bluuebunny/crossref_metadata_2025 huggingface dataset:
Ornithine Transcarbamylase Deficiency Presenting with Symptoms of Mania in a Young Adult Male
Authors: Pentz Jonathan , Igboeli Blessing , Niedermier Julie
Published: May 2021

Study Objective

The purpose of this case study is to review the clinical presentation and medical workup of a young adult male presenting with acute behavior changes in the setting of undiagnosed ornithine transcarbamylase deficiency (OTCD)

Method

This case study involves a 19-year-old male with a psychiatric history of depression and one previous suicide attempt, who presented to a large midwestern university hospital emergency department after being found by police naked in a neighbor’s yard. He displayed manic signs and symptoms, including euphoria, lack of sleep for five days, and attempting to purchase a new car and three large screen TVs. Family reported the patient uncharacteristically announced three weeks earlier that he was vegetarian and stopped eating his frequent customary cheeseburgers. Due to increased anxiety and inability to sleep, the patient received lorazepam 2 mg in the emergency department. Upon transfer to the psychiatric unit, therapy was initiated with aripiprazole 5 mg daily and valproate 1000 mg nightly on Day 1 of treatment. The patient refused medications on hospital Day 2, then received this combination again on Day 3. The next morning, the patient complained of lethargy, headache, nausea, and vomiting.

Results

The patient’s ammonia level was found to be 204 micromol/L with ALT and AST of 714 and 647 IU/L respectively. Tests for infectious hepatitis were negative. Medical consultation recommended discontinuation of current medications, vigorous hydration, and further work up. On further investigation, the patient was found to have low plasma citrulline level of 8 micromol/L, undetectable plasma arginine, and high urinary orotic acid. The laboratory data showed a biochemical phenotype consistent with a diagnosis of partial OTCD, an X-linked urea cycle disorder resulting in toxic hyperammonemia. The patient was treated with a low protein diet modification as well as a combination of sodium benzoate and sodium phenylbutyrate to reduce serum ammonia concentration. With treatment the patient’s laboratory values normalized, and mental status improved.

Conclusions

In conclusion, partial ornithine transcarbamylase deficiency may manifest with psychiatric symptoms in early adulthood. In young patients with elevated ammonia and mental status change, OTCD is an important diagnosis to consider, as it is the most common inherited cause of hyperammonemia.
The role of the p90 ribosomal S6 kinase family in prostate cancer progression and therapy resistance
Authors: Cronin Ryan , Brooke Greg N. , Prischi Filippo
Published: May 2021

Prostate cancer (PCa) is the second most commonly occurring cancer in men, with over a million new cases every year worldwide. Tumor growth and disease progression is mainly dependent on the Androgen Receptor (AR), a ligand dependent transcription factor. Standard PCa therapeutic treatments include androgen-deprivation therapy and AR signaling inhibitors. Despite being successful in controlling the disease in the majority of men, the high frequency of disease progression to aggressive and therapy resistant stages (termed castrate resistant prostate cancer) has led to the search for new therapeutic targets. The p90 ribosomal S6 kinase (RSK1-4) family is a group of highly conserved Ser/Thr kinases that holds promise as a novel target. RSKs are effector kinases that lay downstream of the Ras/Raf/MEK/ERK signaling pathway, and aberrant activation or expression of RSKs has been reported in several malignancies, including PCa. Despite their structural similarities, RSK isoforms have been shown to perform nonredundant functions and target a wide range of substrates involved in regulation of transcription and translation. In this article we review the roles of the RSKs in proliferation and motility, cell cycle control and therapy resistance in PCa, highlighting the possible interplay between RSKs and AR in mediating disease progression. In addition, we summarize the current advances in RSK inhibitor development and discuss their potential clinical benefits.
Stainless steel corrosion via direct iron-to-microbe electron transfer by Geobacter species
Authors: Tang Hai-Yan , Yang Chuntian , Ueki Toshiyuki , Pittman Conor C , Xu Dake , Woodard Trevor L , Holmes Dawn E , Gu Tingyue , Wang Fuhui , Lovley Derek R
Published: May 2021

Microbial corrosion of iron-based materials is a substantial economic problem. A mechanistic understanding is required to develop mitigation strategies, but previous mechanistic studies have been limited to investigations with relatively pure Fe(0), which is not a common structural material. We report here that the mechanism for microbial corrosion of stainless steel, the metal of choice for many actual applications, can be significantly different from that for Fe(0). Although H2 is often an intermediary electron carrier between the metal and microbes during Fe(0) corrosion, we found that H2 is not abiotically produced from stainless steel, making this corrosion mechanism unlikely. Geobacter sulfurreducens and Geobacter metallireducens, electrotrophs that are known to directly accept electrons from other microbes or electrodes, extracted electrons from stainless steel via direct iron-to-microbe electron transfer. Genetic modification to prevent H2 consumption did not negatively impact on stainless steel corrosion. Corrosion was inhibited when genes for outer-surface cytochromes that are key electrical contacts were deleted. These results indicate that a common model of microbial Fe(0) corrosion by hydrogenase-positive microbes, in which H2 serves as an intermediary electron carrier between the metal surface and the microbe, may not apply to the microbial corrosion of stainless steel. However, direct iron-to-microbe electron transfer is a feasible route for stainless steel corrosion.
Diversity and distribution of viruses inhabiting the deepest ocean on Earth
Authors: Jian Huahua , Yi Yi , Wang Jiahua , Hao Yali , Zhang Mujie , Wang Siyuan , Meng Canxing , Zhang Yue , Jing Hongmei , Wang Yinzhao , Xiao Xiang
Published: May 2021

As the most abundant biological entities on the planet, viruses significantly influence the overall functioning of marine ecosystems. The abundance, distribution, and biodiversity of viral communities in the upper ocean have been relatively well studied, but our understanding of viruses in the hadal biosphere remains poor. Here, we established the oceanic trench viral genome dataset (OTVGD) by analysing 19 microbial metagenomes derived from seawater and sediment samples of the Mariana, Yap, and Kermadec Trenches. The trench viral communities harbored remarkably high novelty, and they were predicted to infect ecologically important microbial clades, including Thaumarchaeota and Oleibacter. Significant inter-trench and intra-trench exchange of viral communities was proposed. Moreover, viral communities in different habitats (seawater/sediment and depth-stratified ocean zones) exhibited distinct niche-dependent distribution patterns and genomic properties. Notably, microbes and viruses in the hadopelagic seawater seemed to preferably adopt lysogenic lifestyles compared to those in the upper ocean. Furthermore, niche-specific auxiliary metabolic genes were identified in the hadal viral genomes, and a novel viral D-amino acid oxidase was functionally and phylogenetically characterized, suggesting the contribution of these genes in the utilization of refractory organic matter. Together, these findings highlight the genomic novelty, dynamic movement, and environment-driven diversification of viral communities in oceanic trenches, and suggest that viruses may influence the hadal ecosystem by reprogramming the metabolism of their hosts and modulating the community of keystone microbes.
Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression
Authors: Ryoo Baek-Yeol , Cheng Ann-Li , Ren Zhenggang , Kim Tae-You , Pan Hongming , Rau Kun-Ming , Choi Hye Jin , Park Joong-Won , Kim Jee Hyun , Yen Chia Jui , Lim Ho Yeong , Zhou Dongli , Straub Josef , Scheele Juergen , Berghoff Karin , Qin Shukui
Published: May 2021

Background

This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression.

Methods

In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP).

Results

In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib.

Conclusions

Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression.

Trial registration

ClinicalTrials.gov NCT01988493.
M2 macrophage-derived exosomal long non-coding RNA AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing microRNA-296 and elevating NOTCH2
Authors: Zhang Fuquan , Sang Yonghua , Chen Donglai , Wu Xuejie , Wang Xiaofan , Yang Wentao , Chen Yongbing
Published: May 2021

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play vital roles in human diseases. We aimed to identify the effect of the lncRNA AGAP2 antisense RNA 1 (AGAP2-AS1)/miR-296/notch homolog protein 2 (NOTCH2) axis on the progression and radioresistance of lung cancer. Expression of AGAP2-AS1, miR-296, and NOTCH2 in lung cancer cells and tissues from radiosensitive and radioresistant patients was determined, and the predictive role of AGAP2-AS1 in the prognosis of patients was identified. THP-1 cells were induced and exosomes were extracted, and the lung cancer cells were respectively treated with silenced AGAP2-AS1, exosomes, and exosomes upregulating AGAP2-AS1 or downregulating miR-296. The cells were radiated under different doses, and the biological processes of cells were assessed. Moreover, the natural killing cell-mediated cytotoxicity on lung cancer cells was determined. The relationships between AGAP2-AS1 and miR-296, and between miR-296 and NOTCH2 were verified. AGAP2-AS1 and NOTCH2 increased while miR-296 decreased in radioresistant patients and lung cancer cells. The malignant behaviors of radioresistant cells were promoted compared with the parent cells. Inhibited AGAP2-AS1, macrophage-derived exosomes, and exosomes overexpressing AGAP2-AS1 or inhibiting miR-296 facilitated the malignant phenotypes of radioresistant lung cancer cells. Furthermore, AGAP2-AS1 negatively regulated miR-296, and NOTCH2 was targeted by miR-296. M2 macrophage-derived exosomal AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing miR-296 and elevating NOTCH2. This study may be helpful for the investigation of radiotherapy of lung cancer.
Predictive performance of international COVID-19 mortality forecasting models
Authors: Friedman Joseph , Liu Patrick , Troeger Christopher E. , Carter Austin , Reiner Robert C. , Barber Ryan M. , Collins James , Lim Stephen S. , Pigott David M. , Vos Theo , Hay Simon I. , Murray Christopher J. L. , Gakidou Emmanuela
Published: May 2021

Forecasts and alternative scenarios of COVID-19 mortality have been critical inputs for pandemic response efforts, and decision-makers need information about predictive performance. We screen n = 386 public COVID-19 forecasting models, identifying n = 7 that are global in scope and provide public, date-versioned forecasts. We examine their predictive performance for mortality by weeks of extrapolation, world region, and estimation month. We additionally assess prediction of the timing of peak daily mortality. Globally, models released in October show a median absolute percent error (MAPE) of 7 to 13% at six weeks, reflecting surprisingly good performance despite the complexities of modelling human behavioural responses and government interventions. Median absolute error for peak timing increased from 8 days at one week of forecasting to 29 days at eight weeks and is similar for first and subsequent peaks. The framework and public codebase (https://github.com/pyliu47/covidcompare) can be used to compare predictions and evaluate predictive performance going forward.
MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography
Authors: Clabbers Max T. B. , Holmes Susannah , Muusse Timothy W. , Vajjhala Parimala R. , Thygesen Sara J. , Malde Alpeshkumar K. , Hunter Dominic J. B. , Croll Tristan I. , Flueckiger Leonie , Nanson Jeffrey D. , Rahaman Md. Habibur , Aquila Andrew , Hunter Mark S. , Liang Mengning , Yoon Chun Hong , Zhao Jingjing , Zatsepin Nadia A. , Abbey Brian , Sierecki Emma , Gambin Yann , Stacey Katryn J. , Darmanin Connie , Kobe Bostjan , Xu Hongyi , Ve Thomas
Published: May 2021

MyD88 and MAL are Toll-like receptor (TLR) adaptors that signal to induce pro-inflammatory cytokine production. We previously observed that the TIR domain of MAL (MALTIR) forms filaments in vitro and induces formation of crystalline higher-order assemblies of the MyD88 TIR domain (MyD88TIR). These crystals are too small for conventional X-ray crystallography, but are ideally suited to structure determination by microcrystal electron diffraction (MicroED) and serial femtosecond crystallography (SFX). Here, we present MicroED and SFX structures of the MyD88TIR assembly, which reveal a two-stranded higher-order assembly arrangement of TIR domains analogous to that seen previously for MALTIR. We demonstrate via mutagenesis that the MyD88TIR assembly interfaces are critical for TLR4 signaling in vivo, and we show that MAL promotes unidirectional assembly of MyD88TIR. Collectively, our studies provide structural and mechanistic insight into TLR signal transduction and allow a direct comparison of the MicroED and SFX techniques.
Dipolar-stabilized first and second-order antiskyrmions in ferrimagnetic multilayers
Authors: Heigl Michael , Koraltan Sabri , Vaňatka Marek , Kraft Robert , Abert Claas , Vogler Christoph , Semisalova Anna , Che Ping , Ullrich Aladin , Schmidt Timo , Hintermayr Julian , Grundler Dirk , Farle Michael , Urbánek Michal , Suess Dieter , Albrecht Manfred
Published: May 2021

Skyrmions and antiskyrmions are topologically protected spin structures with opposite vorticities. Particularly in coexisting phases, these two types of magnetic quasi-particles may show fascinating physics and potential for spintronic devices. While skyrmions are observed in a wide range of materials, until now antiskyrmions were exclusive to materials with D2d symmetry. In this work, we show first and second-order antiskyrmions stabilized by magnetic dipole–dipole interaction in Fe/Gd-based multilayers. We modify the magnetic properties of the multilayers by Ir insertion layers. Using Lorentz transmission electron microscopy imaging, we observe coexisting antiskyrmions, Bloch skyrmions, and type-2 bubbles and determine the range of material properties and magnetic fields where the different spin objects form and dissipate. We perform micromagnetic simulations to obtain more insight into the studied system and conclude that the reduction of saturation magnetization and uniaxial magnetic anisotropy leads to the existence of this zoo of different spin objects and that they are primarily stabilized by dipolar interaction.
Genoppi is an open-source software for robust and standardized integration of proteomic and genetic data
Authors: Pintacuda Greta , Lassen Frederik H. , Hsu Yu-Han H. , Kim April , Martín Jacqueline M. , Malolepsza Edyta , Lim Justin K. , Fornelos Nadine , Eggan Kevin C. , Lage Kasper
Published: May 2021

Combining genetic and cell-type-specific proteomic datasets can generate biological insights and therapeutic hypotheses, but a technical and statistical framework for such analyses is lacking. Here, we present an open-source computational tool called Genoppi (lagelab.org/genoppi) that enables robust, standardized, and intuitive integration of quantitative proteomic results with genetic data. We use Genoppi to analyze 16 cell-type-specific protein interaction datasets of four proteins (BCL2, TDP-43, MDM2, PTEN) involved in cancer and neurological disease. Through systematic quality control of the data and integration with published protein interactions, we show a general pattern of both cell-type-independent and cell-type-specific interactions across three cancer cell types and one human iPSC-derived neuronal cell type. Furthermore, through the integration of proteomic and genetic datasets in Genoppi, our results suggest that the neuron-specific interactions of these proteins are mediating their genetic involvement in neurodegenerative diseases. Importantly, our analyses suggest that human iPSC-derived neurons are a relevant model system for studying the involvement of BCL2 and TDP-43 in amyotrophic lateral sclerosis.
Agricultural subsidies and global greenhouse gas emissions
Authors: Laborde David , Mamun Abdullah , Martin Will , Piñeiro Valeria , Vos Rob
Published: May 2021

Agricultural production is strongly affected by and a major contributor to climate change. Agriculture and land-use change account for a quarter of total global emissions of greenhouse gases (GHG). Agriculture receives around US$600 billion per year worldwide in government support. No rigorous quantification of the impact of this support on GHG emissions has been available. This article helps fill the void. Here, we find that, while over the years the government support has incentivized the development of high-emission farming systems, at present, the support only has a small impact in terms of inducing additional global GHG emissions from agricultural production; partly because support is not systematically biased towards high-emission products, and partly because support generated by trade protection reduces demand for some high-emission products by raising their consumer prices. Substantially reducing GHG emissions from agriculture while safeguarding food security requires a more comprehensive revamping of existing support to agriculture and food consumption.
Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
Authors: Lauterborn Julie C. , Scaduto Pietro , Cox Conor D. , Schulmann Anton , Lynch Gary , Gall Christine M. , Keene C. Dirk , Limon Agenor
Published: May 2021

Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer’s disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.
Unconventional singularities and energy balance in frictional rupture
Authors: Brener Efim A. , Bouchbinder Eran
Published: May 2021

A widespread framework for understanding frictional rupture, such as earthquakes along geological faults, invokes an analogy to ordinary cracks. A distinct feature of ordinary cracks is that their near edge fields are characterized by a square root singularity, which is intimately related to the existence of strict dissipation-related lengthscale separation and edge-localized energy balance. Yet, the interrelations between the singularity order, lengthscale separation and edge-localized energy balance in frictional rupture are not fully understood, even in physical situations in which the conventional square root singularity remains approximately valid. Here we develop a macroscopic theory that shows that the generic rate-dependent nature of friction leads to deviations from the conventional singularity, and that even if this deviation is small, significant non-edge-localized rupture-related dissipation emerges. The physical origin of the latter, which is predicted to vanish identically in the crack analogy, is the breakdown of scale separation that leads an accumulated spatially-extended dissipation, involving macroscopic scales. The non-edge-localized rupture-related dissipation is also predicted to be position dependent. The theoretical predictions are quantitatively supported by available numerical results, and their possible implications for earthquake physics are discussed.
Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
Authors: Wang Feng , Morita Kiyomi , DiNardo Courtney D. , Furudate Ken , Tanaka Tomoyuki , Yan Yuanqing , Patel Keyur P. , MacBeth Kyle J. , Wu Bin , Liu Guowen , Frattini Mark , Matthews Jairo A. , Little Latasha D. , Gumbs Curtis , Song Xingzhi , Zhang Jianhua , Thompson Erika J. , Kadia Tapan M. , Garcia-Manero Guillermo , Jabbour Elias , Ravandi Farhad , Bhalla Kapil N. , Konopleva Marina , Kantarjian Hagop M. , Andrew Futreal P. , Takahashi Koichi
Published: May 2021

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.
Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers
Authors: Peng David H. , Rodriguez B. Leticia , Diao Lixia , Gaudreau Pierre-Olivier , Padhye Aparna , Konen Jessica M. , Ochieng Joshua K. , Class Caleb A. , Fradette Jared J. , Gibson Laura , Chen Limo , Wang Jing , Byers Lauren A. , Gibbons Don. L.
Published: May 2021

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.
Author Correction: Direct identification of Mott Hubbard band pattern beyond charge density wave superlattice in monolayer 1T-NbSe2
Authors: Liu Liwei , Yang Han , Huang Yuting , Song Xuan , Zhang Quanzhen , Huang Zeping , Hou Yanhui , Chen Yaoyao , Xu Ziqiang , Zhang Teng , Wu Xu , Sun Jiatao , Huang Yuan , Zheng Fawei , Li Xianbin , Yao Yugui , Gao Hong-Jun , Wang Yeliang
Published: May 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23418-z
MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study
Authors: Mitchell Jennifer M. , Bogenschutz Michael , Lilienstein Alia , Harrison Charlotte , Kleiman Sarah , Parker-Guilbert Kelly , Ot’alora G. Marcela , Garas Wael , Paleos Casey , Gorman Ingmar , Nicholas Christopher , Mithoefer Michael , Carlin Shannon , Poulter Bruce , Mithoefer Ann , Quevedo Sylvestre , Wells Gregory , Klaire Sukhpreet S. , van der Kolk Bessel , Tzarfaty Keren , Amiaz Revital , Worthy Ray , Shannon Scott , Woolley Joshua D. , Marta Cole , Gelfand Yevgeniy , Hapke Emma , Amar Simon , Wallach Yair , Brown Randall , Hamilton Scott , Wang Julie B. , Coker Allison , Matthews Rebecca , de Boer Alberdina , Yazar-Klosinski Berra , Emerson Amy , Doblin Rick
Published: May 2021

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001,d = 0.91) and to significantly decrease the SDS total score (P = 0.0116,d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.
Structural and physical properties of 99 complex bulk chalcogenides crystals using first-principles calculations
Authors: Hasan Sahib , Baral Khagendra , Li Neng , Ching Wai-Yim
Published: May 2021

Chalcogenide semiconductors and glasses have many applications in the civil and military fields, especially in relation to their electronic, optical and mechanical properties for energy conversion and in enviormental materials. However, they are much less systemically studied and their fundamental physical properties for a large class chalcogenide semiconductors are rather scattered and incomplete. Here, we present a detailed study using well defined first-principles calculations on the electronic structure, interatomic bonding, optical, and mechanical properties for 99 bulk chalcogenides including thirteen of these crytals which have never been calculated. Due to their unique composition and structures, these 99 bulk chalcogenides are divided into two main groups. The first group contains 54 quaternary crystals with the structure composition (A2BCQ4) (A = Ag, Cu; B = Zn, Cd, Hg, Mg, Sr, Ba; C = Si, Ge, Sn; Q = S, Se, Te), while the second group contains scattered ternary and quaternary chalcogenide crystals with a more diverse composition (AxByCzQn) (A = Ag, Cu, Ba, Cs, Li, Tl, K, Lu, Sr; B = Zn, Cd, Hg, Al, Ga, In, P, As, La, Lu, Pb, Cu, Ag; C = Si, Ge, Sn, As, Sb, Bi, Zr, Hf, Ga, In; Q = S, Se, Te; $$\hbox {x} = 1$$

x
=
1

, 2, 3; $$\hbox {y} = 0$$

y
=
0

, 1, 2, 5; $$\hbox {z} = 0$$

z
=
0

, 1, 2 and $$\hbox {n} = 3$$

n
=
3

, 4, 5, 6, 9). Moreover, the total bond order density (TBOD) is used as a single quantum mechanical metric to characterize the internal cohesion of these crystals enabling us to correlate them with the calculated properties, especially their mechanical properties. This work provides a very large database for bulk chalcogenides crucial for the future theoretical and experimental studies, opening opportunities for study the properties and potential application of a wide variety of chalcogenides.
Texture analysis of muscle MRI: machine learning-based classifications in idiopathic inflammatory myopathies
Authors: Nagawa Keita , Suzuki Masashi , Yamamoto Yuuya , Inoue Kaiji , Kozawa Eito , Mimura Toshihide , Nakamura Koichiro , Nagata Makoto , Niitsu Mamoru
Published: May 2021

To develop a machine learning (ML) model that predicts disease groups or autoantibodies in patients with idiopathic inflammatory myopathies (IIMs) using muscle MRI radiomics features. Twenty-two patients with dermatomyositis (DM), 14 with amyopathic dermatomyositis (ADM), 19 with polymyositis (PM) and 19 with non-IIM were enrolled. Using 2D manual segmentation, 93 original features as well as 93 local binary pattern (LBP) features were extracted from MRI (short-tau inversion recovery [STIR] imaging) of proximal limb muscles. To construct and compare ML models that predict disease groups using each set of features, dimensional reductions were performed using a reproducibility analysis by inter-reader and intra-reader correlation coefficients, collinearity analysis, and the sequential feature selection (SFS) algorithm. Models were created using the linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), support vector machine (SVM), k-nearest neighbors (k-NN), random forest (RF) and multi-layer perceptron (MLP) classifiers, and validated using tenfold cross-validation repeated 100 times. We also investigated whether it was possible to construct models predicting autoantibody status. Our ML-based MRI radiomics models showed the potential to distinguish between PM, DM, and ADM. Models using LBP features provided better results, with macro-average AUC values of 0.767 and 0.714, accuracy of 61.2 and 61.4%, and macro-average recall of 61.9 and 59.8%, in the LDA and k-NN classifiers, respectively. In contrast, the accuracies of radiomics models distinguishing between non-IIM and IIM disease groups were low. A subgroup analysis showed that classification models for anti-Jo-1 and anti-ARS antibodies provided AUC values of 0.646–0.853 and 0.692–0.792, with accuracy of 71.5–81.0 and 65.8–78.3%, respectively. ML-based TA of muscle MRI may be used to predict disease groups or the autoantibody status in patients with IIM and is useful in non-invasive assessments of disease mechanisms.
3-D health trajectories and related childhood predictors among older adults in China
Authors: Pan Chaoping , Wang Cen , Shrestha Bhawana , Wang Peigang
Published: May 2021

This study aimed to identify the multi-trajectories of 3-D health of older adults in China and to explore whether the childhood predictors are associated with 3-D health trajectory. Data came from five waves of the China Health and Retirement Longitudinal Study (CHARLS, 2011 to 2018). A multi-trajectory modeling approach was carried out to jointly estimate the trajectories of 3-D health. A multinomial regression model was used to investigate the relationships between childhood predictors and the joint trajectories. We identified three typical joint 3-D health trajectories. Female, childhood health, maternal and paternal educations, childhood friendships, family and neighborhood predictors could all affect 3-D health trajectories of older adults directly or indirectly through adult variables. The 3-D health trajectories showed increasing trends, thus the government should perform more interventions toward the childhood predictors for better health of older adults.
Implementation of a deep learning model for automated classification of Aedes aegypti (Linnaeus) and Aedes albopictus (Skuse) in real time
Authors: Ong Song-Quan , Ahmad Hamdan , Nair Gomesh , Isawasan Pradeep , Majid Abdul Hafiz Ab
Published: May 2021

Classification of Aedes aegypti (Linnaeus) and Aedes albopictus (Skuse) by humans remains challenging. We proposed a highly accessible method to develop a deep learning (DL) model and implement the model for mosquito image classification by using hardware that could regulate the development process. In particular, we constructed a dataset with 4120 images of Aedes mosquitoes that were older than 12 days old and had common morphological features that disappeared, and we illustrated how to set up supervised deep convolutional neural networks (DCNNs) with hyperparameter adjustment. The model application was first conducted by deploying the model externally in real time on three different generations of mosquitoes, and the accuracy was compared with human expert performance. Our results showed that both the learning rate and epochs significantly affected the accuracy, and the best-performing hyperparameters achieved an accuracy of more than 98% at classifying mosquitoes, which showed no significant difference from human-level performance. We demonstrated the feasibility of the method to construct a model with the DCNN when deployed externally on mosquitoes in real time.
Author Correction: Methodological synthesis of Bayesian phylodynamics, HIV-TRACE, and GEE: HIV-1 transmission epidemiology in a racially/ethnically diverse Southern U.S. context
Authors: Fujimoto Kayo , Bahl Justin , Wertheim Joel O. , Del Vecchio Natascha , Hicks Joseph T. , Damodaran Lambodhar , Hallmark Camden J. , Lavingia Richa , Mora Ricardo , Carr Michelle , Yang Biru , Schneider John A. , Hwang Lu-Yu , McNeese Marlene
Published: May 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Optimizing pressure-driven pulsatile flows in microfluidic devices
Authors: Recktenwald Steffen M. , Wagner Christian , John Thomas
Published: May 2021

The presented software-based approach enables precise pulsatile flow generation in microfluidics without any hardware modifications to study time-dependent flows using commercial pressure controllers.
Separation of distinct exosome subpopulations: isolation and characterization approaches and their associated challenges
Authors: Singh Karishma , Nalabotala Ruchika , Koo Kevin M. , Bose Sudeep , Nayak Ranu , Shiddiky Muhammad J. A.
Published: May 2021

Currently, there exists a multitude of different exosome isolation and characterization approaches based on biophysical and/or biochemical characteristics. Herein we review various technologies for separation of distinct exosome subpopulations.
Anatase porous titania nanosheets for resonant-gravimetric detection of ppb-level NO2 at room-temperature
Authors: Yang Jialin , Wang Ding , Li Ming , Yu Haitao , Xu Pengcheng , Li Xinxin
Published: May 2021

Two-dimensional (2D) anatase porous TiO2 nanosheets are proposed as sensing materials for the resonant-gravimetric detection of ppb-level NO2 at room-temperature.
A cysteine-selective fluorescent probe for monitoring stress response cysteine fluctuations
Authors: Yang Yang , Zhang Liangwei , Zhang Xia , Liu Shudi , Wang Yue , Zhang Li , Ma Zhuo , You Huiyan , Chen Lingxin
Published: May 2021

A cysteine-selective fluorescent probe 1 was developed and successfully applied for monitoring stress response cysteine fluctuations.
Yield-prediction models for efficient exfoliation of soft layered materials into nanosheets
Authors: Noda Kyohei , Igarashi Yasuhiko , Imai Hiroaki , Oaki Yuya
Published: May 2021

A straightforward yield-prediction model constructed with the assistance of machine learning guides the appropriate solvents for efficient exfoliation of layered materials in high yield.
Furan warheads for covalent trapping of weak protein–protein interactions: cross-linking of thymosin β4 to actin
Authors: Miret-Casals Laia , Vannecke Willem , Hoogewijs Kurt , Arauz-Garofalo Gianluca , Gay Marina , Díaz-Lobo Mireia , Vilaseca Marta , Ampe Christophe , Van Troys Marleen , Madder Annemieke
Published: May 2021

Furan is used as a caged warhead to covalently target weak protein–protein interactions. Furan-thymosin β4 cross-links selectively and irreversibly with actin targeting lysine. Furan technology could be further exploited for covalent drug design.
Tandem catalysts for the selective hydrogenation of butadiene with hydrogen generated from the decomposition of formic acid
Authors: Carrales-Alvarado D. H. , Dongil A. B. , Guerrero-Ruiz A. , Rodríguez-Ramos I.
Published: May 2021

We report for the first time the selective hydrogenation of 1,3-butadiene to butene using formic acid as the hydrogen source with 1 wt% Pd/carbon in a continuous flow reactor.
Determining the mechanisms of deformation in flexible crystals using micro-focus X-ray diffraction
Authors: Thompson Amy J. , Worthy Anna , Grosjean Arnaud , Price Jason R. , McMurtrie John C. , Clegg Jack K.
Published: May 2021

A newly developed methodology allows for the determination of the mechanisms of deformation in flexible crystals with atomic precision. With broader applications, mapping experiments have wide reaching potential within the field of materials science.
Nitrate electroreduction: mechanism insight, in situ characterization, performance evaluation, and challenges
Authors: Wang Yuting , Wang Changhong , Li Mengyang , Yu Yifu , Zhang Bin
Published: May 2021

In this review, we summarize the reaction mechanism, in situ characterization, theoretical simulation, and kinetics analysis. The performance evaluation parameters, standard test methods, and an outlook for nitrate electroreduction are discussed.
Enhanced luminescence and tunable color in [Eu2+, Si4+]/Mn2+ doped K2BaCa(PO4)2 based on charge compensation and energy transfer
Authors: Wang Peng , Qiu Liting , Wei Xiantao , Yin Min , Chen Yonghu
Published: May 2021

After designing an [Eu2+, Si4+] → [K+, P5+] charge compensation strategy, the luminescence tuning performance of K2BaCa(PO4)2:[Eu2+, Si4+], Mn2+, which originated from energy transfer, was studied in detail.
Paired electrolysis of 5-(hydroxymethyl)furfural in flow cells with a high-performance oxide-derived silver cathode
Authors: Liu Hengzhou , Lee Ting-Han , Chen Yifu , Cochran Eric W. , Li Wenzhen
Published: May 2021

Paired electrolysis of HMF in a flow cell markedly reduces cell voltage and realizes co-production of BHMF and FDCA.
Hierarchical Ti-beta with a three-dimensional ordered mesoporosity for catalytic epoxidation of bulky cyclic olefins
Authors: You Qing , Wang Xu , Wu Yushuai , Bi Chenyao , Yang Xin , Sun Ming , Zhang Jianbo , Hao Qingqing , Chen Huiyong , Ma Xiaoxun
Published: May 2021

Hierarchical beta zeolites with a three-dimensionally ordered mesoporous-imprinted (3DOm-i) structure and post-synthetic Ti grafting for catalytic epoxidation of cyclic olefins.
Colorimetric determination of xanthine with xanthine oxidase and WSe2 nanosheets as a peroxidase mimic
Authors: Hong Chengyi , Guan Lingyan , Huang Lei , Hong Xiaoshan , Huang Zhiyong
Published: May 2021

A colorimetric method combining WSe2 nanosheets with peroxidase-like activity and xanthine oxidase was developed for xanthine detection in serum samples.
Fused triazolotriazine bearing a gem-dinitro group: a promising high energy density material
Authors: Wang Shaoqing , Li Congcong , Lu Tian , Wang Guilong , Yin Hongquan , Ma Qing , Fan Guijuan , Chen Fu-Xue
Published: May 2021

Improving the density and detonation velocity, and reducing the sensitivity by introducing the fluorodinitromethyl group.
Cationic tetra- and pentacoordinate complexes of nickel based on POCN- and POCOP-type pincer ligands: synthesis, characterization, and ligand exchange studies
Authors: Rahimi Naser , Zargarian Davit
Published: May 2021

The closely related pincer ligands POCN and POCOP display different electron donating properties and different degrees of resistance to ligand exchange reactions proceeding via cationic reaction intermediates.
Recent quinone diazide based transformations via metal–carbene formation
Authors: Bera Satabdi , Sarkar Souradip , Samanta Rajarshi
Published: May 2021

Recent advancements in versatile synthetic transformations using quinone diazide based metal carbenes have been summarized.
Asymmetric α-electrophilic difluoromethylation of β-keto esters by phase transfer catalysis
Authors: Wang Yakun , Wang Shuaifei , Qiu Peiyong , Fang Lizhen , Wang Ke , Zhang Yawei , Zhang Conghui , Zhao Ting
Published: May 2021

Enantioselective electrophilic difluoromethylation by phase transfer catalysis.
Cancer cachexia: molecular mechanism and pharmacological management
Authors: Li Yonghua , Jin Huan , Chen Yibing , Huang Ting , Mi Yanjun , Zou Zhengzhi
Published: May 2021

Cancer cachexia often occurs in malignant tumors and is a multifactorial and complex symptom characterized by wasting of skeletal muscle and adipose tissue, resulting in weight loss, poor life quality and shorter survival. The pathogenic mechanism of cancer cachexia is complex, involving a variety of molecular substrates and signal pathways. Advancements in understanding the molecular mechanisms of cancer cachexia have provided a platform for the development of new targeted therapies. Although recent outcomes of early-phase trials have showed that several drugs presented an ideal curative effect, monotherapy cannot be entirely satisfactory in the treatment of cachexia-associated symptoms due to its complex and multifactorial pathogenesis. Therefore, the lack of definitive therapeutic strategies for cancer cachexia emphasizes the need to develop a better understanding of the underlying mechanisms. Increasing evidences show that the progression of cachexia is associated with metabolic alternations, which mainly include excessive energy expenditure, increased proteolysis and mitochondrial dysfunction. In this review, we provided an overview of the key mechanisms of cancer cachexia, with a major focus on muscle atrophy, adipose tissue wasting, anorexia and fatigue and updated the latest progress of pharmacological management of cancer cachexia, thereby further advancing the interventions that can counteract cancer cachexia.
High-Speed Characterization of Vocal Fold Vibrations in Normally Cycling and Postmenopausal Women: Randomized Double-Blind Analyses
Authors: Patel Rita R. , Sandage Mary J. , Kluess Heidi , Plexico Laura W.
Published: May 2021

Purpose

The aim of this study was to examine the influence of menstrual cycle phases (follicular, ovulatory, luteal, and ischemic) and hormone levels (estradiol, testosterone, progesterone, and neuropeptide Y) on vocal fold vibrations in reproductive and postmenopausal women.

Method

Glottal area waveforms were extracted from high-speed videoendoscopy during sustained phonation, inhalation phonation, and voice onset/offset in the reproductive (
n
= 15) and postmenopausal (
n
= 13) groups. Linear mixed-model analysis was conducted to evaluate hormone levels and high-speed videoendoscopy outcome variables between the reproductive and postmenopausal groups. In the reproductive group, simple linear regression and multiple regression were conducted to determine the effects of hormones on the dependent variables.

Results

Group differences between reproductive and postmenopausal women were identified for stiffness index, oscillatory onset time, and oscillatory offset time. Neuropeptide Y hormone in the ischemic phase significantly predicted changes in the reproductive group for some dependent variables; however, the relationship varied for sustained phonation and inhalation phonation.

Conclusion

These findings provide preliminary evidence that vocal fold vibrations in the reproductive group are different predominantly in the ischemic phase due to neuropeptide Y changes.
Blockchain‐enabled secure crowdsensing for trackside infrastructure information collection and validation in railway signalling data preparation
Authors: Muniandi Ganesan
Published: May 2021

Rail operators around the world are adopting advanced control systems for railway signalling and train protection to improve their safety performance. In these re‐signalling projects, the information about the already installed signals, point machines, track circuits etc. along the trackside infrastructure is essential for the configuration of advanced signalling equipment. The conventional information collection method which is based on unmanned aerial vehicles, helicopters etc. has the access limitations in terrains such as tunnels, hilly regions, river bridges, dense forests etc. To overcome these challenges, this paper proposes the railway vehicular crowdsensing method in which one group of trains participates in this information collection and another group of trains confirms the validity of the collected information. For information exchange between the trains and centralized server, this study chooses the permissioned blockchain‐based information transaction mechanism to ensure the trustworthiness. Furthermore, the railway markup language‐based blockchain databases are included for information immutability, crowd information integration, and the automatic execution of data preparation signalling rules. Finally, the case studies are carried out to analyse the adequacy of the proposed combination of crowdsensing based secure trackside infrastructure information collection and validation, permissioned blockchain‐enabled information transaction and blockchain databases in the proposed signalling data preparation process.