bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactions of Remotely Generated Internal Tides With the U.S. West Coast Continental Margin
Authors: Siyanbola Oladeji Q. , Buijsman Maarten C. , Delpech Audrey , Barkan Roy , Pan Yulin , Arbic Brian K.
Published: June 2024

Through interactions with the continental margins, incident low‐mode internal tides (ITs) can be reflected, scattered to high modes, transmitted onto the shelf and dissipated. We investigate the fate of remotely generated mode‐1 ITs in the U.S. West Coast (USWC) continental margin using two 4‐km horizontal resolution regional simulations. These 1‐year long simulations have realistic stratification, and atmospheric, tidal, and sub‐tidal forcings. In addition, one of these simulations has remote internal wave (IW) forcing at the open boundaries while the other does not. To compute the IT reflectivity of the USWC margin, we separate the IT energy fluxes into onshore and offshore propagating components using a Discrete Fourier Transform in space and time. Overall, ∼20% of the remote mode‐1 semidiurnal IT energy fluxes reflect off the USWC margin, 40% is scattered to modes 2–5, and 7% is transmitted onto the shelf while the remaining is dissipated on the continental slope. Furthermore, our results reveal that differences in stratification, slope criticality, topographic roughness and angle of incidence cause these fractions to vary spatially and temporally along the USWC margin. However, there is no clear seasonal variability in these estimates. Remote IWs enhance the advection and diffusion of heat in the continental margin, resulting in cooling at the surface and warming at depth, and a reduction in the thermocline stratification. These results suggest that low‐mode ITs can cause water mass transformation in continental margins that are far away from their generation sites.
Associations between obesity, a composite risk score for probable long COVID, and sleep problems in SARS-CoV-2 vaccinated individuals
Authors: Xue Pei , Merikanto Ilona , Delale Eva A. , Bjelajac Adrijana , Yordanova Juliana , Chan Rachel N. Y. , Korman Maria , Mota-Rolim Sérgio A. , Landtblom Anne-Marie , Matsui Kentaro , Reis Catia , Penzel Thomas , Inoue Yuichi , Nadorff Michael R. , Holzinger Brigitte , Morin Charles M. , Espie Colin A. , Plazzi Giuseppe , De Gennaro Luigi , Chung Frances , Bjorvatn Bjørn , Wing Yun Kwok , Dauvilliers Yves , Partinen Markku , Benedict Christian
Published: June 2024

Background

Preliminary data suggests that obesity might hasten the decline in mRNA vaccine-induced immunity against SARS-CoV-2. However, whether this renders individuals with obesity more susceptible to long COVID symptoms post-vaccination remains uncertain. Given sleep’s critical role in immunity, exploring the associations between obesity, probable long COVID symptoms, and sleep disturbances is essential.

Methods

We analyzed data from a survey of 5919 adults aged 18 to 89, all of whom received two SARS-CoV-2 mRNA vaccinations. Participants were categorized into normal weight, overweight, and obesity groups based on ethnicity-specific BMI cutoffs. The probability of long COVID was evaluated using the Post-Acute Sequelae of SARS-CoV-2 (PASC) score, as our survey did not permit confirmation of acute SARS-CoV-2 infection through methods such as antibody testing. Additionally, sleep patterns were assessed through questionnaires.

Results

Participants with obesity exhibited a significantly higher adjusted odds ratio (OR) of having a PASC score of 12 or higher, indicative of probable long COVID in our study, compared to those with normal weight (OR: 1.55, 95% CI: 1.05, 2.28). No significant difference was observed for overweight individuals (OR: 0.92 [95% CI: 0.63, 1.33]). Both obesity and probable long COVID were associated with increased odds of experiencing a heightened sleep burden, such as the presence of obstructive sleep apnea or insomnia (P < 0.001). However, no significant interaction between BMI and probable long COVID status was found.

Conclusions

Even post-vaccination, individuals with obesity may encounter a heightened risk of experiencing prolonged COVID-19 symptoms. However, confirming our observations necessitates comprehensive studies incorporating rigorous COVID infection testing, such as antibody assays - unavailable in our anonymous survey. Additionally, it is noteworthy that the correlation between probable long COVID and sleep disturbances appears to be independent of BMI.
Advances in large viewing angle and achromatic 3D holography
Authors: Huang Jiaming , Chen Yu , Li Guixin
Published: June 2024

Optical holography is a promising technique to achieve a naked-eye 3D display. However, the narrow viewing angle and chromatic aberration are the two key issues that usually limit the holographic display performance. A recent work proposes a novel way to circumvent these constraints by introducing a color liquid crystal grating into a time-sequenced holography system.
Single-crystalline hole-transporting layers for efficient and stable organic light-emitting devices
Authors: Ye Gao-Da , Ding Ran , Li Su-Heng , Ni Lei , Dai Shu-Ting , Chen Nian-Ke , Liu Yue-Feng , Guo Runda , Wang Lei , Li Xian-Bin , Xu Bin , Feng Jing
Published: June 2024

Efficient charge-carrier injection and transport in organic light-emitting devices (OLEDs) are essential to simultaneously achieving their high efficiency and long-term stability. However, the charge-transporting layers (CTLs) deposited by various vapor or solution processes are usually in amorphous forms, and their low charge-carrier mobilities, defect-induced high trap densities and inhomogeneous thickness with rough surface morphologies have been obstacles towards high-performance devices. Here, organic single-crystalline (SC) films were employed as the hole-transporting layers (HTLs) instead of the conventional amorphous films to fabricate highly efficient and stable OLEDs. The high-mobility and ultrasmooth morphology of the SC-HTLs facilitate superior interfacial characteristics of both HTL/electrode and HTL/emissive layer interfaces, resulting in a high Haacke’s figure of merit (FoM) of the ultrathin top electrode and low series-resistance joule-heat loss ratio of the SC-OLEDs. Moreover, the thick and compact SC-HTL can function as a barrier layer against moisture and oxygen permeation. As a result, the SC-OLEDs show much improved efficiency and stability compared to the OLEDs based on amorphous or polycrystalline HTLs, suggesting a new strategy to developing advanced OLEDs with high efficiency and high stability.
Unique model of chronic hypoxia in fetal lambs demonstrates abnormal contrast-enhanced ultrasound brain perfusion
Authors: Agarwal Divyansh , Hunt Mallory L. , Sridharan Anush , Larson Abby C. , Rychik Jack , Licht Daniel J. , Davey Marcus G. , Flake Alan W. , Gaynor J. William , Didier Ryne A.
Published: June 2024

Background

Children with congenital heart disease (CHD) demonstrate long-term neurodevelopmental impairments. We investigated contrast-enhanced ultrasound (CEUS) cerebral perfusion in a fetal animal model exposed to sub-physiologic oxygen at equivalent levels observed in human fetuses with CHD.

Methods

Fifteen fetal lambs [hypoxic animals (n = 9) and normoxic controls (n = 6)] maintained in an extrauterine environment underwent periodic brain CEUS. Perfusion parameters including microvascular flow velocity (MFV), transit time, and microvascular blood flow (MBF) were extrapolated from a standardized plane; regions of interest (ROI) included whole brain, central/thalami, and peripheral parenchymal analyses. Daily echocardiographic parameters and middle cerebral artery (MCA) pulsatility indices (PIs) were obtained.

Results

Hypoxic lambs demonstrated decreased MFV, increased transit time, and decreased MBF (p = 0.026, p = 0.016, and p < 0.001, respectively) by whole brain analyses. MFV and transit time were relatively preserved in the central/thalami (p = 0.11, p = 0.08, p = 0.012, respectively) with differences in the peripheral parenchyma (all p < 0.001). In general, cardiac variables did not correlate with cerebral CEUS perfusion parameters. Hypoxic animals demonstrated decreased MCA PI compared to controls (0.65 vs. 0.78, respectively; p = 0.027).

Conclusion

Aberrations in CEUS perfusion parameters suggest that in environments of prolonged hypoxia, there are regional microvascular differences incompletely characterized by MCA interrogation offering insights into fetal conditions which may contribute to patient outcomes.

Impact

This work utilizes CEUS to study cerebral microvascular perfusion in a unique fetal animal model subjected to chronic hypoxic conditions equal to fetuses with congenital heart disease. CEUS demonstrates altered parameters with regional differences that are incompletely characterized by MCA Doppler values.

These findings show that routine MCA Doppler interrogation may be inadequate in assessing microvascular perfusion differences.

To our knowledge, this study is the first to utilize CEUS to assess microvascular perfusion in this model.

The results offer insight into underlying conditions and physiological changes which may contribute to known neurodevelopmental impairments in those with congenital heart disease.
Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade
Authors: Owaki Takayuki , Iida Tadashi , Miyai Yuki , Kato Katsuhiro , Hase Tetsunari , Ishii Makoto , Ando Ryota , Hinohara Kunihiko , Akashi Tomohiro , Mizutani Yasuyuki , Ishikawa Takuya , Mii Shinji , Shiraki Yukihiro , Esaki Nobutoshi , Yamamoto Masami , Tsukamoto Tetsuya , Nomura Sachiyo , Murakami Takashi , Takahashi Masahide , Yuguchi Yuri , Maeda Motohiro , Sano Tomoyasu , Sassa Naoto , Matsukawa Yoshihisa , Kawashima Hiroki , Akamatsu Shusuke , Enomoto Atsushi
Published: June 2024

Background

The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs.

Methods

We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models.

Results

High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs.

Conclusion

Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.
ZBP1 causes inflammation by inducing RIPK3-mediated necroptosis and RIPK1 kinase activity-independent apoptosis
Authors: Koerner Lioba , Wachsmuth Laurens , Kumari Snehlata , Schwarzer Robin , Wagner Theresa , Jiao Huipeng , Pasparakis Manolis
Published: June 2024

Z-DNA binding protein 1 (ZBP1) has important functions in anti-viral immunity and in the regulation of inflammatory responses. ZBP1 induces necroptosis by directly engaging and activating RIPK3, however, the mechanisms by which ZBP1 induces inflammation and in particular the role of RIPK1 and the contribution of cell death-independent signaling remain elusive. Here we show that ZBP1 causes skin inflammation by inducing RIPK3-mediated necroptosis and RIPK1-caspase-8-mediated apoptosis in keratinocytes. ZBP1 induced TNFR1-independent skin inflammation in mice with epidermis-specific ablation of FADD by triggering keratinocyte necroptosis. Moreover, transgenic expression of C-terminally truncated constitutively active ZBP1 (ZBP1ca) in mouse epidermis caused skin inflammation that was only partially inhibited by abrogation of RIPK3-MLKL-dependent necroptosis and fully prevented by combined deficiency in MLKL and caspase-8. Importantly, ZBP1ca induced caspase-8-mediated skin inflammation by RHIM-dependent but kinase activity-independent RIPK1 signaling. Furthermore, ZBP1ca-induced inflammatory cytokine production in the skin was completely prevented by combined inhibition of apoptosis and necroptosis arguing against a cell death-independent pro-inflammatory function of ZBP1. Collectively, these results showed that ZBP1 induces inflammation by activating necroptosis and RIPK1 kinase activity-independent apoptosis.
TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway in mice
Authors: Cui Yan , Chen Chao , Tang Zhouqi , Yuan Wenjia , Yue Kaiye , Cui Pengcheng , Qiu Xia , Zhang Hedong , Li Tengfang , Zhu Xuejing , Luo Jiadi , Sun Siyu , Li Yaguang , Feng Chen , Peng Longkai , Xie Xubiao , Guo Yong , Xie Yixin , Jiang Xin , Qi Zhongquan , Thomson Angus W. , Dai Helong
Published: June 2024

The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2−/− mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2−/− BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-β1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.
DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson’s disease
Authors: Zhao Yichen , Shen Weiwei , Zhang Minjie , Guo Min , Dou Yunxiao , Han Sida , Yu Jintai , Cui Mei , Zhao Yanxin
Published: June 2024

The loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson’s disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the critical enzyme responsible for the degradation of asymmetric dimethylarginine (ADMA) which inhibits nitric oxide (NO) synthase and has been implicated in neurodegeneration. Mitochondrial dysfunction, particularly in the mitochondria-associated endoplasmic reticulum membrane (MAM), plays a critical role in this process, although the specific molecular target has not yet been determined. This study aims to examine the involvement of DDAH-1 in the nigrostriatal dopaminergic pathway and PD pathogenesis. The distribution of DDAH-1 in the brain and its colocalization with dopaminergic neurons were observed. The loss of dopaminergic neurons and aggravated locomotor disability after rotenone (ROT) injection were showed in the DDAH-1 knockout rat. l-arginine (ARG) and NO donors were employed to elucidate the role of NO respectively. In vitro, we investigated the effects of DDAH-1 knockdown or overexpression on cell viability and mitochondrial functions, as well as modulation of ADMA/NO levels using ADMA or ARG. MAM formation was assessed by the Mitofusin2 oligomerization and the mitochondrial ubiquitin ligase (MITOL) phosphorylation. We found that DDAH-1 downregulation resulted in enhanced cell death and mitochondrial dysfunctions, accompanied by elevated ADMA and reduced NO levels. However, the recovered NO level after the ARG supplement failed to exhibit a protective effect on mitochondrial functions and partially restored cell viability. DDAH-1 overexpression prevented ROT toxicity, while ADMA treatment attenuated these protective effects. The declines of MAM formation in ROT-treated cells were exacerbated by DDAH-1 downregulation via reduced MITOL phosphorylation, which was reversed by DDAH-1 overexpression. Together, the abundant expression of DDAH-1 in nigral dopaminergic neurons may exert neuroprotective effects by maintaining MAM formation and mitochondrial function probably via ADMA, indicating the therapeutic potential of targeting DDAH-1 for PD.
Prescription and dispensing duration of medicines for hypertension and other chronic conditions: a review of international policies and evidence to inform the Australian setting
Authors: af Geijerstam Peder , Falster Michael O. , Chalmers John , McLachlan Andrew J. , Rodgers Anthony , Schutte Aletta E.
Published: June 2024

The duration of treatment for which a physician may prescribe a medicine, ‘prescription duration’, is often dispensed at the pharmacy on multiple occasions of shorter time periods, ‘dispensing duration’. These durations vary significantly between and within countries. In Australia, the quantity of medication supplied at each dispensing has recently been extended from 30 to 60 days for a selection of medicines used for chronic health conditions, such as diabetes and hypertension. Dispensing durations vary between countries, with 30, 60 or 90 days being the most common—with 90 days aligning with the recommendation of the 2023 Global Report on Hypertension from the World Health Organization. The full impact of shorter vs longer prescription durations on health costs and outcomes is unknown, but current evidence suggests that 90-day dispensing could reduce costs and improve patient convenience and adherence. More rigorous research is needed.
Depth-enhanced high-throughput microscopy by compact PSF engineering
Authors: Opatovski Nadav , Nehme Elias , Zoref Noam , Barzilai Ilana , Orange Kedem Reut , Ferdman Boris , Keselman Paul , Alalouf Onit , Shechtman Yoav
Published: June 2024

High-throughput microscopy is vital for screening applications, where three-dimensional (3D) cellular models play a key role. However, due to defocus susceptibility, current 3D high-throughput microscopes require axial scanning, which lowers throughput and increases photobleaching and photodamage. Point spread function (PSF) engineering is an optical method that enables various 3D imaging capabilities, yet it has not been implemented in high-throughput microscopy due to the cumbersome optical extension it typically requires. Here we demonstrate compact PSF engineering in the objective lens, which allows us to enhance the imaging depth of field and, combined with deep learning, recover 3D information using single snapshots. Beyond the applications shown here, this work showcases the usefulness of high-throughput microscopy in obtaining training data for deep learning-based algorithms, applicable to a variety of microscopy modalities.
An effective and rapidly degradable disinfectant from disinfection byproducts
Authors: Han Jiarui , Li Wanxin , Zhang Xiangru
Published: June 2024

Chloroxylenol is a worldwide commonly used disinfectant. The massive consumption and relatively high chemical stability of chloroxylenol have caused eco-toxicological threats in receiving waters. We noticed that chloroxylenol has a chemical structure similar to numerous halo-phenolic disinfection byproducts. Solar detoxification of some halo-phenolic disinfection byproducts intrigued us to select a rapidly degradable chloroxylenol alternative from them. In investigating antimicrobial activities of disinfection byproducts, we found that 2,6-dichlorobenzoquinone was 9.0–22 times more efficient than chloroxylenol in inactivating the tested bacteria, fungi and viruses. Also, the developmental toxicity of 2,6-dichlorobenzoquinone to marine polychaete embryos decreased rapidly due to its rapid degradation via hydrolysis in receiving seawater, even without sunlight. Our work shows that 2,6-dichlorobenzoquinone is a promising disinfectant that well addresses human biosecurity and environmental sustainability. More importantly, our work may enlighten scientists to exploit the slightly alkaline nature of seawater and develop other industrial products that can degrade rapidly via hydrolysis in seawater.
Evolution of connectivity architecture in the Drosophila mushroom body
Authors: Ellis Kaitlyn Elizabeth , Bervoets Sven , Smihula Hayley , Ganguly Ishani , Vigato Eva , Auer Thomas O. , Benton Richard , Litwin-Kumar Ashok , Caron Sophie Jeanne Cécile
Published: June 2024

Brain evolution has primarily been studied at the macroscopic level by comparing the relative size of homologous brain centers between species. How neuronal circuits change at the cellular level over evolutionary time remains largely unanswered. Here, using a phylogenetically informed framework, we compare the olfactory circuits of three closely related Drosophila species that differ in their chemical ecology: the generalists Drosophila melanogaster and Drosophila simulans and Drosophila sechellia that specializes on ripe noni fruit. We examine a central part of the olfactory circuit that, to our knowledge, has not been investigated in these species—the connections between projection neurons and the Kenyon cells of the mushroom body—and identify species-specific connectivity patterns. We found that neurons encoding food odors connect more frequently with Kenyon cells, giving rise to species-specific biases in connectivity. These species-specific connectivity differences reflect two distinct neuronal phenotypes: in the number of projection neurons or in the number of presynaptic boutons formed by individual projection neurons. Finally, behavioral analyses suggest that such increased connectivity enhances learning performance in an associative task. Our study shows how fine-grained aspects of connectivity architecture in an associative brain center can change during evolution to reflect the chemical ecology of a species.
Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS
Authors: Mora Santiago , Stuckert Anna , von Huth Friis Rasmus , Pietersz Kimberly , Noes-Holt Gith , Montañana-Rosell Roser , Wang Haoyu , Sørensen Andreas Toft , Selvan Raghavendra , Verhaagen Joost , Allodi Ilary
Published: June 2024

Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1G93A mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1G93A mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.
Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries
Authors: Misek Sean A. , Fultineer Aaron , Kalfon Jeremie , Noorbakhsh Javad , Boyle Isabella , Roy Priyanka , Dempster Joshua , Petronio Lia , Huang Katherine , Saadat Alham , Green Thomas , Brown Adam , Doench John G. , Root David E. , McFarland James M. , Beroukhim Rameen , Boehm Jesse S.
Published: June 2024

Reducing disparities is vital for equitable access to precision treatments in cancer. Socioenvironmental factors are a major driver of disparities, but differences in genetic variation likely also contribute. The impact of genetic ancestry on prioritization of cancer targets in drug discovery pipelines has not been systematically explored due to the absence of pre-clinical data at the appropriate scale. Here, we analyze data from 611 genome-scale CRISPR/Cas9 viability experiments in human cell line models to identify ancestry-associated genetic dependencies essential for cell survival. Surprisingly, we find that most putative associations between ancestry and dependency arise from artifacts related to germline variants. Our analysis suggests that for 1.2-2.5% of guides, germline variants in sgRNA targeting sequences reduce cutting by the CRISPR/Cas9 nuclease, disproportionately affecting cell models derived from individuals of recent African descent. We propose three approaches to mitigate this experimental bias, enabling the scientific community to address these disparities.
Optimizing cell therapy by sorting cells with high extracellular vesicle secretion
Authors: Koo Doyeon , Cheng Xiao , Udani Shreya , Baghdasarian Sevana , Zhu Dashuai , Li Junlang , Hall Brian , Tsubamoto Natalie , Hu Shiqi , Ko Jina , Cheng Ke , Di Carlo Dino
Published: June 2024

Critical challenges remain in clinical translation of extracellular vesicle (EV)-based therapeutics due to the absence of methods to enrich cells with high EV secretion. Current cell sorting methods are limited to surface markers that are uncorrelated to EV secretion or therapeutic potential. Here, we utilize a nanovial technology for enrichment of millions of single cells based on EV secretion. This approach is applied to select mesenchymal stem cells (MSCs) with high EV secretion as therapeutic cells for improving treatment. The selected MSCs exhibit distinct transcriptional profiles associated with EV biogenesis and vascular regeneration and maintain high levels of EV secretion after sorting and regrowth. In a mouse model of myocardial infarction, treatment with high-secreting MSCs improves heart functions compared to treatment with low-secreting MSCs. These findings highlight the therapeutic importance of EV secretion in regenerative cell therapies and suggest that selecting cells based on EV secretion could enhance therapeutic efficacy.
Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target
Authors: Caldi Gomes Lucas , Hänzelmann Sonja , Hausmann Fabian , Khatri Robin , Oller Sergio , Parvaz Mojan , Tzeplaeff Laura , Pasetto Laura , Gebelin Marie , Ebbing Melanie , Holzapfel Constantin , Columbro Stefano Fabrizio , Scozzari Serena , Knöferle Johanna , Cordts Isabell , Demleitner Antonia F. , Deschauer Marcus , Dufke Claudia , Sturm Marc , Zhou Qihui , Zelina Pavol , Sudria-Lopez Emma , Haack Tobias B. , Streb Sebastian , Kuzma-Kozakiewicz Magdalena , Edbauer Dieter , Pasterkamp R. Jeroen , Laczko Endre , Rehrauer Hubert , Schlapbach Ralph , Carapito Christine , Bonetto Valentina , Bonn Stefan , Lingor Paul
Published: June 2024

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.
Protein translation rate determines neocortical neuron fate
Authors: Borisova Ekaterina , Newman Andrew G. , Couce Iglesias Marta , Dannenberg Rike , Schaub Theres , Qin Bo , Rusanova Alexandra , Brockmann Marisa , Koch Janina , Daniels Marieatou , Turko Paul , Jahn Olaf , Kaplan David R. , Rosário Marta , Iwawaki Takao , Spahn Christian M. T. , Rosenmund Christian , Meierhofer David , Kraushar Matthew L. , Tarabykin Victor , Ambrozkiewicz Mateusz C.
Published: June 2024

The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5’-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.
Ultrafast light-activated polymeric nanomotors
Authors: Wang Jianhong , Wu Hanglong , Zhu Xiaowei , Zwolsman Robby , Hofstraat Stijn R. J. , Li Yudong , Luo Yingtong , Joosten Rick R. M. , Friedrich Heiner , Cao Shoupeng , Abdelmohsen Loai K. E. A. , Shao Jingxin , van Hest Jan C. M.
Published: June 2024

Synthetic micro/nanomotors have been extensively exploited over the past decade to achieve active transportation. This interest is a result of their broad range of potential applications, from environmental remediation to nanomedicine. Nevertheless, it still remains a challenge to build a fast-moving biodegradable polymeric nanomotor. Here we present a light-propelled nanomotor by introducing gold nanoparticles (Au NP) onto biodegradable bowl-shaped polymersomes (stomatocytes) via electrostatic and hydrogen bond interactions. These biodegradable nanomotors show controllable motion and remarkable velocities of up to 125 μm s−1. This unique behavior is explained via a thorough three-dimensional characterization of the nanomotor, particularly the size and the spatial distribution of Au NP, with cryogenic transmission electron microscopy (cryo-TEM) and cryo-electron tomography (cryo-ET). Our in-depth quantitative 3D analysis reveals that the motile features of these nanomotors are caused by the nonuniform distribution of Au NPs on the outer surface of the stomatocyte along the z-axial direction. Their excellent motile features are exploited for active cargo delivery into living cells. This study provides a new approach to develop robust, biodegradable soft nanomotors with application potential in biomedicine.
Harbinger transposon insertion in ethylene signaling gene leads to emergence of new sexual forms in cucurbits
Authors: Huang Hsin-Ya , Zhang Siqi , Choucha Fadi Abou , Verdenaud Marion , Tan Feng-Quan , Pichot Clement , Parsa Hadi Shirazi , Slavkovic Filip , Chen Qinghe , Troadec Christelle , Marcel Fabien , Dogimont Catherine , Quadrana Leandro , Boualem Adnane , Bendahmane Abdelhafid
Published: June 2024

In flowering plants, the predominant sexual morph is hermaphroditism, and the emergence of unisexuality is poorly understood. Using Cucumis melo (melon) as a model system, we explore the mechanisms driving sexual forms. We identify a spontaneous mutant exhibiting a transition from bisexual to unisexual male flower, and identify the causal mutation as a Harbinger transposon impairing the expression of Ethylene Insensitive 2 (CmEIN2) gene. Genetics and transcriptomic analysis reveal a dual role of CmEIN2 in both sex determination and fruit shape formation. Upon expression of CmACS11, EIN2 is recruited to repress the expression of the carpel inhibitor, CmWIP1. Subsequently, EIN2 is recruited to mediate stamina inhibition. Following the sex determination phase, EIN2 promotes fruit shape elongation. Genome-wide analysis reveals that Harbinger transposon mobilization is triggered by environmental cues, and integrates preferentially in active chromatin, particularly within promoter regions. Characterization of a large collection of melon germplasm points to active transpositions in the wild, compared to cultivated accessions. Our study underscores the association between chromatin dynamics and the temporal aspects of mobile genetic element insertions, providing valuable insights into plant adaptation and crop genome evolution.
Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression
Authors: Hao Ruo-Han , Zhang Tian-Pei , Jiang Feng , Liu Jun-Hui , Dong Shan-Shan , Li Meng , Guo Yan , Yang Tie-Lin
Published: June 2024

The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality. Here, we developed an analytical framework, Cell-Stratified MR (csMR), to investigate cell-stratified causality through colocalizing GWAS signals with single-cell eQTL from different brain cells. By applying to obesity-related traits, our results demonstrate the cell-type-specific effects of GWAS variants on gene expression, and indicate the benefits of csMR to identify cell-type-specific causal effect that is often hidden from bulk analyses. We also found csMR valuable to reveal distinct causal pathways between different obesity indicators. These findings suggest the value of our approach to prioritize target cells for extending genetic causation studies.
MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease
Authors: Urbut Sarah M. , Yeung Ming Wai , Khurshid Shaan , Cho So Mi Jemma , Schuermans Art , German Jakob , Taraszka Kodi , Paruchuri Kaavya , Fahed Akl C. , Ellinor Patrick T. , Trinquart Ludovic , Parmigiani Giovanni , Gusev Alexander , Natarajan Pradeep
Published: June 2024

Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk. We designed a general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. This model is designed to handle longitudinal data over the lifetime to address this unmet need and support clinical decision-making. We analyze longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improves discrimination (C-index 0.71 vs 0.66), age of high-risk detection (C-index 0.73 vs 0.52), and overall prediction (RMSE 1.1% vs 10.9%), in held-out data. We also use MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore our multistate model’s potential public health value for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics toward earlier more effective prevention.
Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma
Authors: El-Hachem Najla , Leclercq Marine , Susaeta Ruiz Miguel , Vanleyssem Raphael , Shostak Kateryna , Körner Pierre-René , Capron Coralie , Martin-Morales Lorena , Roncarati Patrick , Lavergne Arnaud , Blomme Arnaud , Turchetto Silvia , Goffin Eric , Thandapani Palaniraja , Tarassov Ivan , Nguyen Laurent , Pirotte Bernard , Chariot Alain , Marine Jean-Christophe , Herfs Michael , Rapino Francesca , Agami Reuven , Close Pierre
Published: June 2024

Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.
Reducing sectoral hard-to-abate emissions to limit reliance on carbon dioxide removal
Authors: Edelenbosch Oreane Y. , Hof Andries F. , van den Berg Maarten , de Boer Harmen Sytze , Chen Hsing-Hsuan , Daioglou Vassilis , Dekker Mark M. , Doelman Jonathan C. , den Elzen Michel G. J. , Harmsen Mathijs , Mikropoulos Stratos , van Sluisveld Mariësse A. E. , Stehfest Elke , Tagomori Isabela S. , van Zeist Willem-Jan , van Vuuren Detlef P.
Published: June 2024

To reach net-zero greenhouse gas targets, carbon dioxide removal (CDR) technologies are required to compensate for residual emissions in the hard-to-abate sectors. However, dependencies on CDR technologies involve environmental, technical and social risks, particularly related to increased land requirements for afforestation and bioenergy crops. Here, using scenarios consistent with the 1.5 °C target, we show that demand and technological interventions can substantially lower emission levels in four hard-to-abate sectors (industry, agriculture, buildings and transport) and reduce reliance on the use of bioenergy with carbon capture and storage. Specifically, demand measures and technology-oriented measures could limit peak annual bioenergy with carbon capture and storage use to 0.5–2.2 GtCO2e per year and 1.9–7.0 GtCO2e per year, respectively, compared with 10.3 GtCO2e per year in the default 1.5 °C scenario. Dietary change plays a critical role in the demand measures given its large share in residual agricultural emissions.
Probing the opto-electronic, phonon spectrum, and thermoelectric properties of lead-free fluoride perovskites A2GeSnF6 (A = K, Rb, Cs) for energy harvesting devices
Authors: Abdullah Danish , Gupta Dinesh C.
Published: June 2024

The present work employs density functional theory to explore the structural, optoelectronic, and thermoelectric attributes of the halide-based double perovskite A2GeSnF6 (A = K, Rb, and Cs) compounds. The stable phonon dispersion spectrum affirms dynamical stability, whereas the enthalpy of formation and tolerance factor evaluated collectively verify structural stability. Considering the Tran Blaha modified Becke Johnson potentials (mBJ), the predicted direct band gaps along the symmetry point are 3.19 eV for K2GeSnF6, 3.16 eV for Rb2GeSnF6 and 3.12 eV Cs2GeSnF6. According to an in-depth examination of the optoelectronic features, A2GeSnF6 (A = K, Rb, and Cs), double perovskites are assuring contenders for optoelectronic devices due to their suitable bandgap. The extremely high figure of merit values (0.94–0.97) obtained from the numerical calculation of power factor and thermal conductivity suggest the intriguing prospects of these compositions for thermoelectric devices. These studies offer a perceptive comprehension of the materials for their potential applications in the future.
Changes in protein fluxes in skeletal muscle during sequential stages of muscle regeneration after acute injury in male mice
Authors: Bizieff Alec , Cheng Maggie , Chang Kelvin , Mohammed Hussein , Ziari Naveed , Nyangau Edna , Fitch Mark , Hellerstein Marc K.
Published: June 2024

Changes in protein turnover play an important role in dynamic physiological processes, including skeletal muscle regeneration, which occurs as an essential part of tissue repair after injury. The inability of muscle tissue to recapitulate this regenerative process can lead to the manifestation of clinical symptoms in various musculoskeletal diseases, including muscular dystrophies and pathological atrophy. Here, we employed a workflow that couples deuterated water (2H2O) administration with mass spectrometry (MS) to systematically measure in-vivo protein turnover rates across the muscle proteome in 8-week-old male C57BL6/J mice. We compared the turnover kinetics of over 100 proteins in response to cardiotoxin (CTX) induced muscle damage and regeneration at unique sequential stages along the regeneration timeline. This analysis is compared to gene expression data from mRNA-sequencing (mRNA-seq) from the same tissue. The data reveals quantitative protein flux signatures in response to necrotic damage, in addition to sequential differences in cell proliferation, energy metabolism, and contractile gene expression. Interestingly, the mRNA changes correlated poorly with changes in protein synthesis rates, consistent with post-transcriptional control mechanisms. In summary, the experiments described here reveal the signatures and timing of protein flux changes during skeletal muscle regeneration, as well as the inability of mRNA expression measurements to reveal changes in directly measured protein turnover rates. The results of this work described here provide a better understanding of the muscle regeneration process and could help to identify potential biomarkers or therapeutic targets.
Exact solutions for the Cahn–Hilliard equation in terms of Weierstrass-elliptic and Jacobi-elliptic functions
Authors: Hussain Akhtar , Ibrahim Tarek F. , Birkea F. M. Osman , Alotaibi Abeer M. , Al-Sinan Bushra R. , Mukalazi Herbert
Published: June 2024

Despite the historical position of the F-expansion method as a method for acquiring exact solutions to nonlinear partial differential equations (PDEs), this study highlights its superiority over alternative auxiliary equation methods. The efficacy of this method is demonstrated through its application to solve the convective–diffusive Cahn–Hilliard (cdCH) equation, describing the dynamic of the separation phase for ternary iron alloys (Fe–Cr–Mo) and (Fe–X–Cu). Significantly, this research introduces an extensive collection of exact solutions by the auxiliary equation, comprising fifty-two distinct types. Six of these are associated with Weierstrass-elliptic function solutions, while the remaining solutions are expressed in Jacobi-elliptic functions. I think it is important to emphasize that, exercising caution regarding the statement of the term ’new,’ the solutions presented in this context are not entirely unprecedented. The paper examines numerous examples to substantiate this perspective. Furthermore, the study broadens its scope to include soliton-like and trigonometric-function solutions as special cases. This underscores that the antecedently obtained outcomes through the recently specific cases encompassed within the more comprehensive scope of the present findings.
Investigation and characterization of changes in potato peels by thermochemical acidic pre-treatment for extraction of various compounds
Authors: Mushtaq Qudsia , Ishtiaq Uzair , Joly Nicolas , Martin Patrick , Qazi JavedIqbal
Published: June 2024

Potato peel waste (PPW) is an underutilized substrate which is produced in huge amounts by food processing industries. Using PPW a feedstock for production of useful compounds can overcome the problem of waste management as well as cost-effective. In present study, potential of PPW was investigated using chemical and thermochemical treatment processes. Three independent variables i.e., PPW concentration, dilute sulphuric acid concentration and liberation time were selected to optimize the production of fermentable sugars (TS and RS) and phenolic compounds (TP). These three process variables were selected in the range of 5–15 g w/v substrate, 0.8–1.2 v/v acid conc. and 4–6 h. Whole treatment process was optimized by using box-behnken design (BBD) of response surface methodology (RSM). Highest yield of total and reducing sugars and total phenolic compounds obtained after chemical treatment was 188.00, 144.42 and 43.68 mg/gds, respectively. The maximum yield of fermentable sugars attained by acid plus steam treatment were 720.00 and 660.62 mg/gds of TS and RS, respectively w.r.t 5% substrate conc. in 0.8% acid with residence time of 6 h. Results recorded that acid assisted autoclaved treatment could be an effective process for PPW deconstruction. Characterization of substrate before and after treatment was checked by SEM and FTIR. Spectras and micrographs confirmed the topographical variations in treated substrate. The present study was aimed to utilize biowaste and to determine cost-effective conditions for degradation of PWW into value added compounds.