bluuebunny/crossref_metadata_2025 huggingface dataset:
Cutoff Latitudes of Solar Proton Events Measured by GPS Satellites
Authors: van Hazendonk C. M. , Heino E. , Jiggens P. T. A. , Taylor M. G. G. T. , Partamies N. , Mulders H. C. J.
Published: March 2022

Solar energetic particles (SEPs), one of the main causes of particle radiation in interplanetary space, can disrupt radio communication, induce spacecraft failures and change the heating and cooling rates in the atmosphere among others. To investigate the impact of SEPs and more specifically solar proton events (SPEs), we established a cutoff latitude database based on energetic particle data from Combined X‐ray Dosimeters (CXDs) on board the Global Positioning System (GPS) spacecraft. Introducing a novel normalization method involving proton fluxes from the Geostationary Operational Environmental Satellites enabled us to include the CXD data from its introduction (2001) onwards. The database contains 5714 cutoff latitudes divided over six energies between 18 and 115 MeV which occur during 58 SPEs from 2001 to 2015. Based on the database, a cutoff latitude parameterization as a function of solar wind dynamic pressure and geomagnetic indices Kp and Dst is created for each energy. Moreover, comparisons to previous studies on energetic particle data from the Polar Orbiting Environmental Satellites have been performed to put the GPS data into perspective. A 1–2° poleward offset is found for the GPS based cutoff latitude models, for which several causes are discussed. Furthermore, the limitation of GPS data to geomagnetic latitudes above 60° should be considered. All in all, the usage of the long time span of GPS data in this study combined with its recent release (2016) opens up a new range of studies involving GPS energetic particle data such as investigating long‐term trends with respect to our solar cycle or magnetospheric trends.
Plasma Parameters From Quasi‐Thermal Noise Observed by Parker Solar Probe: A New Model for the Antenna Response
Authors: Martinović Mihailo M. , Ðorđević Antonije R. , Klein Kristopher G. , Maksimović Milan , Issautier Karine , Liu Mingzhe , Pulupa Marc , Bale Stuart D. , Halekas Jasper S. , McManus Michael D.
Published: March 2022

Quasi‐Thermal Noise (QTN) spectroscopy is a reliable diagnostic routinely used for measuring electron density and temperature in space plasmas. The observed spectrum depends on both antenna geometry and plasma kinetic properties. Parker solar probe (PSP), launched in 2018, is equipped with an antenna system consisting of two linear dipoles with a significant gap between the antenna arms. Such a configuration, not utilized on previous missions, cannot be completely described by current models of the antenna response function. In this work, we calculate the current distribution and the corresponding response function for the PSP antenna geometry, and use these results to generate synthetic QTN spectra. Applying this model to the Encounter 7 observations from PSP provides accurate estimations of electron density and temperature, which are in very good agreement with particle analyzer measurements.
The State of Pore Fluid Pressure and 3‐D Megathrust Earthquake Dynamics
Authors: Madden Elizabeth H. , Ulrich Thomas , Gabriel Alice‐Agnes
Published: March 2022

We study the effects of pore fluid pressure (Pf) on the pre‐earthquake, near‐fault stress state, and 3‐D earthquake rupture dynamics through six scenarios utilizing a structural model based on the 2004 Mw 9.1 Sumatra‐Andaman earthquake. As pre‐earthquake Pf magnitude increases, effective normal stress and fault shear strength decrease. As a result, magnitude, slip, peak slip rate, stress drop, and rupture velocity of the scenario earthquakes decrease. Comparison of results with observations of the 2004 earthquake support that pre‐earthquake Pf averages near 97% of lithostatic pressure, leading to pre‐earthquake average shear and effective normal tractions of 4–5 and 22 MPa. The megathrust in these scenarios is weak, in terms of low mean shear traction at static failure and low dynamic friction coefficient during rupture. Apparent co‐seismic principal stress rotations and absolute post‐seismic stresses in these scenarios are consistent with the variety of observed aftershock focal mechanisms. In all scenarios, the mean apparent stress rotations are larger above than below the megathrust. Scenarios with larger Pf magnitudes exhibit lower mean apparent principal stress rotations. We further evaluate pre‐earthquake Pf depth distribution. If Pf follows a sublithostatic gradient, pre‐earthquake effective normal stress increases with depth. If Pf follows the lithostatic gradient exactly, then this normal stress is constant, shifting peak slip and peak slip rate updip. This renders constraints on near‐trench strength and constitutive behavior crucial for mitigating hazard. These scenarios provide opportunity for future calibration with site‐specific measurements to constrain dynamically plausible megathrust strength and Pf gradients.
Radiocarbon in the Atmosphere and Seawater in the South China Sea: Flux, Inventory and Air‐Sea CO2 Exchange Rate Tracing
Authors: Niu Zhenchuan , Zhou Weijian , Zhao Huiyizhe , Feng Xue , Lyu Mengni
Published: March 2022

Δ14C values of the atmosphere and seawater dissolved inorganic carbon (DIC) were measured during a cruise in the South China Sea (SCS) in September 2015, in order to determine the 14C flux and bomb 14C‐based air‐sea CO2 exchange rates for this region. The background atmospheric Δ14C value (13.8 ± 5.0‰) for the SCS during that period was lower than that (35.4 ± 3.4‰) of surface seawater (5 m) DIC, and a net transfer of 14C from the sea to the atmosphere (7.4 ± 5.0 × 1011 atoms m−2 yr−1) was determined at the wind speed of 5.2 ± 1.7 m s−1. Seawater DIC Δ14C profiles showed the highest value (37.9 ± 3.7‰) at a depth of 100 m, a rapid decrease below that depth to −220.3 ± 3.2‰ at 1,500 m, and nearly constant values below 1,500 m. The average mean penetration depth of bomb 14C was 585.5 ± 99.2 m, and a value of 8.2 ± 1.0 × 109 atoms cm−2 was obtained for the bomb 14C inventory in this region. Based on this inventory, a long‐term (1954–2015) average air‐sea CO2 exchange rate of 20.2 ± 2.8 mol m−2 yr−1 was traced for the SCS. Combined with the pCO2 measurements in this region, a net CO2 flux rate of 0.54 ± 0.08 mol m−2 yr−1 was yielded for the SCS, which is comparable to the cruise measured flux (0.44 ± 0.62 mol m−2 yr−1) obtained from a synthesis study (Li et al., 2020, https://doi.org/10.1016/j.pocean.2020.102272). Our study highlights the importance of continued atmospheric and seawater 14C observations on determining the air‐sea flux in this region.
Martian Meteorites Reveal Evidence of a Large Impact
Authors: Kornei Katherine
Published: March 2022

By analyzing rare Martian meteorites, researchers have uncovered a crystalline structure created by a large asteroid or comet impact that potentially affected the Red Planet’s habitability.
Tree Carbon Data That Ring True
Authors: Averett Nancy
Published: March 2022

An international group of researchers may have found a way to better account for carbon storage in forests.
Worldwide Signature of the 2022 Tonga Volcanic Tsunami
Authors: Carvajal Matías , Sepúlveda Ignacio , Gubler Alejandra , Garreaud René
Published: March 2022

The eruption of the Hunga Tonga‐Hunga Ha'apai Volcano in January 2022 in the southwest Pacific islands of Tonga triggered a tsunami that was detected beyond the Pacific basin. Here we show its spatiotemporal signature as revealed by hundreds of publicly available coastal tide gauge records from around the world. The Tonga tsunami was characterized by a uniformly small leading wave that arrived earlier than theoretically expected for a tsunami wave freely propagating away from the volcano. In contrast, the largest waves, of up to +3 m high, were concentrated in the Pacific and their timing agrees well with tsunami propagation times from the volcano. While the leading waves were caused by a previously reported fast‐moving atmospheric pressure pulse generated in the volcanic explosion, the large waves observed later in the Pacific were likely originated in the vicinity of the volcano although its generation mechanism(s) cannot be identified by the tide gauge data alone.
Effect of Meteoric Ions on Ionospheric Conductance at Jupiter
Authors: Nakamura Yuki , Terada Koichiro , Tao Chihiro , Terada Naoki , Kasaba Yasumasa , Leblanc François , Kita Hajime , Nakamizo Aoi , Yoshikawa Akimasa , Ohtani Shinichi , Tsuchiya Fuminori , Kagitani Masato , Sakanoi Takeshi , Murakami Go , Yoshioka Kazuo , Kimura Tomoki , Yamazaki Atsushi , Yoshikawa Ichiro
Published: March 2022

Ionospheric Pedersen and Hall conductances play significant roles in electromagnetic coupling between the planetary ionosphere and magnetosphere. Several observations and models have suggested the existence of meteoric ions with interplanetary origins in the lower part of Jupiter’s ionosphere; however, no models have considered the contributions of meteoric ions to ionospheric conductance. This study is designed to evaluate the contribution of meteoric ions to ionospheric conductance by developing an ionospheric model combining a meteoroid ablation model and a photochemical model. We find that the largest contribution to Pedersen and Hall conductivities occurs in the meteoric ion layer at altitudes of 350–600 km due to the large concentration of meteoric ions resulting from their long lifetimes of more than 100 Jovian days. Pedersen and Hall conductances are enhanced by factors of 3 and 10, respectively, in the middle‐ and low‐latitude and auroral regions when meteoric ions are included. The distribution of Pedersen and Hall conductances becomes axisymmetric in the middle‐ and low‐latitude regions. Enhanced axisymmetric ionospheric conductance should impact magnetospheric plasma convection. The contribution of meteoric ions to the ionospheric conductance is expected to be important only on Jupiter in our solar system because of Jupiter’s intense magnetic and gravitational fields.
Sirtuins are crucial regulators of T cell metabolism and functions
Authors: Hamaidi Imene , Kim Sungjune
Published: March 2022

It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes in T cell metabolic activity directly impact the effector functions and fate of T cells. Thus, understanding how metabolic pathways influence immune responses and ultimately affect disease progression is paramount. Epigenetic and posttranslational modification mechanisms have been found to control immune responses and metabolic reprogramming. Sirtuins are NAD+-dependent histone deacetylases that play key roles during cellular responses to a variety of stresses and have recently been reported to have potential roles in immune responses. Therefore, sirtuins are of significant interest as therapeutic targets to treat immune-related diseases and enhance antitumor immunity. This review aims to illustrate the potential roles of sirtuins in different subtypes of T cells during the adaptive immune response.
Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters
Authors: Palomer Ernest , Martín-Flores Núria , Jolly Sarah , Pascual-Vargas Patricia , Benvegnù Stefano , Podpolny Marina , Teo Samuel , Vaher Kadi , Saito Takashi , Saido Takaomi C. , Whiting Paul , Salinas Patricia C.
Published: March 2022

Growing evidence supports a role for deficient Wnt signalling in Alzheimer’s disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-β-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reducedFZD1andFZD7mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGFmouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 atFzd1andFzd7promoters in AD. In vitro and in vivo inhibition of Sirt2 rescuedFzd1andFzd7mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment toFzd1andFzd7promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of SIRT2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increase in the SIRT2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favoursFzd1andFzd7repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated SIRT2 in repressingFzd1andFzd7expressionviaH4K16ac deacetylation in AD. We propose SIRT2 as an attractive target to ameliorate AD pathology.
Exploration and functionalization of M1-macrophage extracellular vesicles for effective accumulation in glioblastoma and strong synergistic therapeutic effects
Authors: Wang Xiaojun , Ding Hui , Li Zongyang , Peng Yaonan , Tan Hui , Wang Changlong , Huang Guodong , Li Weiping , Ma Guanghui , Wei Wei
Published: March 2022

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an extremely low survival rate. New and effective approaches for treatment are therefore urgently needed. Here, we successfully developed M1-like macrophage-derived extracellular vesicles (M1EVs) that overcome multiple challenges via guidance from two macrophage-related observations in clinical specimens from GBM patients: enrichment of M2 macrophages in GBM; and origination of a majority of infiltrating macrophage from peripheral blood. To maximize the synergistic effect, we further functionalized the membranes of M1EVs with two hydrophobic agents (the chemical excitation source CPPO (C) and the photosensitizer Ce6 (C)) and loaded the hydrophilic hypoxia-activated prodrug AQ4N (A) into the inner core of the M1EVs. After intravenous injection, the inherent nature of M1-derived extracellular vesicles CCA-M1EVs allowed for blood-brain barrier penetration, and modulated the immunosuppressive tumor microenvironment via M2-to-M1 polarization, which increased hydrogen peroxide (H2O2) levels. Furthermore, the reaction between H2O2 and CPPO produced chemical energy, which could be used for Ce6 activation to generate large amounts of reactive oxygen species to achieve chemiexcited photodynamic therapy (CDT). As this reaction consumed oxygen, the aggravation of tumor hypoxia also led to the conversion of non-toxic AQ4N into toxic AQ4 for chemotherapy. Therefore, CCA-M1EVs achieved synergistic immunomodulation, CDT, and hypoxia-activated chemotherapy in GBM to exert a potent therapeutic effect. Finally, we demonstrated the excellent effect of CCA-M1EVs against GBM in cell-derived xenograft and patient-derived xenograft models, underscoring the strong potential of our highly flexible M1EVs system to support multi-modal therapies for difficult-to-treat GBM.
Correlation between miRNA-124, miRNA-544a, and TNF-α levels in acute spinal cord injury
Authors: Ma Xiaomin , Ma Tao , Chang Long , Chen Xiaolei , Xia Gen , Li Chen , Liu Huan
Published: March 2022

Study design

Retrospective.

Objectives

Acute spinal cord injury (ASCI) is caused by direct or indirect strikes from external forces on the spinal cord. Here, we investigated the correlation between the miR-124, miR-544a, and TNF-α levels in patients with ASCI, aiming to evaluate the potential usage of miR-124 and miR-544a in ASCI diagnosis.

Setting

University/hospital.

Methods

A total of 90 (58 male/32 female) ASIA patients and 15 (9 male/6 female) control patients (with acute limb trauma) were involved in the presented study. The ASIA patients were further subclustered based on the International Standards for the Neurological Classification of SCI (ISNCSCI) exam. 30 (18 male/12 female)cases were determined to have complete spinal cord injury (CSCI) and classified as ASIA grade A (Complete); 30 (20 male/10 female) cases were determined to have incomplete spinal cord injury (ISCI) and classified as ASIA grade B (sensory incomplete), C (motor incomplete), or D (motor incomplete); 30 (20 male/10 female) cases were determined to have normal neurological function (NNF) and classified as ASIA grade E (Normal). Plasma miR-124, miRNA-544a, and tumor necrosis factor-alpha (TNF-α) levels were measured from the blood samples collected 24 h, 48 h, and 72 h after trauma.

Results

The levels of miR-124 and miR-544a in the CSCI and ISCI groups were significantly higher than those of the NNF and the control group 24 h after injury (P < 0.05). The increased levels gradually declined from 24 h to 72 h after injury. The area under the receiver operating characteristic curve (ROC) of miR-124, miR-544a and TNF-α 24 h after trauma in patients with acute spinal cord injury were 0.948 [95% CI (0.890, 1.000)], 0.815 [95% CI (0.638, 0.994)] and 0.770 [95% CI (0.641, 0.879)], respectively.

Conclusion

The miRNA-124 and miRNA-544a levels increased significantly in ASCI patients compared with control patients 24 h after injury. These increased levels gradually reduced from 24 h to 72 h after injury. There is a strong positive correlation between miRNA-124, miRNA-544a, and acute spinal cord injury.

Sponsorship

The present study was supported by a University-level project of Ningxia Medical University (Project Number: XY2017147).
Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging
Authors: Strating Esther , Wassenaar Emma , Verhagen Mathijs , Rauwerdink Paulien , van Schelven Susanne , de Hingh Ignace , Rinkes Inne Borel , Boerma Djamila , Witkamp Arjen , Lacle Miangela , Fodde Riccardo , Volckmann Richard , Koster Jan , Stedingk Kris , Giesel Frederik , de Roos Remmert , Poot Alex , Bol Guus , Lam Marnix , Elias Sjoerd , Kranenburg Onno
Published: March 2022

Background

In colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) is associated with therapy resistance and poor prognosis. Clinical diagnosis of CMS4 is hampered by locoregional and temporal variables influencing CMS classification. Diagnostic tools that comprehensively detect CMS4 are therefore urgently needed.

Methods

To identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. Heterogeneity of marker expression in relation to CMS4 status was assessed by analysing 3–5 tumour regions and 91.103 single-tumour cells (7 and 29 tumours, respectively). Candidate marker expression was validated in CMS4 peritoneal metastases (PM; n = 59). Molecular imaging was performed using the 68Ga-DOTA-FAPI-46 PET tracer.

Results

Fibroblast activation protein (FAP) mRNA identified CMS4 with very high sensitivity and specificity (AUROC > 0.91), and was associated with significantly shorter relapse-free survival (P = 0.0038). Heterogeneous expression of FAP among and within tumour lesions correlated with CMS4 heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were missed using conventional imaging. Extra-peritoneal metastases displayed extensive heterogeneity of tracer uptake.

Conclusion

FAP expression identifies CMS4 CRC. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking.
Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma
Authors: Thieme Elana , Liu Tingting , Bruss Nur , Roleder Carly , Lam Vi , Wang Xiaoguang , Nechiporuk Tamilla , Shouse Geoffrey , Danilova Olga V. , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Kurtz Stephen E. , Danilov Alexey V.
Published: March 2022

Aberrant B-cell receptor (BCR) signaling is a key driver in lymphoid malignancies. Bruton tyrosine kinase (BTK) inhibitors that disrupt BCR signaling have received regulatory approvals in therapy of mantle cell lymphoma (MCL). However, responses are incomplete and patients who experience BTK inhibitor therapy failure have dire outcomes. CG-806 (luxeptinib) is a dual BTK/SYK inhibitor in clinical development in hematologic malignancies. Here we investigated the pre-clinical activity of CG-806 in MCL. In vitro treatment with CG-806 thwarted survival of MCL cell lines and patient-derived MCL cells in a dose-dependent manner. CG-806 blocked BTK and SYK activation and abrogated BCR signaling. Contrary to ibrutinib, CG-806 downmodulated the anti-apoptotic proteins Mcl-1 and Bcl-xL, abrogated survival of ibrutinib-resistant MCL cell lines, and partially reversed the pro-survival effects of stromal microenvironment-mimicking conditions in primary MCL cells. Dual BTK/SYK inhibition led to mitochondrial membrane depolarization accompanied by mitophagy and metabolic reprogramming toward glycolysis. In vivo studies of CG-806 demonstrated improved survival in one of the two tested aggressive MCL PDX models. While suppression of the anti-apoptotic Bcl-2 family proteins and NFκB signaling correlated with in vivo drug sensitivity, OxPhos and MYC transcriptional programs were upregulated in the resistant model following treatment with CG-806. BAX and NFKBIA were implicated in susceptibility to CG-806 in a whole-genome CRISPR-Cas9 library screen (in a diffuse large B-cell lymphoma cell line). A high-throughput in vitro functional drug screen demonstrated synergy between CG-806 and Bcl-2 inhibitors. In sum, dual BTK/SYK inhibitor CG-806 disrupts BCR signaling and induces metabolic reprogramming and apoptosis in MCL. The Bcl-2 network is a key mediator of sensitivity to CG-806 and combined targeting of Bcl-2 demonstrates synergy with CG-806 warranting continued exploration in lymphoid malignancies.
Regulation of the Tec family of non-receptor tyrosine kinases in cardiovascular disease
Authors: Yin Zeyu , Zou Yuanming , Wang Dong , Huang Xinyue , Xiong Shengjun , Cao Liu , Zhang Ying , Sun Yingxian , Zhang Naijin
Published: March 2022

Tyrosine phosphorylation by protein tyrosine kinases (PTKs) is a type of post-translational modification. Tec kinases, which are a subfamily of non-receptor PTKs, were originally discovered in the hematopoietic system and include five members: Tec, Btk, Itk/Emt/Tsk, Etk/Bmx, and Txk/Rlk. With the progression of modern research, certain members of the Tec family of kinases have been found to be expressed outside the hematopoietic system and are involved in the development and progression of a variety of diseases. The role of Tec family kinases in cardiovascular disease is receiving increasing attention. Tec kinases are involved in the occurrence and progression of ischemic heart disease, atherosclerosis, cardiac dysfunction associated with sepsis, atrial fibrillation, myocardial hypertrophy, coronary atherosclerotic heart disease, and myocardial infarction and post-myocardial. However, no reviews have comprehensively clarified the role of Tec kinases in the cardiovascular system. Therefore, this review summarizes research on the role of Tec kinases in cardiovascular disease, providing new insights into the prevention and treatment of cardiovascular disease.
Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase
Authors: Cheng Jiaxuan , Li Ningning , Huo Yunjing , Dang Shangyu , Tye Bik-Kwoon , Gao Ning , Zhai Yuanliang
Published: March 2022

The Dbf4-dependent kinase Cdc7 (DDK) regulates DNA replication initiation by phosphorylation of the MCM double hexamer (MCM-DH) to promote helicase activation. Here, we determine a series of cryo electron microscopy (cryo-EM) structures of yeast DDK bound to the MCM-DH. These structures, occupied by one or two DDKs, differ primarily in the conformations of the kinase core. The interactions of DDK with the MCM-DH are mediated exclusively by subunit Dbf4 straddling across the hexamer interface on the three N-terminal domains (NTDs) of subunits Mcm2, Mcm6, and Mcm4. This arrangement brings Cdc7 close to its only essential substrate, the N-terminal serine/threonine-rich domain (NSD) of Mcm4. Dbf4 further displaces the NSD from its binding site on Mcm4-NTD, facilitating an immediate targeting of this motif by Cdc7. Moreover, the active center of Cdc7 is occupied by a unique Dbf4 inhibitory loop, which is disengaged when the kinase core assumes wobbling conformations. This study elucidates the versatility of Dbf4 in regulating the ordered multisite phosphorylation of the MCM-DH by Cdc7 kinase during helicase activation.
Representations of molecules and materials for interpolation of quantum-mechanical simulations via machine learning
Authors: Langer Marcel F. , Goeßmann Alex , Rupp Matthias
Published: March 2022

Computational study of molecules and materials from first principles is a cornerstone of physics, chemistry, and materials science, but limited by the cost of accurate and precise simulations. In settings involving many simulations, machine learning can reduce these costs, often by orders of magnitude, by interpolating between reference simulations. This requires representations that describe any molecule or material and support interpolation. We comprehensively review and discuss current representations and relations between them. For selected state-of-the-art representations, we compare energy predictions for organic molecules, binary alloys, and Al–Ga–In sesquioxides in numerical experiments controlled for data distribution, regression method, and hyper-parameter optimization.
Development and validation of a web-based prediction tool on minor physical anomalies for schizophrenia
Authors: Wang Xin-Yu , Lin Jin-Jia , Lu Ming-Kun , Jang Fong-Lin , Tseng Huai-Hsuan , Chen Po-See , Chen Po-Fan , Chang Wei-Hung , Huang Chih-Chun , Lu Ke-Ming , Tan Hung-Pin , Lin Sheng-Hsiang
Published: March 2022

In support of the neurodevelopmental model of schizophrenia, minor physical anomalies (MPAs) have been suggested as biomarkers and potential pathophysiological significance for schizophrenia. However, an integrated, clinically useful tool that used qualitative and quantitative MPAs to visualize and predict schizophrenia risk while characterizing the degree of importance of MPA items was lacking. We recruited a training set and a validation set, including 463 schizophrenia patients and 281 healthy controls to conduct logistic regression and the least absolute shrinkage and selection operator (Lasso) regression to select the best parameters of MPAs and constructed nomograms. Two nomograms were built to show the weights of these predictors. In the logistic regression model, 11 out of a total of 68 parameters were identified as the best MPA items for distinguishing between patients with schizophrenia and controls, including hair whorls, epicanthus, adherent ear lobes, high palate, furrowed tongue, hyperconvex fingernails, a large gap between first and second toes, skull height, nasal width, mouth width, and palate width. The Lasso regression model included the same variables of the logistic regression model, except for nasal width, and further included two items (interpupillary distance and soft ears) to assess the risk of schizophrenia. The results of the validation dataset verified the efficacy of the nomograms with the area under the curve 0.84 and 0.85 in the logistic regression model and lasso regression model, respectively. This study provides an easy-to-use tool based on validated risk models of schizophrenia and reflects a divergence in development between schizophrenia patients and healthy controls (https://www.szprediction.net/).
Investigating repetitive transcranial magnetic stimulation on cannabis use and cognition in people with schizophrenia
Authors: Bidzinski Karolina Kozak , Lowe Darby J. E. , Sanches Marcos , Sorkhou Maryam , Boileau Isabelle , Kiang Michael , Blumberger Daniel M. , Remington Gary , Ma Clement , Castle David J. , Rabin Rachel A. , George Tony P.
Published: March 2022

Cannabis use disorder (CUD) occurs at high rates in schizophrenia, which negatively impacts its clinical prognosis. These patients have greater difficulty quitting cannabis which may reflect putative deficits in the dorsolateral prefrontal cortex (DLPFC), a potential target for treatment development. We examined the effects of active versus sham high-frequency (20-Hz) repetitive transcranial magnetic stimulation (rTMS) on cannabis use in outpatients with schizophrenia and CUD. Secondary outcomes included cannabis craving/withdrawal, psychiatric symptoms, cognition and tobacco use. Twenty-four outpatients with schizophrenia and CUD were enrolled in a preliminary double-blind, sham-controlled randomized trial. Nineteen participants were randomized to receive active (n = 9) or sham (n = 10) rTMS (20-Hz) applied bilaterally to the DLPFC 5x/week for 4 weeks. Cannabis use was monitored twice weekly. A cognitive battery was administered pre- and post-treatment. rTMS was safe and well-tolerated with high treatment retention (~90%). Contrast estimates suggested greater reduction in self-reported cannabis use (measured in grams/day) in the active versus sham group (Estimate = 0.33,p = 0.21; Cohen’sd = 0.72), suggesting a clinically relevant effect of rTMS. A trend toward greater reduction in craving (Estimate = 3.92,p = 0.06), and significant reductions in PANSS positive (Estimate = 2.42,p = 0.02) and total (Estimate = 5.03,p = 0.02) symptom scores were found in the active versus sham group. Active rTMS also improved attention (Estimate = 6.58,p < 0.05), and suppressed increased tobacco use that was associated with cannabis reductions (Treatment x Time:p = 0.01). Our preliminary findings suggest that rTMS to the DLPFC is safe and potentially efficacious for treating CUD in schizophrenia.
Reduced erythrocyte membrane polyunsaturated fatty acid levels indicate diminished treatment response in patients with multi- versus first-episode schizophrenia
Authors: Li Nana , Yang Ping , Tang Mimi , Liu Yong , Guo Wenbin , Lang Bing , Wang Jianjian , Wu Haishan , Tang Hui , Yu Yan , Wu Xiangxin , Zeng Cuirong , Cao Ting , Cai Hualin
Published: March 2022

Antipsychotic effects seem to decrease in relapsed schizophrenia patients and the underlying mechanisms remain to be elucidated. Based on the essential role of polyunsaturated fatty acids in brain function and the treatment of schizophrenia, we hypothesize that disordered fatty acid metabolism may contribute to treatment resistance in multi-episode patients. We analyzed the erythrocyte membrane fatty acids in 327 schizophrenia patients under various episodes (numbers of patients: first-episode drug naïve 89; 2–3 episodes 110; 4–6 episodes 80; over 6 episodes 48) and 159 age- and gender-matched healthy controls. Membrane fatty acid levels and PANSS scales were assessed at baseline of antipsychotic-free period and one-month of follow-up after treatment. Totally, both saturated and unsaturated fatty acids were reduced at baseline when compared to healthy controls. Subgroup analyses among different episodes indicated that in response to atypical antipsychotic treatment, the membrane fatty acids were only increased in patients within 3 episodes, and this therapeutic effects on omega-3 index were merely present in the first episode. Results of fatty acid ratios suggested that dysregulations of enzymes such as D6 desaturase, D5 desaturase, and elongases for polyunsaturated fatty acids in patients with multi-episode schizophrenia could account for the differences. Additionally, certain fatty acid level/ratio changes were positively correlated with symptom improvement. The alterations of C22:5n3 and omega-3 index, gender, and the number of episodes were significant risk factors correlated with treatment responsiveness. Using targeted metabolomic approach, we revealed the potential mechanisms underlying abnormal fatty acid metabolism responsible for reduced treatment response in patients with multi-episode schizophrenia.
Machine learning and phone data can improve targeting of humanitarian aid
Authors: Aiken Emily , Bellue Suzanne , Karlan Dean , Udry Chris , Blumenstock Joshua E.
Published: March 2022

The COVID-19 pandemic has devastated many low- and middle-income countries, causing widespread food insecurity and a sharp decline in living standards1. In response to this crisis, governments and humanitarian organizations worldwide have distributed social assistance to more than 1.5 billion people2. Targeting is a central challenge in administering these programmes: it remains a difficult task to rapidly identify those with the greatest need given available data3,4. Here we show that data from mobile phone networks can improve the targeting of humanitarian assistance. Our approach uses traditional survey data to train machine-learning algorithms to recognize patterns of poverty in mobile phone data; the trained algorithms can then prioritize aid to the poorest mobile subscribers. We evaluate this approach by studying a flagship emergency cash transfer program in Togo, which used these algorithms to disburse millions of US dollars worth of COVID-19 relief aid. Our analysis compares outcomes—including exclusion errors, total social welfare and measures of fairness—under different targeting regimes. Relative to the geographic targeting options considered by the Government of Togo, the machine-learning approach reduces errors of exclusion by 4–21%. Relative to methods requiring a comprehensive social registry (a hypothetical exercise; no such registry exists in Togo), the machine-learning approach increases exclusion errors by 9–35%. These results highlight the potential for new data sources to complement traditional methods for targeting humanitarian assistance, particularly in crisis settings in which traditional data are missing or out of date.
Reproducible brain-wide association studies require thousands of individuals
Authors: Marek Scott , Tervo-Clemmens Brenden , Calabro Finnegan J. , Montez David F. , Kay Benjamin P. , Hatoum Alexander S. , Donohue Meghan Rose , Foran William , Miller Ryland L. , Hendrickson Timothy J. , Malone Stephen M. , Kandala Sridhar , Feczko Eric , Miranda-Dominguez Oscar , Graham Alice M. , Earl Eric A. , Perrone Anders J. , Cordova Michaela , Doyle Olivia , Moore Lucille A. , Conan Gregory M. , Uriarte Johnny , Snider Kathy , Lynch Benjamin J. , Wilgenbusch James C. , Pengo Thomas , Tam Angela , Chen Jianzhong , Newbold Dillan J. , Zheng Annie , Seider Nicole A. , Van Andrew N. , Metoki Athanasia , Chauvin Roselyne J. , Laumann Timothy O. , Greene Deanna J. , Petersen Steven E. , Garavan Hugh , Thompson Wesley K. , Nichols Thomas E. , Yeo B. T. Thomas , Barch Deanna M. , Luna Beatriz , Fair Damien A. , Dosenbach Nico U. F.
Published: March 2022

Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1–3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals.
Activation mechanism of the class D fungal GPCR dimer Ste2
Authors: Velazhahan Vaithish , Ma Ning , Vaidehi Nagarajan , Tate Christopher G.
Published: March 2022

The fungal class D1 G-protein-coupled receptor (GPCR) Ste2 has a different arrangement of transmembrane helices compared with mammalian GPCRs and a distinct mode of coupling to the heterotrimeric G protein Gpa1–Ste2–Ste181. In addition, Ste2 lacks conserved sequence motifs such as DRY, PIF and NPXXY, which are associated with the activation of class A GPCRs2. This suggested that the activation mechanism of Ste2 may also differ. Here we determined structures of Saccharomyces cerevisiae Ste2 in the absence of G protein in two different conformations bound to the native agonist α-factor, bound to an antagonist and without ligand. These structures revealed that Ste2 is indeed activated differently from other GPCRs. In the inactive state, the cytoplasmic end of transmembrane helix H7 is unstructured and packs between helices H1–H6, blocking the G protein coupling site. Agonist binding results in the outward movement of the extracellular ends of H6 and H7 by 6 Å. On the intracellular surface, the G protein coupling site is formed by a 20 Å outward movement of the unstructured region in H7 that unblocks the site, and a 12 Å inward movement of H6. This is a distinct mechanism in GPCRs, in which the movement of H6 and H7 upon agonist binding facilitates G protein coupling.
A multidimensional coding architecture of the vagal interoceptive system
Authors: Zhao Qiancheng , Yu Chuyue D. , Wang Rui , Xu Qian J. , Dai Pra Rafael , Zhang Le , Chang Rui B.
Published: March 2022

Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1–4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral–caudal axis of the body and crossing the surface–lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality—three key features of an interoceptive signal—in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a ‘visceral organ’ dimension composed of differentially expressed gene modules that code organs along the body’s rostral–caudal axis. We discover another ‘tissue layer’ dimension with gene modules that code the locations of VSN endings along the surface–lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third ‘stimulus modality’ dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.
A conserved sequence in the small intracellular loop of tetraspanins forms an M-shaped inter-helix turn
Authors: Reppert Nikolas , Lang Thorsten
Published: March 2022

Tetraspanins are a family of small proteins with four transmembrane segments (TMSs) playing multiple roles in human physiology. Nevertheless, we know little about the factors determining their structure. In the study at hand, we focus on the small intracellular loop (SIL) between TMS2 and TMS3. There we have identified a conserved five amino acid core region with three charged residues forming an M-shaped backbone, which we call M-motif. The M´s plane runs parallel to the membrane surface and the central amino acid constitutes the inter-helix turning point. At the second position of the M-motif, in tetraspanin crystal structures we identified a glutamate oriented towards a lysine in the juxtamembrane region of TMS1. Using Tspan17 as example, we find that by mutating either the glutamate or juxtamembrane-lysine, but not upon glutamate/lysine swapping, expression level, maturation and ER-exit are reduced. We conclude that the SIL is more than a short linking segment but propose it is involved in shaping the tertiary structure of tetraspanins.
Impact of the COVID-19 pandemic on oral health and psychosocial factors
Authors: Ciardo Antonio , Simon Marlinde M. , Sonnenschein Sarah K. , Büsch Christopher , Kim Ti-Sun
Published: March 2022

The objective of this study was to investigate oral health-related quality of life (OHRQoL) in times of the COVID-19 pandemic and to examine a possible association to psychosocial factors like psychological stress and symptoms of depression and anxiety disorders. Secondary research questions were whether people changed oral hygiene regimens during the COVID-19 pandemic and to what extent dental symptoms existed and developed compared to pre-pandemic. For this cross-sectional study a survey has been conceptualized to determine OHRQoL, stress, depression and anxiety and their specific confounders in a German cohort. Validated questionnaires as OHIP-G14, PHQ-Stress and PHQ-4 have been implemented. Altogether 1178 participants completed the survey between May and August 2020. The overall OHIP-G14 sum score of 4.8 ± 7.5 indicated good OHRQoL. 21% of the participants (n = 248) reported toothache, 23% (n = 270) mucosal problems, 31% (n = 356) hypersensitivity of the teeth and 27% (n = 305) myofacial pain. The PHQ-Stress score (4.5 ± 3.5) demonstrated a mild severity of stress. Depression and anxiety level has been mild to moderate (PHQ-4 score: 2.4 ± 2.6). 38% of the participants stated subjectively greater emotional burden compared to pre-pandemic. Statistically significant differences exist for OHRQoL, stress, anxiety and depression levels between participants with greater, equal or less emotional burden compared to pre-pandemic. COVID-19 history and aggravated levels of depression, anxiety, and stress seem to associate with lower OHRQoL. Psychosocial consequences during pandemic times and their association to oral health should be further investigated.
The prevalence of dental developmental anomalies among childhood cancer survivors according to types of anticancer treatment
Authors: Halperson Elinor , Matalon Vered , Goldstein Gal , Saieg Spilberg Shirly , Herzog Karin , Fux-Noy Avia , Shmueli Aviv , Ram Diana , Moskovitz Moti
Published: March 2022

Survival following childhood cancer has increased considerably. In an observational cross-sectional study, we assessed the prevalence of dental developmental anomalies (DDA) among childhood cancer survivors according to types of anticancer treatment. Permanent teeth were examined clinically and radiographically in 121 adolescents with a history of childhood malignancies, to identify DDA, namely hypomineralization or hypoplasia, microdontia, root changes and hypodontia. DDA were observed in 56/121 individuals (46%), in 309/3388 teeth (9%). Hypomineralization or hypoplasia of enamel appeared in 21 (17%) patients. Altered root development appeared in 26 patients and hypodontia affected 13 (10%). Dental anomalies were observed in 36 (43%) individuals who received chemotherapy and not radiation, in 20 (52%) who received radiotherapy, and in 15 (60%) of those who received head and neck radiotherapy. Among patients who received only chemotherapy, young age (6 years or younger) was associated with a higher number of malformed teeth. In conclusion, antineoplastic treatment that combines chemotherapy and radiotherapy appears to increase the risk of DDA. Radiation to the head and neck area was shown to particularly increase the risk of DDA. No specific chemotherapy agent was found to be associated more than the others with DDA.
Natural antibodies and CRP drive anaphylatoxin production by urate crystals
Authors: Wessig Anne Kathrin , Hoffmeister Leonie , Klingberg Annika , Alberts Anika , Pich Andreas , Brand Korbinian , Witte Torsten , Neumann Konstantin
Published: March 2022

In gout, crystallization of uric acid in the form of monosodium urate (MSU) leads to a painful inflammatory response. MSU crystals induce inflammation by activating the complement system and various immune cell types, and by inducing necrotic cell death. We previously found that the soluble pattern recognition molecule C-reactive protein (CRP) recognizes MSU crystals, while enhancing complement activation. In the absence of CRP, MSU crystals still induced complement activation, suggesting additional CRP-independent mechanisms of complement activation. In the present study, we searched for additional MSU crystal-binding complement activators. We found that all healthy individuals, even unborn children, have MSU crystal-specific immunoglobulin M (IgM) in their blood. This indicates that innate IgM, also known as natural IgM, recognizes these crystals. In serum lacking IgM and CRP, MSU crystals showed negligible complement activation as assessed by the production of the anaphylatoxins C4a, C3a, and C5a (listed in order of production via the classical complement pathway). We show that IgM and CRP both activate the classical complement pathway on MSU crystals. CRP was more efficient at fixating active C1 on the crystals and inducing release of the most inflammatory anaphylatoxin C5a, indicating non-redundant functions of CRP. Notably, while CRP recognizes MSU crystals but not the related calcium pyrophosphate dihydrate (CPPD) crystals, natural IgM bound to both, suggesting common and distinct mechanisms of recognition of individual crystal types by complement activators.