bluuebunny/crossref_metadata_2025 huggingface dataset:
Can Deep Learning Models Differentiate Atrial Fibrillation from Atrial Flutter?
Authors: Ribeiro Estela , Soares Quenaz Bezerra , Dias Felipe Meneguitti , Krieger Jose Eduardo , Gutierrez Marco Antonio
Published: August 2023

Atrial Fibrillation (AFib) and Atrial Flutter (AFlut) are prevalent irregular heart rhythms that poses significant risks, particularly for the elderly. While automated detection systems show promise, misdiagnoses are common due to symptom similarities. This study investigates the differentiation of AFib from AFlut using standard 12-lead ECGs from the PhysioNet CinC Challenge 2021 (CinC2021) databases, along with data from a private database. We employed both one dimensional-based (1D) and image-based (2D) Deep Learning models, comparing different 1D and 2D Convolutional Neural Network (CNN) architectures for classification. For 1D models, LiteVGG-11 demonstrated the highest performed, achieving an accuracy (Acc) of 77.91 (±1.73%), area under the receiver operating characteristic curve (AUROC) of 87.17 (±1.29%), F1 score of 76.59 (±1.90%), specificity (Spe) of 71.69 (±4.73%), and sensitivity (Se) of 86.53 (±5.33%). On the other hand, for 2D models the EfficientNet-B2 outperformed other architectures, with an Acc of 75.20 (±3.38%), AUROC of 85.50 (±1.14%), F1 of 71.59 (±3.66%), Spe of 74.76 (±13.85%) and Se of 75.74 (±13.85%). Our findings indicate that distinguishing between AFib and AFlut is non-trivial, with 1D signals exhibiting superior performance compared to their 2D counterparts. Furthermore, it’s noteworthy that the performance of our models on the CinC2021 databases was considerably lower than on our private dataset.
Measures of Street Drug Availability and US Drug Overdose Mortality in the Era of Fentanyl and Stimulants
Authors: Cano Manuel , Timmons Patricia , Hooten Madeline , Sweeney Kaylin
Published: August 2023

Background

Street-sold drugs such as illicitly-manufactured fentanyl and stimulants have replaced prescription opioids as the primary contributors to fatal overdoses in the United States (US), yet the street availability of these substances is challenging to quantify. Building on the foundation of prior research on law enforcement drug seizures, the present study compares a variety of publicly-available drug seizure measures to identify which measures account for the most variation in drug overdose mortality between states, within states over time, and in various US demographic groups.

Methods

Drug seizure counts from the National Forensic Laboratory Information System and drug overdose mortality rates from the Centers for Disease Control and Prevention were examined for all US states, 2013-2021 (459 state-years). State- and year-fixed effects models regressed drug overdose mortality rates (in the overall population and subpopulations by sex, age, and race/ethnicity) on various drug seizure measures, including rates per population and proportional shares of fentanyl-related, heroin, cocaine, methamphetamine, and xylazine seizures.

Results

For drug overdose death rates in the overall population and all subpopulations examined by sex, race/ethnicity, and age (except ages 15-29), the model including all drug seizure proportional measures represented the best-performing model examined (as identified via the lowest Akaike Information Criterion and highest within R-squared value), followed by the model including only the fentanyl-related seizure proportion.

Conclusions

Findings support the utility of publicly-available drug seizure composition measures, especially the proportion of fentanyl-related seizures, as potential proxies for street drug availability across the US and in various subpopulations.
Dynamic organization of visual cortical networks inferred from massive spiking datasets
Authors: Graber Colin , Vlasov Yurii , Schwing Alexander
Published: August 2023

Complex cognitive functions in a mammalian brain are distributed across many anatomically and functionally distinct areas and rely on highly dynamic routing of neural activity across the network. While modern electrophysiology methods enable recording of spiking activity from increasingly large neuronal populations at a cellular level, development of probabilistic methods to extract these dynamic inter-area interactions is lagging. Here, we introduce an unsupervised machine learning model that infers dynamic connectivity across the recorded neuronal population from a synchrony of their spiking activity. As opposed to traditional population decoding models that reveal dynamics of the whole population, the model produces cellular-level cell-type specific dynamic functional interactions that are otherwise omitted from analysis. The model is evaluated on ground truth synthetic data and compared to alternative methods to ensure quality and quantification of model predictions. Our strategy incorporates two sequential stages – extraction of static connectivity structure of the network followed by inference of temporal changes of the connection strength. This two-stage architecture enables detailed statistical criteria to be developed to evaluate confidence of the model predictions in comparison with traditional descriptive statistical methods. We applied the model to analyze large-scale in-vivo recordings of spiking activity across mammalian visual cortices. The model enables the discovery of cellular-level dynamic connectivity patterns in local and long-range circuits across the whole visual cortex with temporally varying strength of feedforward and feedback drives during sensory stimulation. Our approach provides a conceptual link between slow brain-wide network dynamics studied with neuroimaging and fast cellular-level dynamics enabled by modern electrophysiology that may help to uncover often overlooked dimensions of the brain code.
Early Deprivation Impairs Perforant Pathway Connectivity and Contextual Memory in Adolescent Male Mice
Authors: Islam Rafiad , White Jordon D. , Arefin Tanzil M. , Mehta Sameet , Liu Xinran , Polis Baruh , Giuliano Lauryn , Ahmed Sahabuddin , Bowers Christian , Zhang Jiangyang , Kaffman Arie
Published: August 2023

Early-life adversity causes reduced hippocampal volume and abnormal hippocampal connectivity and function, with evidence indicating more prominent deficits in males compared to females. Reelin-positive projections from the lateral entorhinal cortex (LEC) to the dorsal hippocampus are essential for encoding contextual and semantic memories in diverse mammalian species, including humans and rodents. However, the impact of early-life adversity on these projections and their contribution to hippocampal-dependent deficits have not been reported. Using a modified limited bedding (LB) mouse model of early adversity that extends the impoverished conditions from birth to postnatal day 25 (P25), we found severe impairment in contextual fear conditioning for adolescent LB male but not LB female mice. Using retrograde tracing, we found that the number of reeling-positive projections from the LEC to the dorsal hippocampus is significantly reduced in LB males but not LB females. Further, the number of projections was highly correlated with deficits in contextual memory and hypomyelination in perforant pathway terminals located in the dorsal hippocampus. Ex vivo high-resolution diffusion magnetic resonance imaging confirmed reduced structural connectivity between the entorhinal cortex and the dorsal hippocampus and revealed extensive cortical atrophy that resembled abnormalities reported in children exposed to severe deprivation. Given the essential role that reelin-positive projections play in contextual memory, these findings suggest a novel mechanism to explain the pronounced contextual memory deficits seen in LB males.
Post-COVID conditions during Delta and early-Omicron SARS-CoV-2 variant periods among adults in the United States
Authors: Edwards Deja , Logan Pamela , Feldstein Leora R. , Fairlie Tarayn , Accorsi Emma , Saydah Sharon
Published: August 2023

Background

Post-COVID conditions after infection with new SARS-CoV-2 variants have been incompletely described. We compared the prevalence and risk factors for ongoing symptoms lasting 4 weeks or longer (often referred to as post-COVID Conditions) among adults who had tested positive vs. negative during the Delta and early-Omicron periods.

Methods

Self-reported survey data regarding symptoms and previous SARS-CoV 2 test results were collected from May 31 – July 6, 2022, from a probability sampling of United States adults. Respondents were classified according to their test result, predominant circulating variant when respondents first tested positive (Delta vs early-Omicron), and demographic risk factors.

Results

Among 2,421 respondents, 256 tested positive during Delta, 460 during early-Omicron, and 1,705 always tested negative. Nearly one-fourth (22.3%) of negative respondents reported ≥1symptom that lasted ≥4 weeks, compared to 60.6% (p<0.05) of respondents who tested positive during the Delta period and 47.8% (p<0.05) during the early-Omicron period. Fatigue, change in smell/taste, and cough were commonly reported by respondents who tested positive. Demographic risk factors associated with ongoing symptoms were being female and unemployed (aOR 1.28, 95% CI 1.06–1.55; aOR 1.48, 95% CI: 1.17–1.87).

Conclusion

The reported occurrence of ongoing symptoms associated with post-COVID conditions was reduced during the early-Omicron period, compared with Delta.
Assessing clinical acuity in the Emergency Department using the GPT-3.5 Artificial Intelligence Model
Authors: Williams Christopher Y.K. , Zack Travis , Miao Brenda Y. , Sushil Madhumita , Wang Michelle , Butte Atul J.
Published: August 2023

This paper evaluates the performance of the Chat Generative Pre-trained Transformer (ChatGPT; GPT-3.5) in accurately identifying higher acuity patients in a real-world clinical context. Using a dataset of 10,000 pairs of patient Emergency Department (ED) visits with varying acuity levels, we demonstrate that GPT-3.5 can successfully determine the patient with higher acuity based on clinical history sections extracted from ED physician notes. The model achieves an accuracy of 84% and an F1 score of 0.83, with improved performance for more disparate acuity scores. Among the 500 pair subsample that was also manually classified by a resident physician, GPT-3.5 achieved similar performance (Accuracy = 0.84; F1 score = 0.85) compared to the physician (Accuracy = 0.86, F1 score = 0.87). Our results suggest that, in real-world settings, GPT-3.5 can perform comparably to physicians on the clinical reasoning task of ED acuity determination.
High 3-hydroxybutyrate concentrations in the placenta-produced amniotic fluid in the human uterus
Authors: Satoh Takumi , Shibata Takeo , Takata Emi , Takakura Masahiro , Han Jia , Yamada Sohsuke
Published: August 2023

In this study, we report first high concentrations of a ketone body, 3-hydroxybutyrate (3HB) in the amniotic fluid in humans. Although 3HB concentrations in the maternal blood are approximately 0.1, those in the amniotic fluid are approximately 0.6 mM. High placental 3HB production is potentially key for producing and maintaining high 3HB levels in the amniotic fluid. The rate-limiting enzyme, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), is highly expressed in the cells of the chorionic plate and responsible for 3HB production. Therefore, high HMGCS2 expression maintenance is supposed to be pivotal for maintaining the 3HB supply for the human fetus. Here, we propose that humans display two pathways, an amniotic fluid- and another umbilical vein-mediated, for supplying 3HB to the human fetus. These supply pathways are supposedly essential for human brain development during the late phase of pregnancy.

Graphical abstract

Human fetuses are supported by 3HB from the amniotic fluid for their brain development.

HIGHLIGTS

3-Hydroxybutyrate concentrations are high in the amniotic fluid in the human uterus.

The chorionic plate of the placenta highly expresses 3-hydroxy-3-methylglutaryl-CoA synthase 2.

Human fetuses may be supplied with 3HB for brain development through the amniotic fluid.
Epigenome-wide association study of incident type 2 diabetes in Black and White participants from the Atherosclerosis Risk in Communities Study
Authors: Venkataraghavan Sowmya , Pankow James S. , Boerwinkle Eric , Fornage Myriam , Selvin Elizabeth , Ray Debashree
Published: August 2023

DNA methylation studies of incident type 2 diabetes in US populations are limited, and to our knowledge none included individuals of African descent living in the US. We performed an epigenome-wide association analysis of blood-based methylation levels at CpG sites with incident type 2 diabetes using Cox regression in 2,091 Black and 1,029 White individuals from the Atherosclerosis Risk in Communities study. At an epigenome-wide significance threshold of 10−7, we detected 7 novel diabetes-associated CpG sites inC1orf151(cg05380846: HR= 0.89,p= 8.4 × 10−12),ZNF2(cg01585592: HR= 0.88,p= 1.6 × 10−9),JPH3(cg16696007: HR= 0.87,p= 7.8 × 10−9),GPX6(cg02793507: HR= 0.85,p= 2.7 × 10−8and cg00647063: HR= 1.20,p= 2.5 × 10−8), chr17q25 (cg16865890: HR= 0.8,p= 6.9 × 10−8), and chr11p15 (cg13738793: HR= 1.11,p= 7.7 × 10−8). The CpG sites atC1orf151,ZNF2, JPH3andGPX6, were identified in Black adults, chr17q25 was identified in White adults, and chr11p15 was identified upon meta-analyzing the two groups. The CpG sites atJPH3andGPX6were likely associated with incident type 2 diabetes independent of BMI. All the CpG sites, except atJPH3, were likely consequences of elevated glucose at baseline. We additionally replicated known type 2 diabetes-associated CpG sites including cg19693031 atTXNIP, cg00574958 atCPT1A, cg16567056 atPLBC2, cg11024682 atSREBF1, cg08857797 atVPS25, and cg06500161 atABCG1, 3 of which were replicated in Black adults at the epigenome-wide threshold. We observed modest increase in type 2 diabetes variance explained upon addition of the significantly associated CpG sites to a Cox model that included traditional type 2 diabetes risk factors and fasting glucose (increase from 26.2% to 30.5% in Black adults; increase from 36.9% to 39.4% in White adults). We examined if groups of proximal CpG sites were associated with incident type 2 diabetes using a gene-region specific and a gene-region agnostic differentially methylated region (DMR) analysis. Our DMR analyses revealed several clusters of significant CpG sites, including a DMR consisting of a previously discovered CpG site atADCY7and promoter regions ofTP63which were differentially methylated across all race groups. This study illustrates improved discovery of CpG sites/regions by leveraging both individual CpG site and DMR analyses in an unexplored population. Our findings include genes linked to diabetes in experimental studies (e.g.,GPX6,JPH3,andTP63), and future gene-specific methylation studies could elucidate the link between genes, environment, and methylation in the pathogenesis of type 2 diabetes.
Immunogenicity of mRNA-1273 and BNT162b2 in Immunocompromised Patients: Systematic Review and Meta-Analysis Using GRADE
Authors: Kavikondala Sushma , Haeussler Katrin , Wang Xuan , Spellman Anne , Bausch-Jurken Mary T. , Sharma Pawana , Amiri Mohammadreza , Krivelyova Anna , Vats Sonam , Nassim Maria , Kumar Nitendra , Van de Velde Nicolas
Published: August 2023

Aim

Immunocompromised (IC) patients mount poor immune responses to vaccination. Higher-dose COVID-19 vaccines may offer increased immunogenicity.

Materials & methods

A pairwise meta-analysis of 98 studies reporting comparisons of mRNA-1273 (50 or 100 mcg/dose) and BNT162b2 (30 mcg/dose) in IC adults was performed. Outcomes were seroconversion, total and neutralizing antibody titers, and cellular immune responses.

Results

mRNA-1273 was associated with a significantly higher seroconversion likelihood (relative risk, 1.11 [95% CI, 1.08, 1.14];P<0.0001;I2=66.8%) and higher total antibody titers (relative increase, 50.45% [95% CI, 34.63%, 66.28%];P<0.0001;I2=89.5%) versus BNT162b2. mRNA-1273 elicited higher but statistically nonsignificant relative increases in neutralizing antibody titers and cellular immune responses versus BNT162b2.

Conclusion

Higher-dose mRNA-1273 had increased immunogenicity versus BNT162b2 in IC patients.
Dopamine D2 receptor upregulation in dorsal striatum in theLRRK2-R1441C rat model of early Parkinson’s disease revealed byin vivoPET imaging
Authors: Delgado-Goñi Teresa , Connor-Robson Natalie , Cioroch Milena , Paisey Stephen , Marshall Christopher , Lane Emma L. , Hauton David , McCullagh James , Magill Peter J. , Cragg Stephanie J. , Mackay Clare E. , Wade-Martins Richard , Klein Johannes C.
Published: August 2023

LRRK2mutations are the most common cause of dominantly inherited Parkinson’s disease (PD). Here, we conducted PET imaging in aged transgenic rats carrying human pathogenicLRRK2R1441C or G2019S mutations with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride. We interrogate presynaptic integrity and postsynaptic dopamine receptor availability, and compared these to non-transgenic rats.

LRRK2mutant rats displayed similar [18F]FDOPA uptake to non-transgenic animals, consistent with intact dopamine synthesis in striatal axons. However,LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride thanLRRK2-G2019S or non-transgenic controls, exhibiting regionally selective binding increase in the dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors inLRRK2-R1441C than other genotypes restricted to the dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit observed in this genotype.

These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in theLRRK2-R1441C rat, detecting upregulation of D2 receptors that parallels observations in early human sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.
Actomyosin-II Proactively Shields Axons of the Central Nervous System from Mild Mechanical Stress
Authors: Pan Xiaorong , Lei Gaowei , Li Jie , Luan Tongshu , Hu Yiqing , Chu Yuanyuan , Feng Yu , Zhan Wenrong , Zhao Chunxia , Meunier Frédéric A. , Liu Yifan , Li Yi , Wang Tong
Published: August 2023

Panet alfound that actomyosin-II-driven radial contractility underpins the resilience of central axons to mild mechanical stress by suppressing the propagation and firing of injurious Ca2+waves. Boosting actomyosin-II activity alleviates axon degeneration in mice with traumatic brain injury.

Traumatic brain injury (TBI) remains a significant and unmet health challenge. However, our understanding of how neurons, particularly their fragile axons, withstand the abrupt mechanical impacts within the central nervous system remains largely unknown. Using a microfluidic device applying discrete levels of transverse forces to axons, we identified the stress levels that most axons could resist and explored their instant responses at nanoscale resolution. Mild stress induces rapid and reversible axon beading, driven by actomyosin-II-dependent radial contraction, which restricts the spreading and bursting of stress-induced Ca2+waves. More severe stress causes irreversible focal swelling and Ca2+overload, ultimately leading to focal axonal swelling and degeneration. Up-regulating actomyosin-II activity prevented the progression of initial injuryin vivo, protecting commissural axons from degeneration in a mice TBI model. Our study established a scalable axon injury model and uncovered the critical roles of actomyosin-II in shielding neurons against detrimental mechanical stress.
Small fibre neuropathy in Fabry disease: a human-derived neuronalin vitrodisease model
Authors: Klein Thomas , Grüner Julia , Breyer Maximilian , Schlegel Jan , Schottmann Nicole Michelle , Hofmann Lukas , Gauss Kevin , Mease Rebecca , Erbacher Christoph , Finke Laura , Klein Alexandra , Klug Katharina , Karl-Schöller Franziska , Vignolo Bettina , Reinhard Sebastian , Schneider Tamara , Günther Katharina , Fink Julian , Dudek Jan , Maack Christoph , Klopocki Eva , Seibel Jürgen , Edenhofer Frank , Wischmeyer Erhard , Sauer Markus , Üçeyler Nurcan
Published: August 2023

Acral burning pain triggered by fever, thermal hyposensitivity, and skin denervation are hallmarks of small fibre neuropathy in Fabry disease, a life-threatening X-linked lysosomal storage disorder. Variants in the gene encoding alpha-galactosidase A may lead to impaired enzyme activity with cellular accumulation of globotriaosylceramide (Gb3). To study the underlying pathomechanism of Fabry-associated small fibre neuropathy, we generated a neuronalin vitrodisease model using patient-derived induced pluripotent stem cells from three Fabry patients and one healthy control. We further generated an isogenic control line via CRISPR/Cas9 gene editing. We subjected iPSC to targeted peripheral neuronal differentiation and observed intra-lysosomal Gb3 accumulations in somas and neurites of Fabry sensory neurons using super-resolution microscopy. At functional level, patch-clamp analysis revealed a hyperpolarizing shift of voltage-gated sodium channel steady-state inactivation kinetics in Fabry cell lines as compared to the healthy control. Moreover, we demonstrate a drastic increase in Fabry sensory neuron Ca2+levels at 39°C mimicking clinical fever (p < 0.001). This pathophysiological phenotype was accompanied by thinning of neurite calibres in sensory neurons obtained from Fabry patients compared to healthy control cells (p < 0.001). Linear-Nonlinear cascade models fit to spiking responses revealed that Fabry cell lines exhibit altered single neuron encoding properties relative to control. We further observed jam of mitochondrial trafficking at sphingolipid accumulations within Fabry sensory neurites utilizing a click-chemistry approach together with mitochondrial dysmorphism compared to healthy control cells. We pioneer insights into the cellular mechanisms contributing to pain, thermal hyposensitivity, and denervation in Fabry small fibre neuropathy, and pave the way for further mechanisticin vitrostudies in Fabry disease and the development of novel treatment approaches.
Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy
Authors: Wang Lei , Xiao Yufeng , Luo Yuewan , Master Rohan P , Mo Jiao , Kim Myung-Chul , Liu Yi , Patel Urvi M , Li Xiangming , Shaffer Donald , Guertin Kevin R , Moser Emily , Smalley Keiran S. , Zhou Daohong , Zheng Guangrong , Zhang Weizhou
Published: August 2023

An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatmentin vitroand sustains for at least 4 daysin vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti- cancer immune responses and offers a new avenue for treating various types of cancer.
SCI-VCF: A cross-platform GUI solution to Summarise, Compare, Inspect, and Visualise the Variant Call Format
Authors: Kamaraj Venkatesh , Sinha Himanshu
Published: August 2023

As genomics advances swiftly and its applications extend to diverse fields, bioinformatics tools must enable researchers and clinicians to work with genomic data irrespective of their programming expertise. We developed SCI-VCF, a Shiny-based comprehensive analysis utility to summarise, compare, inspect, analyse, and design interactive visualisations of the genetic variants from the variant call format. With an intuitive GUI, SCI-VCF aims to bridge the approachability gap in genomics that arises from the existing predominantly command-line utilities. SCI-VCF is written with R and is freely available athttps://github.com/HimanshuLab/SCI-VCF. For installation-free access, users can avail of an online version athttps://ibse.shinyapps.io/sci-vcf-online/.
Sustained Generation of Neurons Destined for Neocortex with Oxidative Metabolic Upregulation upon Filamin Abrogation
Authors: Kopsidas Caroline A. , Lowe Clara C. , McDaniel Dennis P. , Zhou Xiaoming , Feng Yuanyi
Published: August 2023

Neurons in the neocortex are generated during embryonic development. While the adult ventricular-subventricular zone (V-SVZ) contains cells with neural stem/progenitors’ characteristics, it remains unclear whether it has the capacity of producing neocortical neurons. Here we show that the generation of neurons exhibiting transcriptomic resemblance to neurons of the upper cortical layers continues in the V-SVZ of mouse models of a human condition known as periventricular heterotopia by abrogating filamin. We found such surplus neurogenesis was associated with V-SVZ’s transcriptional upregulation of oxidative phosphorylation, mitochondrial biogenesis, and increased vascularization. Our spatial transcriptomics analysis also showed that the neurogenic activation of V-SVZ was coupled with enriched expression of genes in diverse pathways for energetics, signaling, neuronal activities, and metabolic turnovers of nucleic acids and proteins in upper cortical layers. These findings support the potential of generating neocortical neurons in adulthood through enhancing brain-wide vascular circulation, aerobic ATP synthesis, and neuronal vitality.
Trapping studies reveal phenology and reproductive behaviour in two solitary sweat bees (Hymenoptera: Halictidae)
Authors: Proulx Alex , Richards Miriam H.
Published: August 2023

A transition from univoltine to bivoltine life histories, potentially due to the lengthening of flight seasons, is thought to have preceded the evolutionary transition from solitary to eusocial behaviour in halictid bees. Most behavioral studies which allow us to map these demographic and social transitions on phylogenies have focused on eusocial species, leaving a gap in behavioral data regarding solitary halictid bees. This lack of behavioral trait data is due to the great difficulty in locating the nests of solitary bees for study. However, long-term trapping studies are an effective method providing insights into the demography and social status of halictid bees. We used pan-trapped specimens to investigate flight phenology and solitary reproductionLasioglossum leucozonium(Schrank) andL. zonulum(Smith), from the socially and demographically labile subgenusLeuchalictus. We foundL. leucozoniumto be univoltine and solitary across its range, regardless of the length of flight season. In contrast,L. zonulumis phenologically flexible, being univoltine in the shorter flight seasons of Alberta, but bivoltine in southern Ontario. In bothL. leucozoniumand univoltineL. zonulum, higher than expected numbers of old, worn females with declining ovarian development foraged late into the season, suggesting that an indeterminate breeding strategy represents an ancestral condition not found in eusocial species. In bivoltineL. zonulum, the large size and higher fecundity of Brood 1 offspring suggest that after evolutionary reversion from eusocial to solitary behaviour, selection for worker-sized daughters may be reversed to selection for larger body sizes. The demographic plasticity demonstrated byL. zonulummay hint that partial bivoltinism is more widespread than currently documented. Future studies aimed at clarifying the demographic and social traits of more halictids will pave the way for comparative studies and eventual confidence in tracing how behavioral traits have changed and evolved in halictid bees.
Differences in the Pupillary Responses to Evening Light between Children and Adolescents
Authors: Hartstein Lauren E. , LeBourgeois Monique K. , Durniak Mark T. , Najjar Raymond P.
Published: August 2023

Purpose

To assess differences in the pupillary light responses (PLRs) to blue and red evening lights between children and adolescents.

Methods

Forty healthy participants (8-9 years, n=21; 15-16 years, n=19) completed a PLR assessment 1 h before their habitual bedtime. After a 1 h dim-light adaptation period (<1 lux), baseline pupil diameter was measured in darkness for 30 s, followed by a 10 s exposure to 3.0×1013photons/cm2/s of either red (627 nm) or blue (459 nm) light, and a 40 s recovery in darkness to assess pupillary re-dilation. Subsequently, participants underwent 7 min of dim-light re-adaptation followed by an exposure to the other light condition. Lights were counterbalanced across participants.

Results

Across both age groups, maximum pupil constriction was significantly greater (p< 0.001, ηp2=0.48) and more sustained (p< 0.001, ηp2=0.41) during exposure to blue compared to red light. For adolescents, the post-illumination pupillary response (PIPR), a hallmark of melanopsin function, was larger after blue compared with red light (p= 0.02, d=0.60). This difference was not observed in children. Across light exposures, children had larger phasic (p< 0.01, ηp2=0.20) and maximal (p< 0.01, ηp2=0.22) pupil constrictions compared to adolescents.

Conclusions

Blue light elicited a greater and more sustained pupillary response than red light across participants. However, the overall amplitude of the rod/cone-driven phasic response was greater in children than in adolescents. Our findings using the PLR highlight a higher sensitivity to evening light in children compared to adolescents, and continued maturation of the human non-visual photoreception/system throughout development.
A deep neural network estimation of brain age is sensitive to cognitive impairment and decline
Authors: Yang Yisu , Sathe Aditi , Schilling Kurt , Shashikumar Niranjana , Moore Elizabeth , Dumitrescu Logan , Pechman Kimberly R. , Landman Bennett A. , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L. , Archer Derek B.
Published: August 2023

The greatest known risk factor for Alzheimer’s disease (AD) is age. While both normal aging and AD pathology involve structural changes in the brain, their trajectories of atrophy are not the same. Recent developments in artificial intelligence have encouraged studies to leverage neuroimaging-derived measures and deep learning approaches to predict brain age, which has shown promise as a sensitive biomarker in diagnosing and monitoring AD. However, prior efforts primarily involved structural magnetic resonance imaging and conventional diffusion MRI (dMRI) metrics without accounting for partial volume effects. To address this issue, we post-processed our dMRI scans with an advanced free-water (FW) correction technique to compute distinct FW-corrected fractional anisotropy (FAFWcorr) and FW maps that allow for the separation of tissue from fluid in a scan. We built 3 densely connected neural networks from FW-corrected dMRI, T1-weighted MRI, and combined FW+T1 features, respectively, to predict brain age. We then investigated the relationship of actual age and predicted brain ages with cognition. We found that all models accurately predicted actual age in cognitively unimpaired (CU) controls (FW: r=0.66,p=1.62×10−32; T1: r=0.61,p=1.45×10−26, FW+T1: r=0.77,p=6.48×10−50) and distinguished between CU and mild cognitive impairment participants (FW:p=0.006; T1:p=0.048; FW+T1:p=0.003), with FW+T1-derived age showing best performance. Additionally, all predicted brain age models were significantly associated with cross-sectional cognition (memory, FW: β=−1.094,p=6.32×10−7; T1: β=−1.331,p=6.52×10−7; FW+T1: β=−1.476,p=2.53×10−10; executive function, FW: β=−1.276,p=1.46×10−9; T1: β=−1.337,p=2.52×10−7; FW+T1: β=−1.850,p=3.85×10−17) and longitudinal cognition (memory, FW: β=−0.091,p=4.62×10−11; T1: β=−0.097,p=1.40×10−8; FW+T1: β=−0.101,p=1.35×10−11; executive function, FW: β=−0.125,p=1.20×10−10; T1: β=−0.163,p=4.25×10−12; FW+T1: β=−0.158,p=1.65×10−14). Our findings provide evidence that both T1-weighted MRI and dMRI measures improve brain age prediction and support predicted brain age as a sensitive biomarker of cognition and cognitive decline.
SMB controls decompartmentalization in Arabidopsis root cap cells to execute programmed cell death
Authors: Wang Jie , Bollier Norbert , Buono Rafael Andrade , Vahldick Hannah , Lin Zongcheng , Feng Qiangnan , Hudecek Roman , Jiang Qihang , Mylle Evelien , Damme Daniel Van , Nowack Moritz K.
Published: August 2023

Programmed cell death (PCD) is a fundamental cellular process crucial to development, homeostasis, and immunity in multicellular eukaryotes. In contrast to our knowledge on the regulation of diverse animal cell death subroutines, information on execution of PCD in plants remains fragmentary. Here we make use of the accessibility of theArabidopsis thalianaroot cap to visualize the execution process of developmentally controlled PCD. We identify a succession of selective decompartmentalization events and ion fluxes that are controlled by a gene regulatory network downstream of the NAC transcription factor SOMBRERO (SMB). Surprisingly, breakdown of the large central vacuole is a relatively late and variable event, preceded by an increase of intracellular calcium levels and acidification, release of mitochondrial matrix proteins, leakage of nuclear and endoplasmic reticulum lumina, and release of fluorescent membrane reporters into the cytosol. Elevated intracellular calcium levels and acidification are sufficient to trigger cell death execution specifically in cells that are rendered competent to undergo PCD by SMB activity, suggesting that these ion fluxes act as PCD-triggering signals.
Simulating animal space use from fitted integrated Step-Selection Functions (iSSF)
Authors: Signer J. , Fieberg J. , Reineking B. , Schlägel U. , Smith B. , Balkenhol N. , Avgar T.
Published: August 2023

A standing challenge in the study of animal movement ecology is the capacity to predict where and when an individual animal might occur on the landscape, the so-called, Utilization Distribution (UD). Under certain assumptions, the steady-state UD can be predicted from a fitted exponential habitat selection function. However, these assumptions are rarely met. Furthermore, there are many applications that require the estimation of transient dynamics rather than steady-state UDs (e.g. when modeling migration or dispersal). Thus, there is a clear need for computational tools capable of predicting UDs based on observed animal movement data.

Integrated Step-Selection Analyses (iSSAs) are widely used to study habitat selection and movement of wild animals, and result in a fully parametrized individual-based model of animal movement, which we refer to as an integrated Step Selection Function (iSSF). An iSSF can be used to generate stochastic animal paths based on random draws from a series of Markovian redistribution kernels, each consisting of a selection-free, but possibly habitat-influenced, movement kernel and a movement-free selection function. The UD can be approximated by a sufficiently large set of such stochastic paths.

Here, we present a set of functions in R to facilitate the simulation of animal space use from fitted iSSFs. Our goal is to provide a general purpose simulator that is easy to use and is part of an existing workflow for iSSAs (within theamtR package).

We demonstrate through a series of applications how the simulator can be used to address a variety of questions in applied movement ecology. By providing functions inamtand coded examples, we hope to encourage ecologists using iSSFs to explore their predictions and model goodness-of-fit using simulations, and to further explore mechanistic approaches to modeling landscape connectivity.
Environmental Uncertainty Affects Movement and Space-use in Sheep
Authors: Bartsch Sarah T. , van Wettere William H. E. J. , Griffith Simon C. , Leu Stephan T.
Published: August 2023

Animals constantly experience periods of uncertainty due to seasonal changes in food distribution. The changing climate results in more variable weather patterns, which in turn alter environmental conditions, and can result in resource distribution being less predictable in space and time. How animals respond to these uncertain conditions, in particular the changing distribution of food resources, remains largely unclear and is an important question in the field of movement and animal ecology. Here we used an experimental approach to study how Merino sheep (Ovis aries) responded to different levels of environmental uncertainty in a drought-impacted region of the Australian arid zone. Sheep were unfamiliar with the experimental resource distribution at the start and progressively decreased their uncertainty (i.e., increased their environmental knowledge) when discovering an increasing number of foraging patches. We tracked 50 sheep with GPS collars (1 location every 15 sec) and deduced their movement and space use behaviour. When environmental uncertainty decreased, individuals moved more directionally (greater step length, smaller turn angles) and moved greater distances per day. They also had larger daily home ranges but rested in similar areas on consecutive nights (similar displacement, with the exception when five patches were discovered). Our study demonstrates how an arid zone, free-ranging ungulate adjusts its movement and space use behaviour as it gains environmental information in order to forage efficiently during periods of uncertainty. Our study provides important insights into how animals cope with variable environments and different levels of uncertainty.
Distribution and extent of suitable habitat for geladas (Theropithecus gelada) in the Anthropocene
Authors: Ahmed Ahmed Seid , Chala Desalegn , Kufa Chala Adugna , Atickem Anagaw , Bekele Afework , Svenning Jens-Christian , Zinner Dietmar
Published: August 2023

Background

Climate change coupled with other anthropogenic pressures may affect species distributions, often causing extinctions at different scales. This is particularly true for species occupying marginal habitats such as gelada,Theropithecus gelada.Our study aimed to model the impact of climate change on the distribution of suitable habitats for geladas and draw conservation implications. Our modelling was based on 285 presence locations of geladas, covering their complete current distribution. We used different techniques to generate pseudoabsence datasets, MaxEnt model complexities, and cut-off thresholds to map the potential distribution of gelada under current and future climates (2050 and 2070). We assembled maps from these techniques to produce a final composite map. We also evaluated the change in the topographic features of gelada over the past 200 years by comparing the topography in current and historical settings.

Results

All model runs had high performances, AUC = 0.87 – 0.96. Under the current climate, the suitable habitat predicted with high certainty was 90,891 km2, but it decreased remarkably under future climates, −36% by 2050 and −52% by 2070. Whereas no remarkable range shift was predicted under future climates, currently geladas are confined to higher altitudes and complex landscapes compared to historical sightings, probably qualifying geladas as refugee species.

Conclusions

Our findings indicated that climate change most likely results in a loss of suitable habitat for geladas, particularly south of the Rift Valley. The difference in topography between current and historical sightings is potentially associated with anthropogenic pressures that drove niche truncation to higher altitudes, undermining the climatic and topographic niche our models predicted. We recommend protecting the current habitats of geladas even when they are forecasted to become climatically unsuitable in the future, in particular for the population south of the Rift Valley.
A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity
Authors: Zhou Bingxin , Zheng Lirong , Wu Banghao , Yi Kai , Zhong Bozitao , Tan Yang , Liu Qian , Liò Pietro , Hong Liang
Published: August 2023

Deep learning-based methods for generating functional proteins address the growing need for novel biocatalysts, allowing for precise tailoring of functionalities to meet specific requirements. This emergence leads to the creation of highly efficient and specialized proteins with wide-ranging applications in scientific, technological, and biomedical domains. This study establishes a pipeline for protein sequence generation with a conditional protein diffusion model, namely CPDiffusion, to deliver diverse sequences of proteins with enhanced functions. CPDiffusion accommodates protein-specific conditions, such as secondary structure and highly conserved amino acids (AAs). Without relying on extensive training data, CPDiffusion effectively captures highly conserved residues and sequence features for a specific protein family. We applied CPDiffusion to generate artificial sequences of Argonaute (Ago) proteins based on the backbone structures of wild-type (WT)Kurthia massiliensisAgo (KmAgo) andPyrococcus furiosusAgo (PfAgo), which are complex multi-domain programmable endonucleases. The generated sequences deviate by up to nearly400AAs from their WT templates. Experimental tests demonstrated that the majority of generated proteins show unambiguous activity in DNA cleavage for both KmAgo and PfAgo, with many of them exhibiting superior activity as compared to the WT. These findings underscore CPDiffusion’s remarkable success rate to generate novel sequences for proteins of complex structures and functions in a single step with enhanced activity. This approach facilitates the design of enzymes with multi-domain molecular structures and intricate functions throughin silicogeneration and screening, all accomplished without any supervision from labeled data.
Elevated serotonin in mouse spinal dorsal horn is pronociceptive
Authors: Cramer Nathan , Ji Yadong , Kane Maureen , Pilli Nageswara , Posa Luca , Van Patten Gabrielle , Masri Radi , Keller Asaf
Published: August 2023

Serotonergic neurons in the rostral ventral medulla (RVM) contribute to bidirectional control of pain through modulation of spinal and trigeminal nociceptive networks. Deficits in this pathway are believed to contribute to pathological pain states, but whether changes in serotonergic mechanisms are pro or anti-nociceptive are debated. We used a combination of optogenetics and fiber photometry to examine these mechanisms more closely. We find that optogenetic activation of RVM serotonergic afferents in the spinal cord of naïve mice produces mechanical hypersensitivity and conditioned place aversion. Neuropathic pain, produced by chronic constriction injury of the infraorbital nerve (CCI-ION), evoked a tonic increase in serotonin concentrations within the spinal trigeminal nucleus caudalis (SpVc), measured with liquid chromatography-tandem mass spectroscopy (LC-MS/MS). By contract, CCI-ION had no effect on the phasic serotonin transients in SpVc, evoked by noxious pinch, and measured with fiber photometry of a serotonin sensor. These findings suggest that serotonin release in the spinal cord is pronociceptive and that an increase is sustained serotonin signaling, rather than phasic or event driven increases, potentiate nociception in models of chronic pain.

Significance Statement

Serotonergic neurons of the rostral ventral medulla participate in descending pain modulation by regulating spinal and trigeminal nociceptive circuits. Whether changes in serotonergic mechanisms are pro or anti-nociceptive is debated. We show that serotonin release within the spinal trigeminal nucleus is pronociceptive and that enhanced tonic, but not phasic serotonin release may contribute to sensitization in mouse models of chronic pain. These results further clarify the role of serotonin in nociception and suggest that local inhibition of serotonin release or increase of uptake may be a viable therapeutic approach in treating chronic pain.
Reduced ornamentation became elaborated in benign environments in a bird species
Authors: Hasegawa Masaru , Arai Emi , Kato Takahiro
Published: August 2023

Many empirical studies have focused on highly-ornamented species to identify ecological factors that maintain the ornamentation or favour its exaggeration. By contrast, although reduction or loss of ornamentation appears to be widespread, species with reduced/lost ornamentation and its relationship with ecological factors are rarely focused on. Here, based on data collected over four years, we studied outermost tail feather length, i.e. a well-known sexual ornamentation in this clade, in relation to roosting location in the Pacific swallowHirundo tahiticaduring winter. In contrast to congeners, this species has inconspicuous tail ornamentation, i.e. very shallowly forked tails with vestigial streamers, providing a rare opportunity to study the ecological factors driving reduced ornamentation. We found that Pacific swallows mainly roost in old nests under bridges over rivers, which resemble their original roosting sites, but some roost in old nests under the eaves of houses above the ground. Individuals roosting under the eaves of houses had significantly longer outermost (but not central) tail feathers than those roosting under bridges. Individuals roosting under the eaves of houses were heavier and showed lower physiological stress, and thus might better endure the maintenance cost, favouring ornament elaboration. Because we controlled for the effects of sex and age, these factors would not confound the observed pattern. Reduced ornamentation, as found in Pacific swallows roosting under their original roosting sites, could become elaborated in benign environments (i.e., under eaves, here), stressing the importance of balance between the costs and benefits of ornamentation.