bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered learning from positive feedback in adolescents with anorexia nervosa
Authors: Uniacke Blair , van den Bos Wouter , Wonderlich Joseph , Ojeda Jessica , Posner Jonathan , Steinglass Joanna E. , Foerde Karin
Published: September 2024

Objective:

Anorexia nervosa (AN) is characterized by severe restriction of calorie intake, which persists despite serious medical and psychological sequelae of starvation. Several prior studies have identified impaired feedback learning among individuals with AN, but whether it reflects a disturbance in learning from positive feedback (i.e., reward), negative feedback (i.e., punishment), or both, and the extent to which this impairment is related to severity and duration of illness, has not been clarified.

Method:

Participants were female adolescents with AN (n = 76) and healthy teen volunteers (HC; n = 38) between the ages of 12–18 years who completed a probabilistic reinforcement learning task. A Bayesian reinforcement learning model was used to calculate separate learning rates for positive and negative feedback. Exploratory analyses examined associations between feedback learning and duration of illness, eating disorder severity, and self/parent reports of reward and punishment sensitivity.

Results:

Adolescents with AN had a significantly lower rate of learning from positive feedback relative to HC. Patients and HC did not differ in learning from negative feedback or on overall task performance measures. Feedback learning parameters were not significantly associated with duration of illness, eating disorder severity, or questionnaire-based reports of reward and punishment sensitivity.

Conclusion:

Adolescents with AN showed a circumscribed deficit in learning from reward that was not associated with duration of illness or reported sensitivity to reward or punishment. Subsequent longitudinal research should explore whether differences in learning from positive feedback relate to course of illness in youth with AN.
Anxiety in late-life depression is associated with poorer performance across multiple cognitive domains
Authors: Kryza-Lacombe Maria , Kassel Michelle T. , Insel Philip S. , Rhodes Emma , Bickford David , Burns Emily , Butters Meryl A. , Tosun Duygu , Aisen Paul , Raman Rema , Saykin Andrew J. , Toga Arthur W. , Jack Clifford R. , Weiner Michael W. , Nelson Craig , Mackin R. Scott
Published: September 2024

Objective:

Anxiety is a common comorbid feature of late-life depression (LLD) and is associated with poorer global cognitive functioning independent of depression severity. However, little is known about whether comorbid anxiety is associated with a domain-specific pattern of cognitive dysfunction. We therefore examined group differences (LLD with and without comorbid anxiety) in cognitive functioning performance across multiple domains.

Method:

Older adults with major depressive disorder (N = 228, ages 65–91) were evaluated for anxiety and depression severity, and cognitive functioning (learning, memory, language, processing speed, executive functioning, working memory, and visuospatial functioning). Ordinary least squares regression adjusting for age, sex, education, and concurrent depression severity examined anxiety group differences in performance on tests of cognitive functioning.

Results:

Significant group differences emerged for confrontation naming and visuospatial functioning, as well as for verbal fluency, working memory, and inhibition with lower performance for LLD with comorbid anxiety compared to LLD only, controlling for depression severity.

Conclusions:

Performance patterns identified among older adults with LLD and comorbid anxiety resemble neuropsychological profiles typically seen in neurodegenerative diseases of aging. These findings have potential implications for etiological considerations in the interpretation of neuropsychological profiles.
Using augmented reality to assess spatial neglect: The Free Exploration Test (FET)
Authors: Stammler Britta , Lambert Marian , Schuster Thomas , Flammer Kathrin , Karnath Hans-Otto
Published: September 2024

Background:

To capture the distortion of exploratory activity typical of patients with spatial neglect, traditional diagnostic methods and new virtual reality applications use confined workspaces that limit patients’ exploration behavior to a predefined area. Our aim was to overcome these limitations and enable the recording of patients’ biased activity in real, unconfined space.

Methods:

We developed the Free Exploration Test (FET) based on augmented reality technology. Using a live stream via the back camera on a tablet, patients search for a (non-existent) virtual target in their environment, while their exploration movements are recorded for 30 s. We tested 20 neglect patients and 20 healthy participants and compared the performance of the FET with traditional neglect tests.

Results:

In contrast to controls, neglect patients exhibited a significant rightward bias in exploratory movements. The FET had a high discriminative power (area under the curve = 0.89) and correlated positively with traditional tests of spatial neglect (Letter Cancellation, Bells Test, Copying Task, Line Bisection). An optimal cut-off point of the averaged bias of exploratory activity was at 9.0° on the right; it distinguished neglect patients from controls with 85% sensitivity.

Discussion:

FET offers time-efficient (execution time: ∼3 min), easy-to-apply, and gamified assessment of free exploratory activity. It supplements traditional neglect tests, providing unrestricted recording of exploration in the real, unconfined space surrounding the patient.
Imaging Attenuation From Array Analysis of Surface Waves
Authors: Bao Xueyang , Wang Nian
Published: September 2024

Anelastic attenuation provides key insight in our understanding of thermal and rheological structures and the associated deformation and dynamic mechanisms of the Earth's deep interior. Unfortunately, attenuation tomography is advanced far behind wave‐speed tomography due to the challenge in properly excluding the complex effects of elastic heterogeneities on seismic wave amplitude. By taking advantage of phase tracking in seismic array analysis, here we derive a new theory of Helmholtz tomography that well accounts for attenuation, source radiation, and scattering, etc., and present a technique called Helmholtz Multi‐Event Tomography (HelMET) to retrieve the attenuation properly. The effectiveness of this method is then validated by synthetic inversions. Our synthetic seismograms are calculated using a newly developed three‐dimensional finite‐difference algorithm that accounts for physical dispersion and dissipation in anelastic media and remains accurate and stable even if strong attenuation exists. Compared to the traditional method poorly performed in the synthetic inversion, the HelMET well recovers the input attenuation anomalies, suggesting that this method can be used to successfully isolate attenuation from the complicated effects of elastic heterogeneities. Our results underline the implication of the new theory and method in accurately imaging high‐resolution attenuation structures and unambiguously interpreting the anelastic heterogeneities of the Earth by array‐based earthquake and ambient noise data with inexpensive computation.
Evolution of Turbulent Boundary Conditions on the Surface of Large Barchan Dunes: Anomalies in Aerodynamic Roughness and Shear Velocity, Aeolian Threshold, and the Role of Dune Skewness
Authors: Louge M. Y. , Valance A. , Fang J. , Harnett S. J. , Porté‐Agel F. , Chasle P.
Published: September 2024

We recorded aerodynamic roughness and shear velocity along transects on and around mature crescent‐shaped barchan dunes of and height above the horizontal rock‐covered Qatar desert by fitting to the log‐law time‐averaged vertical velocity profiles acquired from triads of ultrasonic anemometers penetrating the inner turbulent boundary layer. Shear velocity first decreased, then recovered as air climbed on the dune, with a local maximum ahead of the crest as predicted by the Jackson and Hunt (1975, https://doi.org/10.1002/qj.49710143015) theory. Unlike flows over gentler bedforms without a slope discontinuity, an anomalous peak of shear velocity also arose on the dune centerline at the brink, which the theory attributed to skewness in the dune transect profile. The onset of aeolian transport produced a log‐law passing through the Bagnold (1941, https://doi.org/10.1007/978‐94‐009‐5682‐7) focal point. It was bracketed by noticeable hysteretic peaks in the correlation between wind speed and entrained sand flux. The dunes' rocky surroundings and topography produced an aerodynamic roughness at odds with the Nikuradse (1933, https://ntrs.nasa.gov/citations/19930093938) data for fully developed turbulent boundary layers. Large‐eddy numerical simulations illustrated the sensitivity of shear velocity to wide changes in aerodynamic roughness from desert floor to dune surface.
Mechanical Energy Dissipation During Seismic Dynamic Weakening in Calcite‐Bearing Faults
Authors: Aretusini Stefano , Nuñez Cascajero Arantzazu , Cornelio Chiara , Barrero Echevarria Xabier , Spagnuolo Elena , Tapetado Alberto , Vazquez Carmen , Di Toro Giulio , Cocco Massimo
Published: September 2024

Earthquakes are frictional instabilities caused by the shear stress decrease, that is, dynamic weakening, of faults with slip and slip rate. During dynamic weakening, shear stress depends on slip, slip rate, and temperature, according to constitutive laws governing the earthquake rupture process. In the laboratory, technical limitations in measuring temperature during frictional instabilities inhibit the investigation and interpretation of shear stress evolution. Here we conduct high velocity friction experiments on calcite‐bearing simulated faults, both on bare‐rock and on gouge samples, at 20–30 MPa normal stress, 1–6 m/s slip rate and 1–20 m total slip. Seismic slip pulses are reproduced by imposing boxcar and regularized Yoffe slip rate functions. We measured, together with shear stress, slip, and slip rate, the temperature evolution on the fault by employing an innovative two‐color fiber optic pyrometer. The comparison between modeled and measured temperature reveals that for calcite‐bearing faults the heat sink caused by decarbonation reaction controls the temperature evolution. In bare‐rocks, energy is dissipated as frictional heat, and temperature increase is buffered by the heat sink of the calcite decarbonation reaction. In gouges, energy is dissipated as frictional heat and for plastic deformation processes, balanced by the heat sink caused by the decarbonation reaction enhanced by the mechanochemical effect. Our results suggest that in calcite‐bearing rocks, a common fault zone material for earthquake sources in the continental crust at shallow depth, the type of fault materials (bare‐rocks vs. gouges) controls the energy dissipation during seismic slip.
Neural stem cells derived from α-synuclein-knockdown iPS cells alleviate Parkinson’s disease
Authors: Wang Chie-Hong , Lin Guan-Cyun , Fu Ru-Huei , Huang Yu-Chuen , Chen Shih-Yin , Lin Shinn-Zong , Harn Horng-Jyh , Shyu Woei-Cherng , Huang Yi‐Fang , Jeng Long-Bin , Liu Shih-Ping
Published: September 2024

Stem cells have the potential to replace damaged or defective cells and assist in the development of treatments for neurodegenerative diseases, including Parkinson’s disease (PD) and Alzheimer’s disease. iPS cells derived from patient-specific somatic cells are not only ethically acceptable, but they also avoid complications relating to immune rejection. Currently, researchers are developing stem cell-based therapies for PD using induced pluripotent stem (iPS) cells. iPS cells can differentiate into cells from any of the three germ layers, including neural stem cells (NSCs). Transplantation of neural stem cells (NSCs) is an emerging therapy for treating neurological disorders by restoring neuronal function. Nevertheless, there are still challenges associated with the quality and source of neural stem cells. This issue can be addressed by genetically edited iPS cells. In this study, shRNA was used to knock down the expression of mutant α-synuclein (SNCA) in iPS cells that were generated from SNCA A53T transgenic mice, and these iPS cells were differentiated to NSCs. After injecting these NSCs into SNCA A53T mice, the therapeutic effects of these cells were evaluated. We found that the transplantation of neural stem cells produced from SNCA A53T iPS cells with knocking down SNCA not only improved SNCA A53T mice coordination abilities, balance abilities, and locomotor activities but also significantly prolonged their lifespans. The results of this study suggest an innovative therapeutic approach that combines stem cell therapy and gene therapy for the treatment of Parkinson’s disease.
Deubiquitinase JOSD1 tempers hepatic proteotoxicity
Authors: Chowdhury Saheli , Sen Abhishek , Das Debajyoti , Chakrabarti Partha
Published: September 2024

Derangements in protein homeostasis and associated proteotoxicity mark acute, chronic, and drug-induced hepatocellular injury. Metabolic dysfunction-associated proteasomal inhibition and the use of proteasome inhibitors often underlie such pathological hepatic proteotoxicity. In this study, we sought to identify a candidate deubiquitinating enzyme (DUB) responsible for reversing the proteotoxic damage. To this end, we performed a siRNA screening wherein 96 DUBs were individually knocked down in HepG2 cells under proteasomal inhibitor-induced stress for dual readouts, apoptosis, and cell viability. Among the putative hits, we chose JOSD1, a member of the Machado-Josephin family of DUBs that reciprocally increased cell viability and decreased cell death under proteotoxicity. JOSD1-mediated mitigation of proteotoxicity was further validated in primary mouse hepatocytes by gain and loss of function studies. Marked plasma membrane accumulation of monoubiquitinated JOSD1 in proteotoxic conditions is a prerequisite for its protective role, while the enzymatically inactive JOSD1 C36A mutant was conversely polyubiquitinated, does not have membrane localisation and fails to reverse proteotoxicity. Mechanistically, JOSD1 physically interacts with the suppressor of cytokine signalling 1 (SOCS1), deubiquitinates it and enhances its stability under proteotoxic stress. Indeed, SOCS1 expression is necessary and sufficient for the hepatoprotective function of JOSD1 under proteasomal inhibition. In vivo, adenovirus-mediated ectopic expression or depletion of JOSD1 in mice liver respectively protects or aggravates hepatic injury when challenged with proteasome blocker Bortezomib. Our study thus unveils JOSD1 as a potential candidate for ameliorating hepatocellular damage in liver diseases.
Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer
Authors: Yang Wenxiao , Hong Luo , Guo Linwei , Wang Yunjin , Han Xiangchen , Han Boyue , Xing Zheng , Zhang Guoliang , Zhou Hongxia , Chen Chao , Ling Hong , Shao Zhimin , Hu Xin
Published: September 2024

Metabolic dysregulation is prominent in triple-negative breast cancer (TNBC), yet therapeutic strategies targeting cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (n = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8+ T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.
Novel MLH1 nonsense variant in a patient with suspected Lynch syndrome
Authors: Takaiso Nobue , Imoto Issei , Matsumoto Toshihiko , Yoshimura Akiyo
Published: September 2024

Loss-of-function germline variants of MLH1 cause Lynch syndrome. Here, we present the case of a 43-year-old male patient diagnosed with cecal and transverse colon adenocarcinomas. The characteristics of the case met the revised Bethesda guidelines, and the tumors demonstrated a high frequency of microsatellite instability. Genetic testing for mismatch repair genes (indicative of Lynch syndrome) revealed a novel heterozygous germline pathogenic variant, NM_000249.4:c.856A>T/NP_000240.1:p.(Lys286Ter), in MLH1.
Sustainable-use marine protected areas to improve human nutrition
Authors: Viana Daniel F. , Gill David , Zvoleff Alex , Krueck Nils C. , Zamborain-Mason Jessica , Free Christopher M. , Shepon Alon , Grieco Dana , Schmidhuber Josef , Mascia Michael B. , Golden Christopher D.
Published: September 2024

Coral reef fisheries are a vital source of nutrients for thousands of nutritionally vulnerable coastal communities around the world. Marine protected areas are regions of the ocean designed to preserve or rehabilitate marine ecosystems and thereby increase reef fish biomass. Here, we evaluate the potential effects of expanding a subset of marine protected areas that allow some level of fishing within their borders (sustainable-use MPAs) to improve the nutrition of coastal communities. We estimate that, depending on site characteristics, expanding sustainable-use MPAs could increase catch by up to 20%, which could help prevent 0.3-2.85 million cases of inadequate micronutrient intake in coral reef nations. Our study highlights the potential add-on nutritional benefits of expanding sustainable-use MPAs in coral reef regions and pinpoints locations with the greatest potential to reduce inadequate micronutrient intake level. These findings provide critical knowledge given international momentum to cover 30% of the ocean with MPAs by 2030 and eradicate malnutrition in all its forms.
Longitudinal proteome-wide antibody profiling in Marburg virus survivors identifies wing domain immunogen for vaccine design
Authors: Khurana Surender , Grubbs Gabrielle , Ravichandran Supriya , Cluff Emily , Kim JungHyun , Kuehne Ana I. , Zak Samantha , Dye John M. , Lutwama Julius J. , Herbert Andrew S.
Published: September 2024

Limited knowledge exists on the quality of polyclonal antibody responses generated following Marburg virus (MARV) infection and its evolution in survivors. In this study, we evaluate MARV proteome-wide antibody repertoire longitudinally in convalescent phase approximately every six months for five years following MARV infection in ten human survivors. Differential kinetics were observed for IgM vs IgG vs IgA epitope diversity, antibody binding, antibody affinity maturation and Fc-receptor interaction to MARV proteins. Durability of MARV-neutralizing antibodies is low in survivors. MARV infection induces a diverse epitope repertoire with predominance against GP, VP40, VP30 and VP24 that persisted up to 5 years post-exposure. However, the IgM and IgA repertoire declines over time. Within MARV-GP, IgG recognize antigenic sites predominantly in the amino-terminus, wing domain and GP2-heptad repeat. Interestingly, MARV infection generates robust durable FcɣRI, FcɣRIIA and FcɣRIIIA IgG-Fc receptor interactions. Immunization with immunodominant MARV epitopes reveals conserved wing region between GP1 and GP2, induces neutralizing antibodies against MARV. These findings demonstrate that MARV infection generates a diverse, long-lasting, non-neutralizing, IgG antibody repertoire that perturbs disease by FcɣR activity. This information, along with discovery of neutralizing immunogen in wing domain, could aid in development of effective therapeutics and vaccines against Marburg virus.
Establishing coherent momentum-space electronic states in locally ordered materials
Authors: Ciocys Samuel T. , Marsal Quentin , Corbae Paul , Varjas Daniel , Kennedy Ellis , Scott Mary , Hellman Frances , Grushin Adolfo G. , Lanzara Alessandra
Published: September 2024

Rich momentum-dependent electronic structure naturally arises in solids with long-range crystalline symmetry. Reliable and scalable quantum technologies rely on materials that are either not perfect crystals or non-crystalline, breaking translational symmetry. This poses the fundamental questions of whether coherent momentum-dependent electronic states can arise without long-range order, and how they can be characterized. Here we investigate Bi2Se3, which exists in crystalline, nanocrystalline, and amorphous forms, allowing direct comparisons between varying degrees of spatial ordering. Through angle-resolved photoemission spectroscopy, we show for the first time momentum-dependent band structure with Fermi surface repetitions in an amorphous solid. The experimental data is complemented by a model that accurately reproduces the vertical, dispersive features as well as the replication at higher momenta in the amorphous form. These results reveal that well-defined real-space length scales are sufficient to produce dispersive band structures, and that photoemission can expose the imprint of these length scales on the electronic structure.
Quantifying benefits of renewable investments for German residential Prosumers in times of volatile energy markets
Authors: van Ouwerkerk Jonas , Celi Cortés Mauricio , Nsir Najet , Gong Jingyu , Figgener Jan , Zurmühlen Sebastian , Bußar Christian , Sauer Dirk Uwe
Published: September 2024

The COVID-19 pandemic and the Russian invasion of Ukraine have led to unseen disruptions in the global energy markets since the end of 2021. Residential renewable investments like photovoltaic systems, battery home storage systems, and heat pumps are therefore gaining traction. However, the benefits of those technologies during the energy crisis and beyond have not been fully quantified yet. Therefore, in this study, we benchmark renewable investments for a broad variety of single-family homes by evaluating potential cost savings and emission reductions. In addition, the study considers the influence of recent political incentives and subsidies. The results show that photovoltaic systems are a no-regret investment decision, both economically and environmentally. At the climax of the energy crisis, a typical German household with a heat pump could save 1850 € and reduce equivalent CO2 emissions by 250 g/kWh annually. Politically introduced price breaks on electricity and natural gas do not reverse this advantage. Furthermore, when owning an electric vehicle renewable investments are often more beneficial.
Dopamine neurons encode trial-by-trial subjective reward value in an auction-like task
Authors: Hill Daniel F. , Hickman Robert W. , Al-Mohammad Alaa , Stasiak Arkadiusz , Schultz Wolfram
Published: September 2024

The dopamine reward prediction error signal is known to be subjective but has so far only been assessed in aggregate choices. However, personal choices fluctuate across trials and thus reflect the instantaneous subjective reward value. In the well-established Becker-DeGroot-Marschak (BDM) auction-like mechanism, participants are encouraged to place bids that accurately reveal their instantaneous subjective reward value; inaccurate bidding results in suboptimal reward (“incentive compatibility”). In our experiment, male rhesus monkeys became experienced over several years to place accurate BDM bids for juice rewards without specific external constraints. Their bids for physically identical rewards varied trial by trial and increased overall for larger rewards. In these highly experienced animals, responses of midbrain dopamine neurons followed the trial-by-trial variations of bids despite constant, explicitly predicted reward amounts. Inversely, dopamine responses were similar with similar bids for different physical reward amounts. Support Vector Regression demonstrated accurate prediction of the animals’ bids by as few as twenty dopamine neurons. Thus, the phasic dopamine reward signal reflects instantaneous subjective reward value.
Distinct mechanisms regulate ventricular and atrial chamber wall formation
Authors: Albu Marga , Affolter Eileen , Gentile Alessandra , Xu Yanli , Kikhi Khrievono , Howard Sarah , Kuenne Carsten , Priya Rashmi , Gunawan Felix , Stainier Didier Y. R.
Published: September 2024

Tissues undergo distinct morphogenetic processes to achieve similarly shaped structures. In the heart, cardiomyocytes in both the ventricle and atrium build internal structures for efficient contraction. Ventricular wall formation (trabeculation) is initiated by cardiomyocyte delamination. How cardiomyocytes build the atrial wall is poorly understood. Using longitudinal imaging in zebrafish, we found that at least 25% of the atrial cardiomyocytes elongate along the long axis of the heart. These cell shape changes result in cell intercalation and convergent thickening, leading to the formation of the internal muscle network. We tested factors important for ventricular trabeculation including Nrg/ErbB and Notch signaling and found no evidence for their role in atrial muscle network formation. Instead, our data suggest that atrial cardiomyocyte elongation is regulated by Yap, which has not been implicated in trabeculation. Altogether, these data indicate that distinct cellular and molecular mechanisms build the internal muscle structures in the atrium and ventricle.
A comparative analysis of planarian genomes reveals regulatory conservation in the face of rapid structural divergence
Authors: Ivanković Mario , Brand Jeremias N. , Pandolfini Luca , Brown Thomas , Pippel Martin , Rozanski Andrei , Schubert Til , Grohme Markus A. , Winkler Sylke , Robledillo Laura , Zhang Meng , Codino Azzurra , Gustincich Stefano , Vila-Farré Miquel , Zhang Shu , Papantonis Argyris , Marques André , Rink Jochen C.
Published: September 2024

The planarian Schmidtea mediterranea is being studied as a model species for regeneration, but the assembly of planarian genomes remains challenging. Here, we report a high-quality haplotype-phased, chromosome-scale genome assembly of the sexual S2 strain of S. mediterranea and high-quality chromosome-scale assemblies of its three close relatives, S. polychroa, S. nova, and S. lugubris. Using hybrid gene annotations and optimized ATAC-seq and ChIP-seq protocols for regulatory element annotation, we provide valuable genome resources for the planarian research community and a first comparative perspective on planarian genome evolution. Our analyses reveal substantial divergence in protein-coding sequences and regulatory regions but considerable conservation within promoter and enhancer annotations. We also find frequent retrotransposon-associated chromosomal inversions and interchromosomal translocations within the genus Schmidtea and, remarkably, independent and nearly complete losses of ancestral metazoan synteny in Schmidtea and two other flatworm groups. Overall, our results suggest that platyhelminth genomes can evolve without syntenic constraints.
Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements
Authors: Chardon Florence M. , McDiarmid Troy A. , Page Nicholas F. , Daza Riza M. , Martin Beth K. , Domcke Silvia , Regalado Samuel G. , Lalanne Jean-Benoît , Calderon Diego , Li Xiaoyi , Starita Lea M. , Sanders Stephan J. , Ahituv Nadav , Shendure Jay
Published: September 2024

CRISPR-based gene activation (CRISPRa) is a strategy for upregulating gene expression by targeting promoters or enhancers in a tissue/cell-type specific manner. Here, we describe an experimental framework that combines highly multiplexed perturbations with single-cell RNA sequencing (sc-RNA-seq) to identify cell-type-specific, CRISPRa-responsive cis-regulatory elements and the gene(s) they regulate. Random combinations of many gRNAs are introduced to each of many cells, which are then profiled and partitioned into test and control groups to test for effect(s) of CRISPRa perturbations of both enhancers and promoters on the expression of neighboring genes. Applying this method to a library of 493 gRNAs targeting candidate cis-regulatory elements in both K562 cells and iPSC-derived excitatory neurons, we identify gRNAs capable of specifically upregulating intended target genes and no other neighboring genes within 1 Mb, including gRNAs yielding upregulation of six autism spectrum disorder (ASD) and neurodevelopmental disorder (NDD) risk genes in neurons. A consistent pattern is that the responsiveness of individual enhancers to CRISPRa is restricted by cell type, implying a dependency on either chromatin landscape and/or additional trans-acting factors for successful gene activation. The approach outlined here may facilitate large-scale screens for gRNAs that activate genes in a cell type-specific manner.
Re-organization of Pacific overturning circulation across the Miocene Climate Optimum
Authors: Holbourn Ann , Kuhnt Wolfgang , Kulhanek Denise K. , Mountain Gregory , Rosenthal Yair , Sagawa Takuya , Lübbers Julia , Andersen Nils
Published: September 2024

The response of the ocean overturning circulation to global warming remains controversial. Here, we integrate a multiproxy record from International Ocean Discovery Program Site U1490 in the western equatorial Pacific with published data from the Pacific, Southern and Indian Oceans to investigate the evolution of deep water circulation during the Miocene Climate Optimum (MCO) and Middle Miocene Climate Transition (MMCT). We find that the northward export of southern-sourced deep waters was closely tied to high-latitude climate and Antarctic ice cover variations. Global warming during the MCO drove a progressive decrease in carbonate ion concentration and density stratification, shifting the overturning from intermediate to deeper waters. In the western equatorial Pacific, carbonate dissolution was compensated by increased pelagic productivity, resulting in overall elevated carbonate accumulation rates after ~16 Ma. Stepwise global cooling and Antarctic glacial expansion during the MMCT promoted a gradual improvement in carbonate preservation and the initiation of a near-modern Pacific overturning circulation. We infer that changes in the latitudinal thermal gradient and in Southern Ocean zonal wind stress and upper ocean stratification drove radically different modes of deep water formation and overturning across the MCO and MMCT.
Examining the photo catalytic potency of annealed and un-annealed ZnO and nickel doped ZnO for degradation of organic pollutants in waste waters
Authors: Gull Fatima , Riaz Rehana , Ansari Komal , Atiq Haleema
Published: September 2024

Water scarcity and pollution has increased the need for innovative and effective waste water treatment methods. The presented study aims to tackle this difficulty by synthesizing zinc oxide (ZnO) and nickel (Ni) doped ZnO to improve their photo catalytic capacity. This study examines wastewater treatment and organic pollutant breakdown using nanotechnology. The annealing increases photo catalytic activity by 65%, thereby enhancing efficiency. XRD shows that annealing decreased the average crystal size of pure ZnO and nickel doped ZnO (Ni:ZnO) i.e., for pure ZnO average crystal size is decreased from 23.90 to 20.90 nm and for Ni:ZnO, 34.39–28.65 nm. SEM shows that un annealed samples have agglomerates, while annealed samples are quasi-spherical. Using diffuse reflectance spectroscopy (DRS), the study examines how annealing affects optical band gap. Annealed Ni:ZnO has a band gap of 3.09 eV, which is smaller as compared to un annealed Ni:ZnO (3.18 e V). Similarly, the decline in energy band gap is observed for pure ZnO too. This study highlights the significant capacity of Ni:ZnO, for un annealed and annealed synthesis, to effectively meet the urgent requirements for waste water treatment. The extensive research conducted in this work enhances our comprehension of photo catalytic materials and underscores its potential for practical implementation in addressing waste water-related environmental issues.
Ameliorative effects of silymarin on aflatoxin B1 toxicity in weaned rabbits: impact on growth, blood profile, and oxidative stress
Authors: Imbabi Tharwat A. , El‐Sayed Abdelkarim I. , El-Habbak Mohamed H. , Nasr Mohammed A. , Halawa Eman H.
Published: September 2024

Natural plant extracts offer numerous health benefits for rabbits, including improved feed utilization, antimycotic and antiaflatoxigenic effect, antioxidants, immunological modulation, and growth performance. The aim of the current study was to investigate the effects of silymarin on the performance, hemato-biochemical indices, antioxidants, and villus morphology. A total of 45 Moshtohor 4 weeks old weaned male rabbits were randomly allocated into three groups (15 rabbit/each) each group with 5 replicates. The first group served as the control group feed on an infected diet by aflatoxin B1 (AFB1) 0.02 mg/kg BW, while the second and third groups received an infected diet by AFB1 (0.02 mg/kg BW) and was treated with Silymarin 20 mg/kg BW/day or 30 mg/kg BW/day, respectively. Regarding the growth performance, silymarin supplementation significantly improved the final body weight compared with the control group. Physiologically, silymarin induced high level of dose-dependent total red blood cell count, hematocrit, eosinophils, high-density lipoprotein cholesterol, superoxid dismutase, catalase activity, total antioxidant capacityand intestinal villi width and length. Moreover, silymarin significantly restricted oxidative stress indicators, malondialdehyde, Alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceridein rabbits treated with (AFB1). In conclusion, silymarin supplementation to AFB1 contaminated rabbit diet may mitigate the negative effect of AFB1 on the rabbit performance and health status and increase growth performance, average daily gain, immunological modulation and antioxidants and provide a theoretical basis for the application of silymarin in livestock production.
Impairment of affective and cognitive empathy in high functioning autism is mediated by alterations in emotional reactivity
Authors: Kimmig Ann-Christin S. , Burger Lina , Schall Marina , Derntl Birgit , Wildgruber Dirk
Published: September 2024

Empathy impairments are considered a key aspect of autism-spectrum disorders (ASD). Previous research consistently shows reduced cognitive empathy, but findings on affective empathy vary, possibly due to experimental design variations (e.g., stimulus modality, social distance) and individual psychological factors (e.g., perceptual abilities, emotional reactivity). This study aims to clarify deficits in affective and cognitive empathy in ASD by addressing these contributing factors. Empathy was examined in 34 autistic individuals and 33 typically developed controls (TDCs) through the Textual Empathy Test (TET). The TET was developed to assess emotional responses when imagining oneself (emotional reactivity) as compared to a target person (friend, stranger) in emotional situations presented via short verbal descriptions. Participants rated emotional states of the target person (cognitive empathy) as well as their own emotional responses when imagining the target person in that situation (affective empathy). Ratings were interpreted relative to normative mean values through standardized regression coefficients. Results showed that high-functioning autism was associated with lower cognitive and affective empathy irrespective of social distance as well as with decreased emotional reactivity compared to controls. Moreover, emotional reactivity mediated the impact of ASD on both empathic components. In summary, altered emotional reactivity may underlie impaired empathy in autistic individuals.
Machine learning based classification of presence utilizing psychophysiological signals in immersive virtual environments
Authors: Saha Shuvodeep , Dobbins Chelsea , Gupta Anubha , Dey Arindam
Published: September 2024

In Virtual Reality (VR), a higher level of presence positively influences the experience and engagement of a user. There are several parameters that are responsible for generating different levels of presence in VR, including but not limited to, graphical fidelity, multi-sensory stimuli, and embodiment. However, standard methods of measuring presence, including self-reported questionnaires, are biased. This research focuses on developing a robust model, via machine learning, to detect different levels of presence in VR using multimodal neurological and physiological signals, including electroencephalography and electrodermal activity. An experiment has been undertaken whereby participants (N = 22) were each exposed to three different levels of presence (high, medium, and low) in a random order in VR. Four parameters within each level, including graphics fidelity, audio cues, latency, and embodiment with haptic feedback, were systematically manipulated to differentiate the levels. A number of multi-class classifiers were evaluated within a three-class classification problem, using a One-vs-Rest approach, including Support Vector Machine, k-Nearest Neighbour, Extra Gradient Boosting, Random Forest, Logistic Regression, and Multiple Layer Perceptron. Results demonstrated that the Multiple Layer Perceptron model obtained the highest macro average accuracy of $$93\pm 0.03\%$$

93
±
0.03
%

. Posthoc analysis revealed that relative band power, which is expressed as the ratio of power in a specific frequency band to the total baseline power, in both the frontal and parietal regions, including beta over theta and alpha ratio, and differential entropy were most significant in detecting different levels of presence.
Reciprocal cognitive and emotional interaction in STEMM university learning and teaching
Authors: Ippolito Kate , Kingsbury Martyn
Published: September 2024

University learning and teaching involves contrasting and interacting emotional experiences. Even in disciplines considered as objective as Science and Engineering, emotion plays a significant role in catalysing and sustaining learning. Although emotions are individually felt, they are socially constructed between people. This is especially relevant in group-based learning evident in much contemporary higher education. This paper applies the concept of emotion socialization to illustrate how groups of students and teachers cope and succeed in cognitively and emotionally challenging learning settings. The study is based on qualitative data collected across six STEMM university departments, from 280 students via in-situ questionnaires and from 20 teachers via group and follow-up interviews. Two key findings offer insight into processes of reciprocal influence on cognition and emotion. The first relates to ways in which students’ and teachers’ differing knowledge-related goals and relationships with knowledge influenced cognition and emotion, uncovering previously unacknowledged connections. The second relates to how students’ comparisons of progress towards academic goals with peers contributed considerably to their emotional experiences in cognitively and emotionally helpful and unhelpful ways. Practical implications are presented, including possibilities for capitalising on existing emotion socialization processes and enhancing how they influence cognition and emotional well-being.
Biochemical and crystallographic studies of l,d-transpeptidase 2 from Mycobacterium tuberculosis with its natural monomer substrate
Authors: de Munnik Mariska , Lang Pauline A. , Calvopiña Karina , Rabe Patrick , Brem Jürgen , Schofield Christopher J.
Published: September 2024

The essential l,d-transpeptidase of Mycobacterium tuberculosis (LdtMt2) catalyses the formation of 3$$\to$$
→
3 cross-links in cell wall peptidoglycan and is a target for development of antituberculosis therapeutics. Efforts to inhibit LdtMt2 have been hampered by lack of knowledge of how it binds its substrate. To address this gap, we optimised the isolation of natural disaccharide tetrapeptide monomers from the Corynebacterium jeikeium bacterial cell wall through overproduction of the peptidoglycan sacculus. The tetrapeptides were used in binding / turnover assays and biophysical studies on LdtMt2. We determined a crystal structure of wild-type LdtMt2 reacted with its natural substrate, the tetrapeptide monomer of the peptidoglycan layer. This structure shows formation of a thioester linking the catalytic cysteine and the donor substrate, reflecting an intermediate in the transpeptidase reaction; it informs on the mode of entrance of the donor substrate into the LdtMt2 active site. The results will be useful in design of LdtMt2 inhibitors, including those based on substrate binding interactions, a strategy successfully employed for other nucleophilic cysteine enzymes.
Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation
Authors: Zeppillo Tommaso , Ali Heba , Ravichandran Sowbarnika , Ritter Tamara C. , Wenger Sally , López-Murcia Francisco J. , Gideons Erinn , Signorelli Janetti , Schmeisser Michael J. , Wiltfang Jens , Rhee JeongSeop , Brose Nils , Taschenberger Holger , Krueger-Burg Dilja
Published: September 2024

Neuroligin-2 (Nlgn2) is a key synaptic adhesion protein at virtually all GABAergic synapses, which recruits GABAARs by promoting assembly of the postsynaptic gephyrin scaffold. Intriguingly, loss of Nlgn2 differentially affects subsets of GABAergic synapses, indicating that synapse-specific interactors and redundancies define its function, but the nature of these interactions remain poorly understood. Here we investigated how Nlgn2 function in hippocampal area CA1 is modulated by two proposed interaction partners, MDGA1 and MDGA2. We show that loss of MDGA1 expression, but not heterozygous deletion of MDGA2, ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behaviour characterizing Nlgn2 knockout (KO) mice. Additionally, combined Nlgn2 and MDGA1 deletion causes an exacerbated layer-specific loss of gephyrin puncta. Given that both Nlgn2 and the MDGA1 have been correlated with many psychiatric disorders, our data support the notion that cytosolic gephyrin aggregation may represent an interesting target for novel therapeutic strategies.
Computational screening of the effects of mutations on protein-protein off-rates and dissociation mechanisms by τRAMD
Authors: D’Arrigo Giulia , Kokh Daria B. , Nunes-Alves Ariane , Wade Rebecca C.
Published: September 2024

The dissociation rate, or its reciprocal, the residence time (τ), is a crucial parameter for understanding the duration and biological impact of biomolecular interactions. Accurate prediction of τ is essential for understanding protein-protein interactions (PPIs) and identifying potential drug targets or modulators for tackling diseases. Conventional molecular dynamics simulation techniques are inherently constrained by their limited timescales, making it challenging to estimate residence times, which typically range from minutes to hours. Building upon its successful application in protein-small molecule systems, τ-Random Acceleration Molecular Dynamics (τRAMD) is here investigated for estimating dissociation rates of protein-protein complexes. τRAMD enables the observation of unbinding events on the nanosecond timescale, facilitating rapid and efficient computation of relative residence times. We tested this methodology for three protein-protein complexes and their extensive mutant datasets, achieving good agreement between computed and experimental data. By combining τRAMD with MD-IFP (Interaction Fingerprint) analysis, dissociation mechanisms were characterized and their sensitivity to mutations investigated, enabling the identification of molecular hotspots for selective modulation of dissociation kinetics. In conclusion, our findings underscore the versatility of τRAMD as a simple and computationally efficient approach for computing relative protein-protein dissociation rates and investigating dissociation mechanisms, thereby aiding the design of PPI modulators.
Contextualising samples: supporting reference genomes of European biodiversity through sample and associated metadata collection
Authors: Böhne Astrid , Fernández Rosa , Leonard Jennifer A. , McCartney Ann M. , McTaggart Seanna , Melo-Ferreira José , Monteiro Rita , Oomen Rebekah A. , Vinnere Pettersson Olga , Struck Torsten H.
Published: September 2024

The European Reference Genome Atlas (ERGA) consortium aims to generate a reference genome catalogue for all of Europe's eukaryotic biodiversity. The biological material underlying this mission, the specimens and their derived samples, are provided through ERGA’s pan-European network. To demonstrate the community’s capability and capacity to realise ERGA’s ambitious mission, the ERGA Pilot project was initiated. In support of the ERGA Pilot effort to generate reference genomes for European biodiversity, the ERGA Sampling and Sample Processing committee (SSP) was formed by volunteer experts from ERGA’s member base. SSP aims to aid participating researchers through (i) establishing standards for and collecting of sample/specimen metadata; (ii) prioritisation of species for genome sequencing; and (iii) development of taxon-specific collection guidelines including logistics support. SSP serves as the entry point for sample providers to the ERGA genomic resource production infrastructure and guarantees that ERGA’s high-quality standards are upheld throughout sample collection and processing. With the volume of researchers, projects, consortia, and organisations with interests in genomics resources expanding, this manuscript shares important experiences and lessons learned during the development of standardised operational procedures and sample provider support. The manuscript details our experiences in incorporating the FAIR and CARE principles, species prioritisation, and workflow development, which could be useful to individuals as well as other initiatives.
Head and neck cancer incidence is rising but the sociodemographic profile is unchanging: a population epidemiological study (2001–2020)
Authors: Smith Craig D. L. , McMahon Alex D. , Purkayastha Mitana , Creaney Grant , Clements Kelten , Inman Gareth J. , Bhatti Lesley A. , Douglas Catriona M. , Paterson Claire , Conway David I.
Published: September 2024

Background

Increasing incidence of head and neck cancers (HNCs), driven by rising rates of oropharynx cancer (OPC), has been recorded around the world. This study examined trends in HNC and subsites (oral cavity, oropharynx, and larynx cancers) in Scotland focusing on assessing whether the sociodemographic profile has changed over the past 20 years.

Methods

Scottish Cancer Registry data (2001–2020) including European Age Standardised Rates of HNC and subsites were analysed in multivariate Poisson regression by age, sex, area-based socioeconomic status, and year of diagnosis (with interaction tests).

Results

Overall HNC and oral cavity cancer (OCC) incidence remained relatively stable. OPC incidence rates increased by 78%, while larynx cancer incidence declined by 27%. Over time, there were marginal shifts to a slightly older age profile for HNC (p = 0.001) and OCC (p = 0.001), but no changes in OPC (p = 0.86) and larynx cancer (p = 0.29). No shift in the sex profile of HNC was observed except for minor increases in female OCC rates (p = 0.001), and the socioeconomic distribution remained unchanged across all HNC subsites.

Conclusions

There have been no significant changes in the sociodemographic profile of HNC in Scotland over the last 20 years, despite the changing trends in HNCs with dramatically increasing incidence rates in OPC and reducing larynx cancer. This information can be used to target or stratify HNC prevention and control.