bluuebunny/crossref_metadata_2025 huggingface dataset:
Back to Basics: Care of the Stereotactic EEG Implanted Patient
Authors: Alick-Lindstrom Sasha , Venkatesh Pooja , Perven Ghazala , Wabulya Angela , Yang Qian-Zhou (JoJo) , Sirsi Deepa , Podkorytova Irina ,   On behalf of the American SEEG Consortium
Published: June 2024

Purpose:

Stereotactic EEG (SEEG) is gaining increasing popularity in the United States. Patients undergoing SEEG have unique challenges, and their needs are different compared with noninvasive cases. We aim to describe the medical, nursing, and other institutional practices of SEEG evaluations among tertiary referral (level IV) epilepsy centers accredited by the National Association of Epilepsy Centers.

Methods:

We analyzed data obtained from a Research Electronic Data Capture (REDCap) survey we formulated and distributed to directors of all level IV epilepsy centers listed by the National Association of Epilepsy Center. Most questions were addressed to the adult and pediatric SEEG programs separately.

Results:

Among 199 epilepsy center directors invited to complete the survey, 90 (45%) responded. Eighty-three centers (92%) reported they perform SEEG evaluations. Of the 83 respondents, 56 perform SEEG in adult and 47 in pediatric patients. Twenty-two centers evaluate both pediatric and adult subjects. The highest concordance of SEEG workflow was in (1) epilepsy monitoring unit stay duration (1–2 weeks, 79% adult and 85% pediatric programs), (2) use of sleep deprivation (94% both adult and pediatric) and photic stimulation (79% adult and 70% pediatric) for seizure activation, (3) performing electrical cortical stimulation at the end of SEEG evaluation after spontaneous seizures are captured (84% adult and 88% pediatric), and (4) daily head-wrap inspection (76% adult and 80% pediatric). Significant intercenter variabilities were noted in the other aspects of SEEG workflow.

Conclusions:

Results showed significant variability in SEEG workflow across polled centers. Prospective, multicenter protocols will help the future development and harmonization of optimal practice patterns.
A Proposed Stereoelectroencephalography Electrode Nomenclature and Call for Standardization
Authors: Calley Clifford S. , Ho Winson , Babajani-Feremi Abbas , Bodden Carla , Tyler-Kabara Elizabeth , Clarke Dave F.
Published: June 2024

Introduction:

Between 20 and 40% of patients with epilepsy are considered pharmacoresistant. Stereoelectroencephalography (sEEG) is frequently used as an invasive method for localizing seizures in patients with pharmacoresistant epilepsy who are surgical candidates; however, electrode nomenclature varies widely across institutions. This lack of standardization can have many downstream consequences, including difficulty with intercenter or intracenter interpretation, communication, and reliability.

Methods:

The authors propose a novel sEEG nomenclature that is both intuitive and comprehensive. Considerations include clear/precise entry and target anatomical locations, laterality, distinction of superficial and deep structures, functional mapping, and relative labeling of electrodes in close proximity if needed. Special consideration was also given to electrodes approximating radiographically distinct lesions. The accuracy of electrode identification and the use of correct entry-target labels were assessed by neurosurgeons and epileptologists, not directly involved in each case.

Results:

The authors' nomenclature was used in 41 consecutive sEEG cases (497 electrodes total) within their institution. After reconstruction was complete, the accuracy of electrode identification was 100%, and the correct use of entry-target labels was 98%. The last 30 sEEG cases had 100% correct use of entry-target labels.

Conclusions:

The proposed sEEG nomenclature demonstrated both high accuracy in electrode identification and consistent use of entry-target labeling. The authors submit this nomenclature as a model for standardization across epilepsy surgery centers. They intend to improve practicability, ease of use, and specificity of this nomenclature through collaboration with other surgical epilepsy centers.
Transcriptional genes of lysosome-associated membrane protein 2A in sciatic nerve injuries by bioinformatics
Authors: Sohn Eun Jung , Park Kun-Taek
Published: June 2024

Recent studies have shown that autophagy is activated in response to nerve damage and occurs simultaneously with the initial stages of Schwann cell-mediated demyelination. Although several studies have reported that macroautophagy is involved in the peripheral nerve, the role of chaperone-mediated autophagy (CMA) has not yet been investigated in peripheral nerve injury. The present study investigates the role of CMA in the sciatic nerve. Using a mouse model of sciatic nerve injury, the authors employed immunofluorescence analysis to observe the expression of LAMP2A, a critical marker for CMA. RNA sequencing was performed to observe the transcriptional profile of Lamp2a in Schwann cells. Bioinformatics analysis was carried out to observe the hub genes associated with Lamp2a. Expression of Lamp2a, a key gene in CMA, increased following sciatic nerve injury, based on an immunofluorescence assay. To identify differentially expressed genes using Lamp2a, RNA sequence analysis was conducted using rat Schwann cells overexpressing Lamp2a. The nine hub genes (Snrpf, Polr1d, Snip1, Aqr, Polr2h, Ssbp1, Mterf3, Adcy6, and Sbds) were identified using the CytoHubba plugin of Cytoscape. Functional analysis revealed that Lamp2a overexpression affected the transcription levels of genes associated with mitotic spindle organization and mRNA splicing via the spliceosome. In addition, Polr1d and Snrpf1 were downregulated throughout postnatal development but elevated following sciatic nerve injury, according to a bioinformatics study. CMA may be an integral pathway in sciatic nerve injury via mRNA splicing.
Electroacupuncture improves the learning and memory abilities of rats with PSCI by attenuating the TLR4/NF-κB/NLRP3 signaling pathway on the hippocampal microglia
Authors: Bian Jing , Liu Chunxu , Li Xiang , Qin Xiaoye , Wang Feng , Xuan Lina , Zhang Weimin
Published: June 2024

This study aims to investigate how electroacupuncture regulates the learning and memory abilities of poststroke cognitive impairment (PSCI) rats through the TLR4/NF-κB/NLRP3 signaling pathway on the hippocampal microglia. Thirty male rats were randomly divided into three groups: sham surgery group, PSCI model group, and electroacupuncture group, with 10 rats in each group. Middle cerebral artery occlusion was used to establish the PSCI model. The Zea Longa method was used to score the rats’ neurological function. Electroacupuncture was utilized for 21 days to improve PSCI. The learning and memory abilities of rats were tested using the Morris water maze. Hematoxylin–eosin staining and immunofluorescence were used to find the hippocampus’ pathological changes. The concentration of interleukin-1β, interleukin-6, tumor necrosis factor-α, and interleukin-18 were detected by ELISA. The mRNA expression levels of associated inflammatory corpuscles were measured by quantitative real-time PCR. The protein expression levels of TLR4, MyD88, NF-κB, and NLRP3 were measured using western blotting. Electroacupuncture improved not only the learning and memory abilities of PSCI rats but also hippocampal morphology. Electroacupuncture inhibited the activation of microglia and the TLR4/NF-κB/NLRP3 signaling pathway. Electroacupuncture also reduced proinflammatory factors and restrained the mRNA levels of NLRP3-associated inflammatory cytokines. Its mechanism was related to inhibiting the expression of the TLR4/NF-κB/NLRP3 signaling pathway, attenuating the release of inflammatory factors, and regulating the activation of hippocampal microglia in the brain.
Spontaneous brain activity in patients with central retinal artery occlusion: a resting-state functional MRI study using machine learning
Authors: Wen Zhi , He Yu-Xuan , Huang Xin
Published: June 2024

Central retinal artery occlusion (CRAO) is a serious eye condition that poses a risk to vision, resulting from the blockage of the central retinal artery. Because of the anatomical connection between the ocular artery, which derives from the internal carotid artery, and the anterior middle cerebral artery, hemodynamic alterations and sudden vision loss associated with CRAO may impact brain functionality. This study aimed to examine alterations in spontaneous neural activity among patients with CRAO by resting-state functional MRI. In addition, we selected the amplitude of low-frequency fluctuation (ALFF) and fractional amplitude of low-frequency fluctuation (fALFF) values as classification features for distinguishing CRAO from healthy controls (HCs) using a support vector machine classifier. A total of 18 patients diagnosed with CRAO and 18 HCs participated in the study. Resting-state brain function images and structural images were acquired from both groups. Aberrant changes in spontaneous brain functional activity among CRAO patients were investigated utilizing ALFF and fALFF analysis methods. Group differences in ALFF/fALFF values were assessed through a two-sample t-test. Subsequently, a machine learning classifier was developed to evaluate the clinical diagnostic potential of ALFF and fALFF values. In comparison to HCs, individuals with CRAO exhibited significantly higher ALFF values in the left cerebellum_6, vermis_7, left superior frontal gyrus, and left inferior frontal gyrus, triangular part. Conversely, the CRAO group displayed notably lower ALFF values in the left precuneus and left median cingulum gyri. Furthermore, higher fALFF values were observed in the left inferior frontal gyrus, triangular part, whereas lower fALFF values were noted in the right cerebellum_Crus2, left precuneus, right angular gyrus, left angular gyrus, right supramarginal gyrus, right superior parietal gyrus, and left precuneus. Utilizing the ALFF/fALFF values, the receiver operating characteristic curves (area under the curve) yielded 0.99 and 0.94 through machine learning analysis techniques. CRAO patients exhibit atypical neural activity in the brain, characterized by ALFF and fALFF values predominantly localized in the frontal, parietal, and cerebellar regions, which are closely linked to visual cognition and motor control impairments. Furthermore, ALFF and fALFF could serve as potential neuroimaging markers beyond the orbit among CRAO.
Validation of the Spanish version of the multifaceted empathy test: comparison between cannabis use effects and controls in social cognition
Authors: Sainz-Cort Alberto , Martín-Islas Marta , Jimenez-Garrido Daniel , López-Navarro Miriam , Oña Genís , Muñoz-Marron Elena , Heredia Luis , Gil-Pérez Mercè , Torrente Margarita , Vicens Paloma , Bouso José Carlos
Published: June 2024

Objective

While social cognition is shown to be impaired in several mental disorders, the effects of cannabis on social cognition are still not clear. Past studies have used the multifaceted empathy test (MET) to study social cognition. This study aims to test the validity of the MET Spanish version and to evaluate the effects of cannabis use on social cognition.

Methods

In total 116 participants from a Cannabis Social Club (CSC) completed the MET and the reading the mind in the eyes test (RMET) under the effects of cannabis and were compared to 86 university students (control group). Internal consistency and convergent validity were assessed. Cognitive empathy (CE) and emotional empathy (EE) were tested in both groups.

Results

The MET CE scale shows low internal consistency, while the EE scale shows high internal consistency. Items showed similar difficulty for both groups. Cannabis users showed deficient overall emotional recognition, with reduced scores associated with positive stimuli. Overall scores for EE were similar for both groups, but the experimental group scored lower with negative stimuli when compared to controls.

Conclusion

This study validates the MET Spanish version for its use in future studies. Results confirmed deficient emotional recognition in cannabis users and a dampened reaction to negative stimuli for the first time.
RTF: An R package for modelling time course data
Authors: Brombacher Eva , Kreutz Clemens
Published: June 2024

The retarded transient function (RTF) approach has been introduced as a complementary approach to employing ordinary differential equations (ODEs) for modelling dynamics typically observed for cellular signalling processes. Here, we introduce the R package to the RTF approach, which has originally been implemented within the MATLAB-basedData2Dynamicsmodelling framework. The package enables modelling of time and dose dependencies and includes model reduction to minimize overfitting. It can be applied not only to experimental data but also to trajectories of ODE models, to characterize the dynamics or to identify major targets of experimental perturbations in the low-dimensional representations calculated by the package.

Availability and Implementation

The R package RTF is available athttps://github.com/kreutz-lab/RTF.

Contact

clemens.kreutz@uniklinik-freiburg.de
Sweet and sticky: increased cell adhesion through click-mediated functionalization of regenerative liver progenitor cells
Authors: Alipio Amaziah R. , Vieira Melissa R. , Haefeli Tamara , Hoelting Lisa , Frey Olivier , Haj Alicia J. El , Arno Maria C.
Published: June 2024

The burgeoning field of cell therapies is rapidly expanding, offering the promise to tackle complex and unsolved healthcare problems. One prominent example is represented by CAR T-cells, which have been introduced into the clinic for treating a variety of cancers. Promising cell-based candidates have also been developed to promote tissue regeneration, showing high potencies for the treatment of damaged liver. Nevertheless, in the remit of regenerative medicine, cell-therapy efficacies remain suboptimal as a consequence of the low engraftment of injected cells to the existing surrounding tissue. Herein, we present a facile approach to enhance the adhesion and engraftment of therapeutic hepatic progenitor cells (HPCs) through specific and homogeneous cell surface modification with exogenous polysaccharides, without requiring genetic modification. Coated HPCs exhibited significantly increased markers of adhesion and cell spreading, demonstrating preferential interactions with certain extra-cellular matrix proteins. Moreover, they displayed enhanced binding to endothelial cells and 3D liver microtissues. This translatable methodology shows promise for improving therapeutic cell engraftment, offering a potential alternative to liver transplantation in end-stage liver disease.
Diversification of gene expression across extremophytes and stress-sensitive species in the Brassicaceae
Authors: Wang Guannan , Ryu Kook Hui , Dinneny Andrea , Carlson Joseph , Goodstein David , Lee Jiyoung , Oh Dong-Ha , Oliva Marina , Lister Ryan , Dinneny José R. , Schiefelbein John , Dassanayake Maheshi
Published: June 2024

Stress-sensitive and stress-adapted plants respond differently to environmental stresses. To explore the cellular-level stress adaptations, we built root single-cell transcriptome atlases for diverse Brassicaceae species: stress-sensitive plants (Arabidopsis thalianaandSisymbrium irio), extremophytes (Eutrema salsugineumandSchrenkiella parvula) and a polyploid crop (Camelina sativa), under control, NaCl, and abscisic acid treatments. Approximately half of Arabidopsis cell-type markers lacked expression conservation across species. We identified new conserved cell-type markers, along with orthologs showing divergent expressions. We experimentally mapped distinct cortex sub-populations to different cortex layers across species. We found distinct cell-type-specific transcriptomic responses between species and treatments. Lineage-specific losses of stress responses were less prevalent but evolutionarily more favored than gains. InC. sativa, sub-genomes contributed equally to stress responses and homeologs with divergent stress responses typically did not exhibit high coding sequence or expression divergence. Our study provides a foundational root atlas and an analytical framework for multi-species single-cell transcriptomics.
ProBASS – a language model with sequence and structural features for predicting the effect of mutations on binding affinity
Authors: Gurusinghe Sagara N.S. , Wu Yibing , DeGrado William , Shifman Julia M.
Published: June 2024

Protein-protein interactions (PPIs) govern virtually all cellular processes. Even a single mutation within PPI can significantly influence overall protein functionality and potentially lead to various types of diseases. To date, numerous approaches have emerged for predicting the change in free energy of binding (ΔΔGbind) resulting from mutations, yet the majority of these methods lack precision. In recent years, protein language models (PLMs) have been developed and shown powerful predictive capabilities by leveraging both sequence and structural data from protein-protein complexes. Yet, PLMs have not been optimized specifically for predicting ΔΔGbind. We developed an approach to predict effects of mutations on PPI binding affinity based on two most advanced protein language models ESM2 and ESM-IF1 that incorporate PPI sequence and structural features, respectively. We used the two models to generate embeddings for each PPI mutant and subsequently fine-tuned our model by training on a large dataset of experimental ΔΔGbindvalues. Our model, ProBASS (Protein Binding Affinity from Structure and Sequence) achieved a correlation with experimental ΔΔGbindvalues of 0.83 ± 0.05 for single mutations and 0.69 ± 0.04 for double mutations when model training and testing was done on the same PDB. Moreover, ProBASS exhibited very high correlation (0.81 ± 0.02) between prediction and experiment when training and testing was performed on a dataset containing 2325 single mutations in 132 PPIs. ProBASS surpasses the state-of-the-art methods in correlation with experimental data and could be further trained as more experimental data becomes available. Our results demonstrate that the integration of extensive datasets containing ΔΔGbindvalues across multiple PPIs to refine the pre-trained PLMs represents a successful approach for achieving a precise and broadly applicable model for ΔΔGbindprediction, greatly facilitating future protein engineering and design studies.
Exon inclusion signatures enable accurate estimation of splicing factor activity
Authors: Anglada-Girotto Miquel , Moakley Daniel F. , Zhang Chaolin , Miravet-Verde Samuel , Califano Andrea , Serrano Luis
Published: June 2024

Splicing factors control exon inclusion in messenger RNA, shaping transcriptome and proteome diversity. Their catalytic activity is regulated by multiple layers, making single-omic measurements on their own fall short in identifying which splicing factors underlie a phenotype. Here, we propose splicing factor activity can be estimated by interpreting changes in exon inclusion. We benchmark methods to construct splicing factor→exon networks and calculate activity. Combining RNA-seq perturbation-based networks with VIPER (virtual inference of protein activity by enriched regulon analysis) accurately captures splicing factor activation modulated by different regulatory layers. This approach consolidates splicing factor regulation into a single score derived solely from exon inclusion signatures, allowing functional interpretation of heterogeneous conditions. As a proof of concept, we identify recurrent cancer splicing programs, revealing oncogenic- and tumor suppressor-like splicing factors missed by conventional methods. These programs correlate with patient survival and key cancer hallmarks: initiation, proliferation, and immune evasion. Altogether, we show splicing factor activity can be accurately estimated from exon inclusion changes, enabling comprehensive analyses of splicing regulation with minimal data requirements.
The evolution of GC-biased gene conversion by means of natural selection
Authors: Clessin Augustin , Joseph Julien , Lartillot Nicolas
Published: June 2024

GC-biased gene conversion (gBGC) is a recombination-associated evolutionary process that biases the segregation ratio of AT:GC polymorphisms in the gametes of heterozygotes, in favour of GC alleles. This process is the major determinant of variation in base composition across the human genome and can be the cause of a substantial burden of GC deleterious alleles. While the importance of GC-biased gene conversion in molecular evolution is increasingly recognised, the reasons for its existence and its variation between species remain largely unknown. Using simulations and semi-analytical approximations, we investigated the evolution of gBGC as a quantitative trait evolving by mutation, drift and natural selection. We show that in a finite population where most mutations are deleterious, gBGC is under weak stabilising selection around a positive value that mainly depends on the intensity of the mutation bias and on the intensity of selective constraints exerted on the genome. Importantly, the levels of gBGC that evolve by natural selection do not minimize the load in the population, and even increase it substantially in regions of high recombination rate. Therefore, despite reducing the population’s fitness, levels of gBGC that are currently observed in humans could in fact have been (weakly) positively selected.
Genotype-environment association across precipitation regimens reveals the mechanism of plant adaptation to rainy environments
Authors: Castellana Simone , Triozzi Paolo Maria , Dell’Acqua Matteo , Loreti Elena , Perata Pierdomenico
Published: June 2024

In an era characterized by rapidly changing and less-predictable weather conditions fueled by the climate crisis, understanding the mechanisms underlying local adaptation in plants is of paramount importance for the conservation of species. As the frequency and intensity of extreme precipitation events increase, so are the flooding events resulting from soil water saturation. The deriving onset of hypoxic stress is one of the leading causes of crop damage and yield loss. By combining genomics and remote sensing data, today it is possible to probe natural plant populations that have evolved in different rainfall regimes and look for molecular adaptation to hypoxia. Here, using an environmental genome-wide association study (eGWAS) on 934 non-redundant georeferenced Arabidopsis ecotypes, we have identified functional variants for the geneMED25 BINDING RING-H2 PROTEIN 1(MBR1). This is a ubiquitin-protein ligase that regulates MEDIATOR25 (MED25), part of a multiprotein complex that interacts with transcription factors which act as key drivers of the hypoxic response in Arabidopsis, namely the RELATED TO AP2 proteins, RAP2.2 and RAP2.12. Through experimental validation, we show that natural variants ofMBR1have a differential impact on the stability of MED25 and, in turn, on hypoxic tolerance. Our study also highlights the pivotal role of the MBR1/MED25 module in establishing a comprehensive hypoxic response. Our findings show that molecular candidates for plant environmental adaptation can be effectively mined from large datasets. This thus supports the need for the integration of forward and reverse genetics with robust molecular physiology validation of the outcomes.
Confirmation Bias through Selective Use of Evidence in Human Cortex
Authors: Park Hame , Arazi Ayelet , Talluri Bharath Chandra , Celotto Marco , Panzeri Stefano , Stocker Alan A , Donner Tobias H
Published: June 2024

Decision-makers often process new evidence selectively, depending on their current beliefs about the world. We asked whether such confirmation biases result from biases in the encoding of sensory evidence in the brain, or alternatively in the utilization of encoded evidence for behavior. Human participants estimated the source of a sequence of visual-spatial evidence samples while we measured cortical population activity with magnetoencephalography (MEG). Halfway through the sequence, participants were prompted to judge the more likely source category. Their processing of subsequent evidence depended on its consistency with the previously chosen category, but the encoding of evidence in cortical activity did not. Instead, the encoded evidence in parietal and primary visual cortex contributed less to the estimation report when that evidence was inconsistent with the previous choice. We conclude that confirmation bias originates from the way in which decision-makers utilize information encoded in the brain. This provides room for deliberative control.
Dietary protein restriction diminishes sucrose reward and reduces sucrose-evoked mesolimbic dopamine signaling
Authors: Wu Chih-Ting , Magaña Diego Gonzalez , Roshgadol Jacob , Tian Lin , Ryan Karen K.
Published: June 2024

Objective

A growing literature suggests manipulating dietary protein status decreases sweet consumption in rodents and in humans. Underlying neurocircuit mechanisms have not yet been determined, but previous work points towards hedonic rather than homeostatic pathways. Here we hypothesized that a history of protein restriction reduces sucrose seeking by altering mesolimbic dopamine signaling.

Methods

We tested this hypothesis using established behavioral tests of palatability and motivation, including the ‘palatability contrast’ and conditioned place preference (CPP) tests. We used modern optical sensors for measuring real-time nucleus accumbens (NAc) dopamine dynamics during sucrose consumption, via fiber photometry, in male C57/Bl6J mice maintained on low-protein high-carbohydrate (LPHC) or control (CON) diet for ∼5 weeks.

Results

A history of protein restriction decreased the consumption of a sucrose ‘dessert’ in sated mice by ∼50% compared to controls [T-test, p< 0.05]. The dopamine release in NAc during sucrose consumption was reduced, also by ∼50%, in LPHC-fed mice compared to CON [T-test, p< 0.01]. Furthermore, LPHC-feeding blocked the sucrose-conditioned place preference we observed in CON-fed mice [paired T-test, p< 0.05], indicating reduced motivation. This was accompanied by a 33% decrease in neuronal activation of the NAc core, as measured by c-Fos immunolabeling from brains collected directly after the CPP test.

Conclusions

Despite ongoing efforts to promote healthier dietary habits, adherence to recommendations aimed at reducing the intake of added sugars and processed sweets remains challenging. This study highlights chronic dietary protein restriction as a nutritional intervention that suppresses the motivation for sucrose intake, via blunted sucrose-evoke dopamine release in NAc.
Multi-city analysis of synergies and trade-offs between urban bird diversity and carbon storage to inform decision-making
Authors: Kinnunen R.P. , Ziter C.D. , Frei B.
Published: June 2024

Cities are particularly vulnerable to the impacts of biodiversity loss and climate change. Urban greenspaces are important ecosystems that can conserve biodiversity and help offset the carbon footprint of urban areas. However, despite large-scale tree planting and restoration initiatives in cities, it is not well known where trees or vegetation should be planted or restored to achieve multiple benefits. We considered urban greenspaces as nature-based solutions for urban climate mitigation and biodiversity conservation planning. Using bivariate mapping, we examined the spatial synergies and trade-offs between bird functional diversity and carbon storage in ten Canadian cities spanning a gradient of geography and population, and modelled the relationships between vegetation attributes and both bird diversity and amount of carbon. We found carbon and biodiversity are weakly positively correlated across the ten cities, however, this relationship varied in strength, direction and significance. Our maps highlight areas within our target cities where greenspaces could be managed, restored, or protected to maximize carbon storage and conserve biodiversity. Nationwide, our results also show that forest management strategies that promote increases in canopy cover and the proportion of needle-leaved species in urban greenspaces are potential win-win strategies for biodiversity and carbon. Our study shows NbS strategies are not always generalizable across regions. National policies should guide municipalities and cities using regional priorities and science advice, since a NbS promoting biodiversity in one region may, in fact, reduce it in another.
Pathlength-selective, interferometric diffuse correlation spectroscopy (PaLS-iDCS)
Authors: Robinson Mitchell B. , Renna Marco , Otic Nikola , Franceschini Maria Angela , Carp Stefan A.
Published: June 2024

Diffuse correlation spectroscopy (DCS) is an optical method that offers non-invasive assessment of blood flow in tissue through the analysis of intensity fluctuations in diffusely backscattered coherent light. The non-invasive nature of the technique has enabled several clinical applications for deep tissue blood flow measurements, including cerebral blood flow monitoring as well as tumor blood flow mapping. While a promising technique, in measurement configurations targeting deep tissue hemodynamics, the standard DCS implementations suffer from insufficient signal-to-noise ratio (SNR), depth sensitivity, and sampling rate, limiting their utility. In this work, we present an enhanced DCS method called pathlength-selective, interferometric DCS (PaLS-iDCS), which improves upon both the sensitivity of the measurement to deep tissue hemodynamics and the SNR of the measurement using pathlength-specific coherent gain. Through interferometric detection, PaLS-iDCS can provide time-of-flight (ToF) specific blood flow information without the use of expensive time-tagging electronics and low-jitter detectors. The new technique is compared to time-domain DCS (TD-DCS), another enhanced DCS method able to resolve photon ToF in tissue, through Monte Carlo simulation, phantom experiments, and human subject measurements. PaLS-iDCS consistently demonstrates improvements in SNR (>2x) for similar measurement conditions (same photon ToF), and the SNR improvements allow for measurements at extended photon ToFs, which have increased sensitivity to deep tissue hemodynamics (∼50% increase). Further, like TD-DCS, PaLS-iDCS allows direct estimation of tissue optical properties from the sampled ToF distribution without the need for a separate spectroscopic measurement. This method offers a relatively straightforward way to allow DCS systems to make robust measurements of blood flow with greatly enhanced sensitivity to deep tissue hemodynamics, enabling further applications of this non-invasive technology.
Decoding protein language models: insights from embedding space analysis
Authors: Rissom Pia Francesca , Sarmiento Paulo Yanez , Safer Jordan , Coley Connor W. , Renard Bernhard Y. , Heyne Henrike O. , Iqbal Sumaiya
Published: June 2024

Foundation models, which encode patterns in large, high-dimensional data as embeddings, show promise in many machine learning related applications in molecular biology. Embeddings learned by the models provide informative features for downstream prediction tasks, however, the information captured by the model is often not interpretable. One approach to understanding the captured information is through the analysis of their learned embeddings, which in molecular biology so far has mainly focused on visualizing individual embedding spaces. This study introduces a quantitative framework for cross-space comparison, enabling intuitive exploration and comparison of embedding spaces in molecular biology. The framework emphasizes analyzing the distribution of known biological information within embedding space neighborhoods and provides insights into relationships between multiple embedding spaces. Comparison techniques include global pairwise distance measurements as well as local nearest neighbor analyses. By applying our framework to embeddings from protein language models, we demonstrate how embedding space analysis can serve as a valuable pre-filtering step for task-specific supervised machine learning applications and for the recognition of differential patterns in data encoded within and across different embedding spaces. To support a wide usability, we provide a Python library that implements all analysis methods, available athttps://github.com/broadinstitute/EmmaEmb.
Evolutionary branching in multi-level selection models
Authors: Simon Burton , Ispolatov Yaroslav , Doebeli Michael
Published: June 2024

We study a model of group-structured populations featuring individual-level birth and death events, and group-level fission and extinction events. Individuals play games within their groups, while groups play games against other groups. Pay-offs from individual-level games affect birth rates of individuals, and payoffs from group-level games affect group extinction rates. We focus on the the evolutionary dynamics of continuous traits with particular emphasis on the phenomenon of evolutionary diversification. Specifically, we consider two-level processes in which individuals and groups play continuous snowdrift or prisoner’s dilemma games. Individual game strategies evolve due to selection pressure from both the individual and group level interactions. The resulting evolutionary dynamics turns out to be very complex, including branching and type-diversification at one level or the other. We observe that a weaker selection pressure at the individual level results in more adaptable groups and sometimes group-level branching. Stronger individual-level selection leads to more effective adaptation within each group while preventing the groups from optimizing their strategies for group-level games.
Impact of Run-of-River Damming on Increasing Phytoplankton Biomass and Species Shift in a Large Amazonian River
Authors: Pineda Alfonso , Campos Beatriz Melissa , Zanon Felipe , Felicio Renata , Rodrigues Luzia C.
Published: June 2024

Run-of-river (ROR) dams, often perceived as having minimal environmental impact, can induce significant hydrodynamic changes that alter aquatic ecosystems. We investigated the impacts of an ROR dam on the Madeira River, the largest Amazon tributary, focusing on phytoplankton communities, their ecological implications, and related environmental factors. Our study examined changes in biomass and environmental factors (using General Linear Mixed Models - GLMM), species composition (using PERMANOVA) before and after damming, in both the main channel and tributaries (N=549 samples). We also identified indicator species associated with different damming phases and regions through an indicator value analysis. The results showed that, following dam construction, the phytoplankton community changed in both the main channel and tributaries, with a shift from lotic diatoms to lentic phytoflagellates. This transition was likely facilitated by altered hydrodynamics and possibly influenced by the decomposition of flooded vegetation in the dam’s influence zone. The decomposition of this vegetation could explain both the observed increase in oxygen consumption and the subsequent rise in phytoflagellate biomass after damming. However, despite the overall increase in phytoplankton biomass, the values remained within oligotrophic to mesotrophic conditions, consistent with the low nutrient concentrations recorded. However, we caution that the dam-created hydrodynamic conditions are optimal for phytoplankton growth, potentially exacerbating nutrient-related issues in the future. We recommend proactive management strategies to prevent nutrient enrichment from activities such as agriculture and livestock in isolated Amazon areas affected by dams, thereby mitigating potential water quality degradation linked to increased phytoplankton biomass.
Coordinated Regulation of Renal Glucose Reabsorption and Gluconeogenesis by mTORC2 and Potassium
Authors: Demko John , Saha Bidisha , Takagi Enzo , Mannis Anna , Weber Robert , Pearce David
Published: June 2024

Background

The kidney proximal tubule is uniquely responsible for reabsorption of filtered glucose and gluconeogenesis (GNG). Insulin stimulates glucose transport and suppresses GNG in the proximal tubule, however, the signaling mechanisms and coordinated regulation of these processes remain poorly understood. The kinase complex mTORC2 is critical for regulation of growth, metabolism, solute transport, and electrolyte homeostasis in response to a wide array of inputs. Here we examined its role in the regulation of renal glucose reabsorption and GNG.

Methods

Rictor, an essential component of mTORC2, was knocked out using the Pax8-LC1 system to generate inducible tubule specific Rictor knockout (TRKO) mice. These animals were subjected to fasting, refeeding, and variation in dietary K+. Metabolic parameters including glucose homeostasis and renal function were assessed in balance cages. Kidneys and livers were also harvested for molecular analysis of gluconeogenic enzymes, mTORC2-regulated targets, and plasma membrane glucose transporters.

Results

On a normal chow diet, TRKO mice had marked glycosuria despite indistinguishable blood glucose relative to WT controls. Kidney plasma membrane showed lower SGLT2 and SGLT1 in the fed state, supporting reduced renal glucose reabsorption. Additional metabolic testing provided evidence for renal insulin resistance with elevated fasting insulin, impaired pyruvate tolerance, elevated hemoglobin A1c, and increased renal gluconeogenic enzymes in the fasted and fed states. These effects were correlated with reduced downstream phosphorylation of Akt and the transcription factor FOXO4, identifying a novel role of FOXO4 in the kidney. Interestingly, high dietary K+prevented glycosuria and excessive GNG in TRKO mice, despite persistent reduction in mTORC2 substrate phosphorylation.

Conclusion

Renal tubule mTORC2 is critical for coordinated regulation of sodium-glucose cotransport by SGLT2 and SGLT1 as well as renal GNG. Dietary K+promotes glucose reabsorption and suppresses GNG independently of insulin signaling and mTORC2, potentially providing an alternative signaling mechanism in states of insulin resistance.

SIGNIFICANCE STATEMENT

The kidney contributes to regulation of blood glucose through reabsorption of filtered glucose and gluconeogenesis. This study shows that mTORC2 and dietary potassium coordinate the regulation of sodium-glucose cotransport and glucose production in the kidney via independent mechanisms. New insights into the regulation of these processes in the kidney offer promising implications for diabetes mellitus management and treatment.
Infection dynamics of endosymbionts that manipulate arthropod reproduction
Authors: Brenninger Franziska A. , Zug Roman , Kokko Hanna
Published: June 2024

A large proportion of arthropod species are infected with endosymbionts, some of which selfishly alter host reproduction. The currently known forms of parasitic reproductive manipulations are male-killing, feminization, cytoplasmic incompatibility, parthenogenesis induction and distortion of sex allocation. While all of these phenomena represent adaptations that enhance parasite spread, they differ in the mechanisms involved and the consequent infection dynamics. We focus here on the latter aspect, summarizing existing theoretical literature on infection dynamics of all known reproductive manipulation types, and completing the remaining knowledge gaps where dynamics have not been modelled yet. Our unified framework includes the minimal model components required to describe the effects of each manipulation. We establish invasion criteria for all potential combinations of manipulative endosymbionts, yielding predictions for an endosymbionts increase from rarity within a host population that is initially either uninfected or infected with a different symbiont strain. We consider diplodiploid and haplodiploid hosts, as the mechanisms as well as the infection dynamics of reproductive manipulations can differ between them. Our framework reveals that endosymbionts that a priori have the best invasion prospects are not necessarily the most commonly found ones in nature; priority effects play a role too, and cytoplasmic incompatibility excels in this regard. As a whole, considerations of the ease with which a symbiont spreads have to be complemented with knowledge of how easy it is to achieve a particular manipulation, and other factors influencing host switches.
Generation and initial characterization of in vivo knockout of tetherin/BST2 in chicken
Authors: Ungrová Lenka , Trefil Pavel , Plachý Jiří , Mucksová Jitka , Kalina Jiří , Reinišová Markéta , Härtle Sonja , Gáliková Eliška , Kučerová Dana , Krchlíková Veronika , Pečenka Vladimír , Karafiát Vít , Hejnar Jiří , Elleder Daniel
Published: June 2024

Tetherin/BST2 is an antiviral restriction factor initially described in mammals. It is active against multiple enveloped viruses at the budding phase, where it is able to physically link the budding virions to the virus-producing cell. We and others have previously identified tetherin orthologs in birds, and characterized the antiviral activity and interferon-inducibility of chicken tetherin. In this work, we have generated anin vivomodel of tetherin absence in chicken by CRISPR/Cas9 modification of chicken primordial germ cells (PGC). The modified PGCs were transplanted into roosters with suppressed endogenous spermatogenesis, and transgenic (tetherin knockout) progeny was obtained by further crosses. The viability and phenotype of tetherin knockout animals did not differ from wild type chicken. In more detailed investigation, flow cytometry based differential white blood cell count revealed an increased number of heterophils in tetherin knockouts. Upon challenge with avian sarcoma and leukosis virus (ASLV), a prototypic avian retrovirus, we detected increase in viremia at days 6 and 13 post infection in tetherin knockout animals. The increased virus susceptibility is consistent with absence of antiviral tetherin. In summary, we introduce a newin vivoknockout model of chicken antiviral gene tetherin. These animals can be used in further characterizations of avian antiviral defenses and also to define thus far unknown physiological effects of tetherin in birds.
Selection of Fluorinated Aptamer Targeting RNA Element with Different Chirality
Authors: Dantsu Yuliya , Zhang Ying , Zhang Wen
Published: June 2024

The development of RNA aptamers with high specificity and affinity for target molecules is a critical advancement in the field of therapeutic and diagnostic applications. This study presents the selection of a 2’-fluoro modified mirror-image RNA aptamer through thein vitroSELEX process. Using a random RNA library, we performed iterative rounds of selection and amplification to enrich aptamers that bind specifically to the viral frameshift element which contains the opposite chirality. The unnatural chirality of the aptamer improved its enzymatic stability, and the incorporation of 2’-fluoro modifications was crucial in enhancing the binding affinity of the aptamers. After nine rounds of SELEX, the enriched RNA pool was sequenced and analyzed, revealing the dominant aptamer sequences. The selected 2’-fluoro modified mirror-image RNA aptamer demonstrated a dissociation constant of approximately 1.6 μM, indicating moderate binding affinity with the target and exceptional stability against nuclease degradation. Our findings highlight the potential of 2’-fluoro modified mirror-image RNA aptamers in enhancing the stability and utility of RNA-based therapeutics and diagnostics, paving the way for future applications in diverse biomedical fields.
Resolving the three-dimensional interactome of Human Accelerated Regions during human and chimpanzee neurodevelopment
Authors: Pal Atreyo , Noble Mark A. , Morales Matheo , Pal Richik , Baumgartner Marybeth , Yang Je Won , Yim Kristina M. , Uebbing Severin , Noonan James P.
Published: June 2024

Human Accelerated Regions (HARs) are highly conserved across species but exhibit a significant excess of human-specific sequence changes, suggesting they may have gained novel functions in human evolution. HARs include transcriptional enhancers with human-specific activity and have been implicated in the evolution of the human brain. However, our understanding of how HARs contributed to uniquely human features of the brain is hindered by a lack of insight into the genes and pathways that HARs regulate. It is unclear whether HARs acted by altering the expression of gene targets conserved between HARs and their chimpanzee orthologs or by gaining new gene targets in human, a mechanism termed enhancer hijacking. We generated a high-resolution map of chromatin interactions for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs) to comprehensively identify gene targets in both species. HARs and their chimpanzee orthologs targeted a conserved set of 2,963 genes enriched for neurodevelopmental processes including neurogenesis and synaptic transmission. Changes in HAR enhancer activity were correlated with changes in conserved gene target expression. Conserved targets were enriched among genes differentially expressed between human and chimpanzee NSCs or between human and non-human primate developing and adult brain. Species-specific HAR gene targets did not converge on known biological functions and were not significantly enriched among differentially expressed genes, suggesting that HARs did not alter gene expression via enhancer hijacking. HAR gene targets, including differentially expressed targets, also showed cell type-specific expression patterns in the developing human brain, including outer radial glia, which are hypothesized to contribute to human cortical expansion. Our findings support that HARs influenced human brain evolution by altering the expression of conserved gene targets and provide the means to functionally link HARs with novel human brain features.
Broad-scale phenotyping in Arabidopsis reveals varied involvement of RNA interference across diverse plant-microbe interactions
Authors: Ruf Alessa , Thieron Hannah , Nasfi Sabrine , Lederer Bernhard , Fricke Sebastian , Adeshara Trusha , Postma Johannes , Blumenkamp Patrick , Kwon Seomun , Brinkrolf Karina , Feldbrügge Michael , Goesmann Alexander , Kehr Julia , Steinbrenner Jens , Šečić Ena , Göhre Vera , Weiberg Arne , Kogel Karl-Heinz , Panstruga Ralph , Robatzek Silke
Published: June 2024

RNA interference (RNAi) is a crucial mechanism that can contribute to immunity against infectious microbes through the action of DICER-LIKE (DCL) and ARGONAUTE (AGO) proteins. In the case of the fungal pathogenBotrytis cinereaand the oomyceteHyaloperonospora arabidopsidis, plant DCL and AGO proteins have proven roles as negative regulators of immunity, suggesting functional specialization of these proteins. To address this aspect in a broader taxonomic context, we characterized the colonization pattern of an informative set ofDCLandAGOloss-of-function mutants inArabidopsis thalianaupon infection with a panel of pathogenic microbes with different lifestyles, and a fungal mutualist. Our results revealed that AGO1 and AGO4 function as positive regulators of immunity to a bacterial and a fungal pathogen, respectively. Additionally, AGO2 and AGO10 positively modulated the colonization by a fungal mutualist. Therefore, analysing the role of RNAi across a broader range of plant-microbe interactions has identified previously unknown functions for AGO proteins. For some pathogen interactions, however, all tested mutants exhibited wild type-like infection phenotypes, suggesting that the roles of AGO and DCL proteins in these interactions may be more complex to elucidate.