere, taking into account the influence of the ionospheric medium on the propagation characteristics of the high frequency radio waves. Measurements of the radar's transmissions by the Radio Receiver Instrument (RRI) in low‐Earth orbit are used to validate the model during five experiments which occurred between 4 and 8 August 2017. Comparisons between simulated and measured RRI antenna voltages show good agreement, although there are clear instances in which the model underperforms. Nevertheless, the model demonstrates its utility as a tool for interpreting RRI measurements of SuperDARN radars. The model also helps address a lack of knowledge of a SuperDARN radar's Poynting flux profile at ionospheric altitudes. In particular, we assess the assumption that SuperDARN's scattering volume lies along the great‐circle path of the transmitting beam's bearing. Comparisons between the model and RRI's measurements show that this assumption is reasonable for the five experiments investigated in this work. The model presents a new way of carrying out SuperDARN and high frequency radio science investigations.
Aberrant hippocampal transmission and behavior in mice with a stargazin mutation linked to intellectual disability
Authors: Caldeira G. L. , Inácio A. S. , Beltrão N. , Barreto C. A. V. , Rodrigues M. V. , Rondão T. , Macedo R. , Gouveia R. P. , Edfawy M. , Guedes J. , Cruz B. , Louros S. R. , Moreira I. S. , Peça J. , Carvalho A. L.
Published: March 2022

Mutations linked to neurodevelopmental disorders, such as intellectual disability (ID), are frequently found in genes that encode for proteins of the excitatory synapse. Transmembrane AMPA receptor regulatory proteins (TARPs) are AMPA receptor auxiliary proteins that regulate crucial aspects of receptor function. Here, we investigate a mutant form of the TARP family member stargazin, described in an ID patient. Molecular dynamics analyses predicted that the ID-associated stargazin variant, V143L, weakens the overall interface of the AMPAR:stargazin complex and impairs the stability of the complex. Knock-in mice harboring the V143L stargazin mutation manifest cognitive and social deficits and hippocampal synaptic transmission defects, resembling phenotypes displayed by ID patients. In the hippocampus of stargazin V143L mice, CA1 neurons show impaired spine maturation, abnormal synaptic transmission and long-term potentiation specifically in basal dendrites, and synaptic ultrastructural alterations. These data suggest a causal role for mutated stargazin in the pathogenesis of ID and unveil a new role for stargazin in the development and function of hippocampal synapses.
Loss of IRF7 accelerates acute myeloid leukemia progression and induces VCAM1-VLA-4 mediated intracerebral invasion
Authors: Wang Hao , Zhang Dongyue , Cui Xiaoxi , Dai Yibo , Wang Chenchen , Feng Wenli , Lv Xiaoqian , Li Yifei , Wang Lina , Ru Yongxin , Zhang Yingchi , Ren Qian , Zheng Guoguang
Published: March 2022

Interferon regulatory factor 7 (IRF7) is widely studied in inflammatory models. Its effects on malignant progression have been documented mainly from the perspective of the microenvironment. However, its role in leukemia has not been established. Here we used MLL-AF9-induced acute myeloid leukemia (AML) mouse models with IRF7 knockout or overexpression and xenograft mouse models to explore the intrinsic effects of IRF7 in AML. AML-IRF7−/− mice exhibited accelerated disease progression with intracerebral invasion of AML cells. AML-IRF7−/− cells showed increased proliferation and elevated leukemia stem cell (LSC) levels. Overexpression of IRF7 in AML cells decreased cell proliferation and LSC levels. Furthermore, overexpression of transforming growth-interacting factor 1 (TGIF1) rescued the enhanced proliferation and high LSC levels caused by IRF7 deficiency. Moreover, upregulation of vascular cell adhesion molecule 1 (VCAM1), which correlated with high LSC levels, was detected in AML-IRF7−/− cells. In addition, blocking VCAM1-very late antigen 4 (VLA-4) axis delayed disease progression and attenuated intracerebral invasion of AML cells. Therefore, our findings uncover the intrinsic effects of IRF7 in AML and provide a potential strategy to control central nervous system myeloid leukemia.
PSMC2 promotes the progression of gastric cancer via induction of RPS15A/mTOR pathway
Authors: Liu Tao , Zhang Junling , Chen Hu , Bianba Tashi , Pan Yisheng , Wang Xin , Jiang Yong , Yang Zhen
Published: March 2022

As one of the most common malignant tumors, it is particularly important to further understand the development mechanism of gastric cancer and to find more effective therapeutic target genes. The results of immunohistochemical staining showed that PSMC2 was upregulated in gastric cancer. Cell function experiments indicated that PSMC2 knockdown inhibited the proliferation, clone formation and migration of gastric cancer cells, and induced apoptosis. In vivo experiments further showed that PSMC2 knockdown suppressed tumor growth. RPS15A and mTOR pathway were identified the downstream gene and pathway of PSMC2 by GeneChip and IPA. PSMC2 knockdown inhibited RPS15A expression and mTOR pathway, which was neutralized by RPS15A overexpression. Overexpression of RPS15A promoted the proliferation and migration of gastric cancer cells, which alleviated the inhibitory effect caused by PSMC2 knockdown to a certain extent. The mTOR pathway inhibitor Torin1 partially restored the promoting role of RPS15A overexpression on the gastric cancer cell proliferation. Furthermore, bioinformatics analysis and dual-luciferase reporter assays showed that PSMC2 and RPS15A competitively bound to hsa-let-7c-3p. Inhibition of hsa-let-7c-3p promoted the migration of MGC-803 cells and reduced the apoptosis level, while simultaneous inhibition PSMC2 and hsa-let-7c-3p restored the migration and apoptosis levels of gastric cancer cells. In conclusion, PSMC2 and RPS15A were highly expressed in gastric cancer. PSMC2 enhanced RPS15A levels by targeting hsa-let-7c-3p, and then activated mTOR pathway, thereby promoting the progression of gastric cancer.
Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase 2 trial
Authors: Zhang Xiaoying , Miao Miao , Zhang Ruijun , Liu Xu , Zhao Xiaozhen , Shao Miao , Liu Tian , Jin Yuebo , Chen Jiali , Liu Huixin , Zhang Xia , Li Yun , Zhou Yunshan , Yang Yue , Li Ru , Yao Haihong , Liu Yanying , Li Chun , Li Yuhui , Ren Limin , Su Yin , Sun Xiaolin , He Jing , Li Zhanguo
Published: March 2022

Rheumatoid arthritis (RA) is an aggressive autoimmune arthritis, and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects. Low-dose interleukin-2 (Ld-IL2) is potentially a therapeutic approach to further improve the disease. This randomized, double-blind, placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA. Patients were randomly assigned (1:1) to receive Ld-IL2, defined as a dose of 1 million IU, or placebo in a 12-week trial with a 12-week follow-up. Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks (a total of 7 doses), followed by a 2-week break. All patients received a stable dose of methotrexate (MTX). The primary outcomes were the proportion of patients achieving the ACR20, DAS28-ESR <2.6, and the change from baseline in CDAI or SDAI at week 24. Secondary endpoints included other clinical responses and safety. The primary outcomes were achieved in the per-protocol population. The improvements from baseline in CDAI and SDAI were significantly greater across time points for the Ld-IL2 + MTX group (n = 17) than for the placebo+MTX group (n = 23) (P = 0.018 and P = 0.015, respectively). More patients achieved ACR20 response in the Ld-IL2 + MTX group than those in the placebo+MTX group at week 12 (70.6% vs 43.5%) and at week 24 (76.5% vs 56.5%) (P = 0.014). In addition, low Treg and high IL-21 were associated with good responses to Ld-IL2. Ld-IL-2 treatment was well-tolerated in this study. These results suggested that Ld-IL2 was effective and safe in RA. ClinicalTrials.gov number: NCT 02467504.
Cancer and its predictors in Chinese adults with newly diagnosed diabetes and impaired glucose tolerance (IGT): a 30-year follow-up of the Da Qing IGT and Diabetes Study
Authors: He Siyao , Wang Jinping , Shen Xiaoxia , Qian Xin , An Yali , Gong Qiuhong , Zhang Bo , Chen Bo , Zhang Lihong , Chen Xiaoping , Chen Yanyan , Li Guangwei
Published: March 2022

Background

We aimed to explore if hyperglycaemia and hyperinsulinemia in the diabetes and prediabetes population were associated with increased risk of cancer occurence.

Methods

Overall, 1700 participants with different glycaemic statuses were screened from the 110,660 residents of Da-Qing, China, in 1985. They were followed up to 30 years to access cancer outcomes.

Results

Cancer was identified in 15.2% (259/1700) of the participants. The incidence of cancer in the normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes groups was 6.06, 6.77, and 7.18 per 1000 person-years, respectively (P = 0.02). In the Fine-Gray model with all cause death as competing risk, compared with the NGT controls, both IGT and diabetes groups demonstrated significantly higher risk of cancer (for the IGT group, adjusted hazard ratio (aHR) = 1.77, 95% CI 1.38–2.27, P < 0.0001; for the diabetes, aHR = 3.34, 95% CI 2.64–4.22, P < 0.0001). Among the IGT participants, progress to diabetes (aHR = 2.28, 95%CI 1.24–4.20, P = 0.008) and insulin-area under the curve at baseline (for 1 SD increase, aHR = 1.39, P = 0.02) were also associated with the risk of cancer after adjustment of covariables.

Conclusions

Hyperglycaemia in patients with diabetes, hyperinsulinemia, and progression to diabetes in people with IGT is significantly associated with the long-term increased risk of cancer occurrence.
Melatonin abolished proinflammatory factor expression and antagonized osteoarthritis progression in vivo
Authors: Liu Shan-Chi , Tsai Chun-Hao , Wang Yu-Han , Su Chen-Ming , Wu Hsi-Chin , Fong Yi-Chin , Yang Shun-Fa , Tang Chih-Hsin
Published: March 2022

Progressive structural changes in osteoarthritis (OA) involve synovial inflammation and angiogenesis, as well as activation of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL)-8, and the angiogenic factor vascular endothelial growth factor (VEGF). The endogenous hormone melatonin (N-acetyl-5-methoxytryptamine) is involved in antioxidative and anti-inflammatory activities, but how it antagonizes OA progression via its specific receptors is unclear. Here, we demonstrate that the MT1melatonin receptor, but not the MT2receptor, is highly expressed in normal tissue and only minimally in OA tissue. By targeting the MT1receptor, melatonin reversed OA-induced pathology and effectively reduced levels of TNF-α, IL-8, and VEGF expression in OA synovial fibroblasts and synovium from rats with severe OA. Interestingly, we found that the anabolic activities of melatonin involved the MT1receptor, which upregulated microRNA-185a through the PI3K/Akt and ERK signaling pathways in OA synovial fibroblasts. Our investigation confirms the role of the MT1receptor in melatonin-induced anti-catabolic effects in OA disease.
A general fruit acid chelation route for eco-friendly and ambient 3D printing of metals
Authors: Cho Soo Young , Ho Dong Hae , Choi Yoon Young , Lim Soomook , Lee Sungjoo , Suk Ji Won , Jo Sae Byeok , Cho Jeong Ho
Published: March 2022

Recent advances in metal additive manufacturing (AM) have provided new opportunities for prompt designs of prototypes and facile personalization of products befitting the fourth industrial revolution. In this regard, its feasibility of becoming a green technology, which is not an inherent aspect of AM, is gaining more interests. A particular interest in adapting and understanding of eco-friendly ingredients can set its important groundworks. Here, we demonstrate a water-based solid-phase binding agent suitable for binder jetting 3D printing of metals. Sodium salts of common fruit acid chelators form stable metal-chelate bridges between metal particles, enabling elaborate 3D printing of metals with improved strengths. Even further reductions in the porosity between the metal particles are possible through post-treatments. A compatibility of this chelation chemistry with variety of metals is also demonstrated. The proposed mechanism for metal 3D printing can open up new avenues for consumer-level personalized 3D printing of metals.
Effect of Chiral Damping on the dynamics of chiral domain walls and skyrmions
Authors: Safeer C. K. , Nsibi Mohamed-Ali , Nath Jayshankar , Gabor Mihai Sebastian , Yang Haozhe , Joumard Isabelle , Auffret Stephane , Gaudin Gilles , Miron Ioan-Mihai
Published: March 2022

Friction plays an essential role in most physical processes that we experience in our everyday life. Examples range from our ability to walk or swim, to setting boundaries of speed and fuel efficiency of moving vehicles. In magnetic systems, the displacement of chiral domain walls (DW) and skyrmions (SK) by Spin Orbit Torques (SOT), is also prone to friction. Chiral damping (αc), the dissipative counterpart of the Dzyaloshinskii Moriya Interaction (DMI), plays a central role in these dynamics. Despite experimental observation, and numerous theoretical studies confirming its existence, the influence of chiral damping on DW and SK dynamics has remained elusive due to the difficulty of discriminating from DMI. Here we unveil the effect that αc has on the flow motion of DWs and SKs driven by current and magnetic field. We use a static in-plane field to lift the chiral degeneracy. As the in-plane field is increased, the chiral asymmetry changes sign. When considered separately, neither DMI nor αc can explain the sign reversal of the asymmetry, which we prove to be the result of their competing effects. Finally, numerical modelling unveils the non-linear nature of chiral dissipation and its critical role for the stabilization of moving SKs.
Short-term effect of dopaminergic medication on speech in early-stage Parkinson’s disease
Authors: Tykalova Tereza , Novotny Michal , Ruzicka Evzen , Dusek Petr , Rusz Jan
Published: March 2022

The effect of dopaminergic medication on speech has rarely been examined in early-stage Parkinson’s disease (PD) and the respective literature is inconclusive and limited by inappropriate design with lack of PD control group. The study aims to examine the short-term effect of dopaminergic medication on speech in PD using patients with good motor responsiveness to levodopa challenge compared to a control group of PD patients with poor motor responsiveness. A total of 60 early-stage PD patients were investigated before (OFF) and after (ON) acute levodopa challenge and compared to 30 age-matched healthy controls. PD patients were categorised into two clinical subgroups (PD responders vs. PD nonresponders) according to the comparison of their motor performance based on movement disorder society-unified Parkinson’s disease rating scale, part III. Seven distinctive parameters of hypokinetic dysarthria were examined using quantitative acoustic analysis. We observed increased monopitch (p > 0.01), aggravated monoloudness (p > 0.05) and longer duration of stop consonants (p > 0.05) in PD compared to healthy controls, confirming the presence of hypokinetic dysarthria in early PD. No speech alterations from OFF to ON state were revealed in any of the two PD groups and speech dimensions investigated including monopitch, monoloudness, imprecise consonants, harsh voice, slow sequential motion rates, articulation rate, or inappropriate silences, although a subgroup of PD responders manifested obvious improvement in motor function after levodopa intake (p > 0.001). Since the short-term usage of levodopa does not easily affect voice and speech performance in PD, speech assessment may provide a medication state-independent motor biomarker of PD.
Squeezing the periodicity of Néel-type magnetic modulations by enhanced Dzyaloshinskii-Moriya interaction of 4d electrons
Authors: Butykai Ádám , Geirhos Korbinian , Szaller Dávid , Kiss László F. , Balogh László , Azhar Maria , Garst Markus , DeBeer-Schmitt Lisa , Waki Takeshi , Tabata Yoshikazu , Nakamura Hiroyuki , Kézsmárki István , Bordács Sándor
Published: March 2022

In polar magnets, such as GaV4S8, GaV4Se8 and VOSe2O5, modulated magnetic phases namely the cycloidal and the Néel-type skyrmion lattice states were identified over extended temperature ranges, even down to zero Kelvin. Our combined small-angle neutron scattering and magnetization study shows the robustness of the Néel-type magnetic modulations also against magnetic fields up to 2 T in the polar GaMo4S8. In addition to the large upper critical field, enhanced spin-orbit coupling stabilize cycloidal, Néel skyrmion lattice phases with sub-10 nm periodicity and a peculiar distribution of the magnetic modulation vectors. Moreover, we detected an additional single-q state not observed in any other polar magnets. Thus, our work demonstrates that non-centrosymmetric magnets with 4d and 5d electron systems may give rise to various highly compressed modulated states.
Pronounced loss of Amazon rainforest resilience since the early 2000s
Authors: Boulton Chris A. , Lenton Timothy M. , Boers Niklas
Published: March 2022

The resilience of the Amazon rainforest to climate and land-use change is crucial for biodiversity, regional climate and the global carbon cycle. Deforestation and climate change, via increasing dry-season length and drought frequency, may already have pushed the Amazon close to a critical threshold of rainforest dieback. Here, we quantify changes of Amazon resilience by applying established indicators (for example, measuring lag-1 autocorrelation) to remotely sensed vegetation data with a focus on vegetation optical depth (1991–2016). We find that more than three-quarters of the Amazon rainforest has been losing resilience since the early 2000s, consistent with the approach to a critical transition. Resilience is being lost faster in regions with less rainfall and in parts of the rainforest that are closer to human activity. We provide direct empirical evidence that the Amazon rainforest is losing resilience, risking dieback with profound implications for biodiversity, carbon storage and climate change at a global scale.
Hibernation slows epigenetic ageing in yellow-bellied marmots
Authors: Pinho Gabriela M. , Martin Julien G. A. , Farrell Colin , Haghani Amin , Zoller Joseph A. , Zhang Joshua , Snir Sagi , Pellegrini Matteo , Wayne Robert K. , Blumstein Daniel T. , Horvath Steve
Published: March 2022

Species that hibernate generally live longer than would be expected based solely on their body size. Hibernation is characterized by long periods of metabolic suppression (torpor) interspersed by short periods of increased metabolism (arousal). The torpor–arousal cycles occur multiple times during hibernation, and it has been suggested that processes controlling the transition between torpor and arousal states cause ageing suppression. Metabolic rate is also a known correlate of longevity; we thus proposed the ‘hibernation–ageing hypothesis’ whereby ageing is suspended during hibernation. We tested this hypothesis in a well-studied population of yellow-bellied marmots (Marmota flaviventer), which spend 7–8 months per year hibernating. We used two approaches to estimate epigenetic age: the epigenetic clock and the epigenetic pacemaker. Variation in epigenetic age of 149 samples collected throughout the life of 73 females was modelled using generalized additive mixed models (GAMM), where season (cyclic cubic spline) and chronological age (cubic spline) were fixed effects. As expected, the GAMM using epigenetic ages calculated from the epigenetic pacemaker was better able to detect nonlinear patterns in epigenetic ageing over time. We observed a logarithmic curve of epigenetic age with time, where the epigenetic age increased at a higher rate until females reached sexual maturity (two years old). With respect to circannual patterns, the epigenetic age increased during the active season and essentially stalled during the hibernation period. Taken together, our results are consistent with the hibernation–ageing hypothesis and may explain the enhanced longevity in hibernators.
DNA replication fork speed underlies cell fate changes and promotes reprogramming
Authors: Nakatani Tsunetoshi , Lin Jiangwei , Ji Fei , Ettinger Andreas , Pontabry Julien , Tokoro Mikiko , Altamirano-Pacheco Luis , Fiorentino Jonathan , Mahammadov Elmir , Hatano Yu , Van Rechem Capucine , Chakraborty Damayanti , Ruiz-Morales Elias R. , Arguello Pascualli Paola Y. , Scialdone Antonio , Yamagata Kazuo , Whetstine Johnathan R. , Sadreyev Ruslan I. , Torres-Padilla Maria-Elena
Published: March 2022

Totipotency emerges in early embryogenesis, but its molecular underpinnings remain poorly characterized. In the present study, we employed DNA fiber analysis to investigate how pluripotent stem cells are reprogrammed into totipotent-like 2-cell-like cells (2CLCs). We show that totipotent cells of the early mouse embryo have slow DNA replication fork speed and that 2CLCs recapitulate this feature, suggesting that fork speed underlies the transition to a totipotent-like state. 2CLCs emerge concomitant with DNA replication and display changes in replication timing (RT), particularly during the early S-phase. RT changes occur prior to 2CLC emergence, suggesting that RT may predispose to gene expression changes and consequent reprogramming of cell fate. Slowing down replication fork speed experimentally induces 2CLCs. In vivo, slowing fork speed improves the reprogramming efficiency of somatic cell nuclear transfer. Our data suggest that fork speed regulates cellular plasticity and that remodeling of replication features leads to changes in cell fate and reprogramming.
Structural basis of phosphatidylinositol 3-kinase C2α function
Authors: Lo Wen-Ting , Zhang Yingyi , Vadas Oscar , Roske Yvette , Gulluni Federico , De Santis Maria Chiara , Zagar Andreja Vujicic , Stephanowitz Heike , Hirsch Emilio , Liu Fan , Daumke Oliver , Kudryashev Misha , Haucke Volker
Published: March 2022

Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine.
Spatiotemporal 3D image registration for mesoscale studies of brain development
Authors: Shuvaev Sergey , Lazutkin Alexander , Kiryanov Roman , Anokhin Konstantin , Enikolopov Grigori , Koulakov Alexei A.
Published: March 2022

Comparison of brain samples representing different developmental stages often necessitates registering the samples to common coordinates. Although the available software tools are successful in registering 3D images of adult brains, registration of perinatal brains remains challenging due to rapid growth-dependent morphological changes and variations in developmental pace between animals. To address these challenges, we introduce CORGI (Customizable Object Registration for Groups of Images), an algorithm for the registration of perinatal brains. First, we optimized image preprocessing to increase the algorithm’s sensitivity to mismatches in registered images. Second, we developed an attention-gated simulated annealing procedure capable of focusing on the differences between perinatal brains. Third, we applied classical multidimensional scaling (CMDS) to align (“synchronize”) brain samples in time, accounting for individual development paces. We tested CORGI on 28 samples of whole-mounted perinatal mouse brains (P0–P9) and compared its accuracy with other registration algorithms. Our algorithm offers a runtime of several minutes per brain on a laptop and automates such brain registration tasks as mapping brain data to atlases, comparing experimental groups, and monitoring brain development dynamics.
Classification of pig calls produced from birth to slaughter according to their emotional valence and context of production
Authors: Briefer Elodie F. , Sypherd Ciara C.-R. , Linhart Pavel , Leliveld Lisette M. C. , Padilla de la Torre Monica , Read Eva R. , Guérin Carole , Deiss Véronique , Monestier Chloé , Rasmussen Jeppe H. , Špinka Marek , Düpjan Sandra , Boissy Alain , Janczak Andrew M. , Hillmann Edna , Tallet Céline
Published: March 2022

Vocal expression of emotions has been observed across species and could provide a non-invasive and reliable means to assess animal emotions. We investigated if pig vocal indicators of emotions revealed in previous studies are valid across call types and contexts, and could potentially be used to develop an automated emotion monitoring tool. We performed an analysis of an extensive and unique dataset of low (LF) and high frequency (HF) calls emitted by pigs across numerous commercial contexts from birth to slaughter (7414 calls from 411 pigs). Our results revealed that the valence attributed to the contexts of production (positive versus negative) affected all investigated parameters in both LF and HF. Similarly, the context category affected all parameters. We then tested two different automated methods for call classification; a neural network revealed much higher classification accuracy compared to a permuted discriminant function analysis (pDFA), both for the valence (neural network: 91.5%; pDFA analysis weighted average across LF and HF (cross-classified): 61.7% with a chance level at 50.5%) and context (neural network: 81.5%; pDFA analysis weighted average across LF and HF (cross-classified): 19.4% with a chance level at 14.3%). These results suggest that an automated recognition system can be developed to monitor pig welfare on-farm.
NAND and NOR logic-in-memory comprising silicon nanowire feedback field-effect transistors
Authors: Yang Yejin , Jeon Juhee , Son Jaemin , Cho Kyoungah , Kim Sangsig
Published: March 2022

The processing of large amounts of data requires a high energy efficiency and fast processing time for high-performance computing systems. However, conventional von Neumann computing systems have performance limitations because of bottlenecks in data movement between separated processing and memory hierarchy, which causes latency and high power consumption. To overcome this hindrance, logic-in-memory (LIM) has been proposed that performs both data processing and memory operations. Here, we present a NAND and NOR LIM composed of silicon nanowire feedback field-effect transistors, whose configuration resembles that of CMOS logic gate circuits. The LIM can perform memory operations to retain its output logic under zero-bias conditions as well as logic operations with a high processing speed of nanoseconds. The newly proposed dynamic voltage-transfer characteristics verify the operating principle of the LIM. This study demonstrates that the NAND and NOR LIM has promising potential to resolve power and processing speed issues.
Theory of Lehmer transform and its applications in identifying the electroencephalographic signature of major depressive disorder
Authors: Ataei Masoud , Wang Xiaogang
Published: March 2022

We propose a novel transformation called Lehmer transform and establish a theoretical framework used to compress and characterize large volumes of highly volatile time series data. The proposed method is a powerful data-driven approach for analyzing extreme events in non-stationary and highly oscillatory stochastic processes like biological signals. The proposed Lehmer transform decomposes the information contained in a function of the data sample into a domain of some statistical moments. The mentioned statistical moments, referred to as suddencies, can be perceived as the moments that generate all possible statistics when used as inputs of the transformation. Besides, the appealing analytical properties of Lehmer transform makes it a natural candidate to take on the role of a statistic-generating function, a notion that we define in this work for the first time. Possible connections of the proposed transformation to the frequency domain will be briefly discussed, while we extensively study various aspects of developing methodologies based on the time-suddency decomposition framework. In particular, we demonstrate several superior features of the Lehmer transform over the traditional time-frequency methods such as Fourier and Wavelet transforms by analyzing the challenging electroencephalogram signals of the patients suffering from the major depressive disorder. It is shown that our proposed transformation can successfully lead to more robust and accurate classifiers developed for discerning patients from healthy controls.
Oxidative, biochemical and histopathological alterations in fishes from pesticide contaminated river Ganga, India
Authors: Shah Zeshan Umar , Parveen Saltanat
Published: March 2022

The river Ganga basin accommodates large scale of agricultural activities, where large quantities of pesticides are applied. To assess the biological impact of pesticide residues that are continuously entering in the water body, biomarkers are common approach in bio-monitoring study as early warning signals to pollutants. In the present study qualitative and quantitative analyses of gill and liver histopathological and the biochemical parameters were determined in Rita rita and Cyprinus carpio. The difference in the histopathology and oxidative stress responses emphasize the response of selected fishes to the presence of contaminants in the water. Sloughing of lamellar epithelium and their disruption, dilated vessels, lamellar fusion, smooth muscle hypertrophy in the gill and necrosis, Vacuolation in hepatocytes, inflammation and distorted arterial walls were seen in the liver. The biochemical parameters were the main contributors to discriminate the changes in the fish physiology. In conclusion, the gill and liver histopathological responses, although not reflecting specific contaminants, but can be used as biomarkers of environmental contamination.
Structural modeling of human AKAP3 protein and in silico analysis of single nucleotide polymorphisms associated with sperm motility
Authors: Rafaee Alemeh , Kashani-Amin Elaheh , Meybodi Anahita Mohseni , Ebrahim-Habibi Azadeh , Sabbaghian Marjan
Published: March 2022

AKAP3 is a member of the A-kinase anchoring proteins and it is a constituent of the sperm fibrous sheath. AKAP3 is needed for the formation of sperm flagellum structure, sperm motility, and male fertility. This study aims to model the AKAP3 tertiary structure and identify the probable impact of four mutations characterized in infertile men on the AKAP3 structure. The T464S, I500T, E525K, and I661T substitutions were analyzed using in silico methods. The secondary structure and three-dimensional model of AKAP3 were determined using PSI-BLAST based secondary structure prediction and Robetta servers. The TM-score was used to quantitatively measure the structural similarities between native and mutated models. All of the desired substitutions were classified as benign. I-Mutant results showed all of the substitutions decreased AKAP3 stability; however, the I500T and I661T were more effective. Superposition and secondary structure comparisons between native and mutants showed no dramatic deviations. Our study provided an appropriate model for AKAP3. Destabilization of AKAP3 caused by these substitutions did not appear to induce structural disturbances. As AKAP3 is involved in male infertility, providing more structural insights and the impact of mutations that cause protein functional diversity could elucidate the etiology of male fertility problems at molecular level.
Development of high temperature simultaneous saccharification and fermentation by thermosensitive Saccharomyces cerevisiae and Bacillus amyloliquefaciens
Authors: Miah Roni , Siddiqa Ayesha , Chakraborty Udvashita , Tuli Jamsheda Ferdous , Barman Noyon Kumar , Uddin Aukhil , Aziz Tareque , Sharif Nadim , Dey Shuvra Kanti , Yamada Mamoru , Talukder Ali Azam
Published: March 2022

Scarcity of energy and pollution are two major challenges that have become a threat to all living things worldwide. Bioethanol is a renewable, ecological-friendly clean energy that may be utilized to address these issues. This study aimed to develop simultaneous saccharification and fermentation (SSF) process through high temperature-substrate adaptation and co-cultivation of S. cerevisiae with other potential amylolytic strains. In this study, we adapted our previously screened thermosensitive Saccharomyces cerevisiae Dj-3 strain up-to 42 °C and also screened three potential thermotolerant amylolytic strains based on their starch utilization capability. We performed SSF fermentation at high temperature by adapted Dj-3 and amylolytic strains using 10.0% starch feedstock. Interestingly, we observed significant ethanol concentration [3.86% (v/v)] from high temperature simultaneous saccharification and fermentation (HSSF) of adapted Bacillus amyloliquefaciens (C-7) and Dj-3. We attribute the significant ethanol concentration from starch of this HSSF process to C-7’s high levels of glucoamylase activity (4.01 U/ml/min) after adaptation in starch (up-to 42 °C) as well as Dj-3's strong glucose fermentation capacity and also their ethanol stress tolerance capability. This study suggests the significant feasibility of our HSSF process.
Low correlation between Ki67 assessed by qRT-PCR in Oncotype Dx score and Ki67 assessed by Immunohistochemistry
Authors: Selmani Zohair , Molimard Chloé , Overs Alexis , Bazan Fernando , Chaigneau Loic , Dobi Erion , Meneveau Nathalie , Mansi Laura , Paillard Marie-Justine , Meynard Guillaume , Viot Julien , Algros Marie-Paule , Borg Christophe , Feugeas Jean-Paul , Pivot Xavier , Prétet Jean-Luc , Curtit Elsa
Published: March 2022

Breast cancers expressing high levels of Ki67 are associated with poor outcomes. Oncotype DX test was designed for ER+/HER2− early-stage breast cancers to help adjuvant chemotherapy decision by providing a Recurrent Score (RS). RS measures the expression of 21 specific genes from tumor tissue, including Ki67. The primary aim of this study was to assess the agreement between Ki67RNA obtained with Oncotype DX RS and Ki67IHC. Other objectives were to analyze the association between the event free survival (EFS) and the expression level of Ki67RNA; and association between RS and Ki67RNA. Herein, we report a low agreement of 0.288 by Pearson correlation coefficient test between Ki67IHC and Ki67RNA in a cohort of 98 patients with early ER+/HER2− breast cancers. Moreover, Ki67RNAhigh tumors were significantly associated with the occurrence of events (p = 0.03). On the other hand, we did not find any association between Ki67IHC and EFS (p = 0.26). We observed a low agreement between expression level of Ki67RNA and Ki67 protein labelling by IHC. Unlike Ki67IHC and independently of the RS, Ki67RNA could have a prognostic value. It would be interesting to better assess the prognosis and predictive value of Ki67RNA measured by qRT-PCR. The Ki67RNA in medical routine could be a good support in countries where Oncotype DX is not accessible.