bluuebunny/crossref_metadata_2025 huggingface dataset:
The use of a deep learning model in the histopathological diagnosis of actinic keratosis: A case control accuracy study
Authors: Balkenhol J. , Schmidt M. , Schnauder T. , Langhorst J. , Arrastia J. Le’Clerc , Baguer D. Otero , Gilbert G. , Schmitz L. , Dirschka T.
Published: November 2023

Actinic Keratosis (AK) is a frequent dermatological diagnosis which contributes to a large proportion of routine dermatopathology. A current development in histopathology is in the digitization of specimens by creating whole slide images (WSI) with slide scanners. Deep Learning Models (DLM) have been introduced to radiology or pathology for image recognition but dermatopathology lacks available solutions. Building on previous work about skin pathologies, this paper proposes a DLM following the U-Net architecture to detect AK in histopathological samples. In total, 297 histopathological slides (269 with AK and 28 without AK) have been retrospectively selected. They were randomly assigned to training, validation, and testing groups. Performance was evaluated by conducting a Case Control Accuracy Study on three levels of granularity. The DLM model achieved an overall accuracy of 99.13% on the WSI level, 99.02% on the patch level and an intersection over union (IoU) of 83.88%. The proposed DLM reliably recognizes AK in histopathological images, supporting the implementation of DLMs in dermatopathology practice. Given existing technical capabilities and advancements, DLMs could have a significant influence on dermatopathology routine in the future.
A protracted cholera outbreak in Nairobi City County associated with mass gathering events, Kenya, 2017
Authors: Ngere Philip , Langat Daniel , Ngere Isaac , Dawa Jeanette , Okunga Emmanuel , Nasimiyu Carolyne , Kiama Catherine , Lokamar Peter , Ngunu Carol , Makayotto Lyndah , Njenga M. Kariuki , Osoro Eric
Published: November 2023

Cholera continues to cause many outbreaks in low and middle-income countries due to inadequate water, sanitation, and hygiene services. We describe a protracted cholera outbreak in Nairobi City County (NCC), Kenya in 2017. We reviewed the cholera outbreak line lists from NCC in 2017 to determine its extent and factors associated with death. A suspected case of cholera was any person aged >2 years old who had acute watery diarrhea, nausea, or vomiting, whereas a confirmed case was whereVibrio choleraewas isolated from the stool specimen. We summarized cases using for continuous variables and proportions for categorical variables. Associations between admission status, sex, age, residence, time to care seeking, and outbreak settings; and cholera associated deaths were assessed using odds ratio (OR) with 95% confidence interval (CI). Of the 2,737 cholera cases reported, we analyzed 2,347 (85.7%) cases including 1,364 (58.1%) outpatients, 1,724 (73.5%) not associated with mass gathering events (MGEs), 1,356 (57.8%) male and 2,202 (93.8%) aged ≥5 years, and 35 deaths (case fatality rate: 1.5%). Cases were reported from all the Sub Counties of NCC with an overall county attack rate of 50 per 100,000 people.Vibrio choleraeOgawa serotype was isolated from 78 (34.8%) of the 224 specimens tested and all isolates were sensitive to tetracycline and levofloxacin but resistant to amikacin. The odds of cholera-related deaths was lower among outpatient cases (aOR: 0.35; [95% CI: 0.17-0.72]), age ≥5 years old (aOR: 0.21 [95% CI: 0.09-0.55]), and MGEs (aOR: 0.26 [95% CI: 0.07-0.91]) while threefold higher odds among male (aOR: 3.04 [95% CI: 1.30-7.13]). NCC experienced a protracted and widespread cholera outbreak with a high case fatality rate in 2017.

Author Summary

Cholera outbreaks are common in Kenya. The highest number of cases were reported in 2015 with 10,536 cases across the country. The subsequent three years also recorded a high number of cholera cases with 6,137 cases in 2016, 4,217 cases in 2017, and 5,638 cases in 2018. During the four years (2015-2018), NCC contributed less than 20.0% of the cholera cases, except in 2017 when the county reported 56.9% (2,737) of the cases. In this study, we sought to describe the burden of cholera in NCC during the 2017 outbreak. We reviewed the cholera outbreak data from NCC in 2017 to determine its extent and risk factors for cholera-related deaths. The findings depict a prolonged and widespread cholera outbreak with the likelihood of death higher among male cases but lower among outpatients, cases aged ≥5 years old, and cases from the MGEs. More studies on the factors associated with cholera-related deaths are necessary to inform public health response.
Effects of exposure in virtual reality and in vivo on subjective symptom burden and physiological parameters of height-anxious healthy participants – A pilot study
Authors: Renner Vanessa , Witthöft Michael , Hardt Jochen , Conrad Rupert , Petrowski Katja
Published: November 2023

Exposure in vivo is a highly effective treatment for anxiety disorders and acrophobia in particular. Nevertheless, it is rarely implemented in outpatient treatment. Exposure in virtual reality (VR) might be an alternative but its effect on subjective symptom burden and physiological parameters is questionable. Therefore, in this study, N = 33 participants with fear of heights received both in vivo and VR exposure in a randomized order. Subjective symptom burden before and after each exposure as well as heart rate and heart rate variability (SDNN, LF/HF ratio) during exposure sessions were assessed. Linear mixed models were calculated with the effect of condition (VR vs. in vivo) and scenario on HR, SDNN and LF/HF ratio. Subjective symptom burden was significantly reduced after both exposure sessions (p = .002; p < .001). Heart rate was significantly higher during exposure scenarios than baseline (p < .001). SDNN and LF/HF ratio reflected a significantly higher general power of HRV and a significantly higher activation of the sympathetic nervous system during exposure sessions compared to baseline and during VR exposure compared to in vivo. All in all, VR exposure shows comparable or superior effects compared to in vivo exposure regarding acrophobic fears and physiological parameters.
Affect and post-COVID-19 symptoms in daily life: An exploratory experience sampling study
Authors: Schaap Gerko , Wensink Marleen , Doggen Carine J. M. , van der Palen Job , Vonkeman Harald E. , Bode Christina
Published: November 2023

Insight into the daily life experiences of patients with post-COVID-19 syndrome is lacking. The current study explored temporal fluctuations of and associations between positive and negative affect and symptoms throughout the day in previously hospitalised post-COVID-19 patients using an experience sampling methodology. Ten participants (age: median = 60, interquartile range = 9 years; 50% women ; 80% ≥1 comorbidity; 8–12 months since hospital discharge) filled out brief online questionnaires, six times a day for 14 consecutive days. Positive and negative affect, and self-reported symptoms (physical and mental fatigue, cognitive functioning, dyspnoea, and pain) were assessed in real-time. Primarily, graphs were analysed to assess the individual longitudinal courses of and (concurrent and time-lagged) associations between affect and symptoms. Secondly, correlations or multilevel linear regression models were used to support these interpretations. Visual assessment showed limited temporal fluctuation in affect and symptoms. All symptoms appeared to associate positively with each other (correlations between .26 and .85). Positive affect was associated with lower symptoms severity (β’s between -.28 and -.67), and negative affect with higher symptoms severity (β’s between .24 and .66). Time-lagged analyses showed that – adjusted for residual symptom severity of prior measurements – both types of affect predicted symptom severity two hours later (β’s between -.09 and -.31 for positive affect; between .09 and .28 for negative affect). These findings suggest that positive and negative affect may play important roles in post-COVID-19 symptom experience and temporal fluctuation.
Distinct roles of dopamine and acetylcholine in delay- and effort-based decision making in humans
Authors: Abdoust Mani Erfanian , Froböse Monja Isabel , Schnitzler Alfons , Schreivogel Elisabeth , Jocham Gerhard
Published: November 2023

In everyday life, we encounter situations that require tradeoffs between potential rewards and associated costs, such as time and (physical) effort. The literature indicates a prominent role for dopamine in discounting of both delay and effort, with mixed findings for delay discounting in humans. Moreover, the reciprocal antagonistic interaction between dopaminergic and cholinergic transmission in the striatum suggests a potential opponent role of acetylcholine in these processes. We found opposing effects of dopamine D2 (haloperidol) and acetylcholine M1 receptor (biperiden) antagonism on specific components of effort-based decision making in healthy humans: haloperidol decreased, whereas biperiden increased the willingness to exert physical effort. In contrast, delay discounting was reduced under haloperidol, but not affected by biperiden. Together, our data suggest that dopamine, acting at D2 receptors, modulates both effort and delay discounting, while acetylcholine, acting at M1 receptors, appears to exert a more specific influence on effort discounting only.
C-terminal tagging impairs AGO2 function
Authors: Shah Kunal M , Crozier Alex F. F. , Assaraf Anika Assaraf , Arya Mujda , Grevitt Paul , Mardakheh Faraz , Plevin Michael J , Sharp Tyson Valentine
Published: November 2023

A full understanding of RNA silencing requires appropriate molecular biology tools to explore the roles of Argonaute 2 (AGO2) and the RNA-induced silencing complex (RISC). Approaches relying on affinity tagging and antibodies have important limitations that can lead to artificial results. Both the N- and C-terminal domains of AGO2 have been shown to be important for correct activity and yet the consequences of appending tags to either terminus have not been fully investigated. N-terminal tags are frequently used to study AGO2 biology. Recently, an N-terminal HaloTag-Ago2 fusion was reported and examined in mice. While the versatile HaloTag provided new opportunities to study RISC biology, the tagged construct showed certain activity changes compared to unmodified AGO2. CRISPaint, a new CRISPR-Cas9 technique, permits the creation of endogenous C-terminal tag fusions. We used CRISPaint to generate the first reported recombinant AGO2 construct with a C-terminal tag: an endogenous C-terminal HaloTag fusion to AGO2 (AGO2HALO) in human (A549) cells. We found that the AGO2HALO fusion protein has a reduced capacity to interact with the key protein binding partner TNRC6A and that the C-terminal HaloTag does not affect cell viability. However, the AGO2HALO fusion significantly impairs RNA cleavage and RNA silencing activity compared to control cells and reduces nuclear localisation of the fusion protein. Using plasmid constructs and transient transfection, we compared AGO2 tagged with EGFP at the N- or C- terminus in siRNA and miRNA reporter gene assays, and cellular localisation. N-terminally tagged AGO2 functioned and localised similarly to WT untagged AGO2, whereas, C-terminally tagged AGO2 was impaired in siRNA and miRNA silencing and exhibited poor nuclear and P-body localisation. We conclude that the fusion of a C-terminal HaloTag to AGO2 is not appropriate for studying AGO2 and RISC. Our results assert the importance of comprehensively validating recombinant tagging strategies to ensure that any experimental results generated do not arise from, or are not obscured by critical functional defects.
Global functional connectivity of cognitive control network predicts task-switching performance in older adults
Authors: Madero B. , Sodoma M. , Oehler C. , Magnotta V. A. , Long J. D. , Hazeltine E. , Voss M. W.
Published: November 2023

Executive Function (EF) is a complex higher order cognitive process that involves integrating subprocesses of attention, working memory, inhibition, and task switching and known to be one of the first cognitive functions to be affected by age related declines. Global Functional Connectivity (GFC), a measure of whole brain connectivity in brain networks such as the Cognitive Control Network (CCN), has been shown to measure the maintained EF abilities in older adults with cognitive impairment. However, this relationship has not been explored in a sample comprised of mostly cognitively normal older adults nor with the use of an experimental EF task sensitive to sub-processes most sensitive to aging. Task-switch paradigm studies have shown age-related deficits in holding and responding to rule sets while inhibiting another rule set in working memory (i.e., mixing cost). The present study aims to elucidate the relationship seen in EF performance using GFC and leveraging a task-switch paradigm that manipulates response overlap to increase cognitive demands on switching between tasks (e.g., mixing cost). Results show that greater negative DMN GFC coincides with older adults’ lower mixing costs, not CCN GFC. Findings indicate that DMN GFC, not CCN, may be important for EF performance in older adults.
Ammonia inhibits antitumor activity of NK cells by decreasing mature perforin
Authors: Domagala Joanna , Grzywa Tomasz M. , Baranowska Iwona , Kusowska Aleksandra , Fidyt Klaudyna , Marhelava Katsiaryna , Pilch Zofia , Graczyk-Jarzynka Agnieszka , Picard Lea K. , Jastrzebski Kamil , Granica Monika , Justyniarska Magdalena , Urlaub Doris , Bobrowicz Malgorzata , Miaczynska Marta , Watzl Carsten , Winiarska Magdalena
Published: November 2023

Immunotherapy revolutionized cancer treatment in the last decade. Natural killer (NK) cells are one of the key host immunity components against malignant cells. Thus, they are currently extensively investigated in the field of immunotherapy of cancer. Different approaches have been developed to improve the antitumor activity of NK cells. Nonetheless, tumor microenvironment remains an obstacle to effective NK cell-based therapies. Here, we demonstrated that a cancer-conditioned medium suppresses the anti-tumor activity of NK cells. Further, we found that ammonia, a by-product of cancer cell metabolism, accumulates in the cancer-conditioned medium and tumor microenvironment. We identified that ammonia impairs the cytotoxicity of NK cells as well as the effectiveness of antibody-based and chimeric antigen receptor (CAR)-NK-based therapiesin vitro. Inhibited activity of NK cells was caused by decreased levels of perforin. This effect was dependent on the lysosomotropic features of ammonia and its ability to increase pH in acidic compartments. In consequence, upon contact with ammonia the mature form of perforin was decreased in NK cells leading to their dysfunction. Our findings demonstrate that in addition to its previously described role of promoting tumor growth as a nitrogen source for tumor biomass ammonia could promote tumor escape as an NK cells immune checkpoint.

Graphical abstract

Highlights

Cancer-conditioned medium suppresses the antitumor activity of NK cells

Ammonia accumulates in conditioned medium and in the tumor microenvironment

Impaired cytotoxicity of NK cells is caused by ammonia that decreases perforin levels

Ammonia causes NK cell dysfunction
Differential expression of core metabolic functions inCandidatusAltiarchaeum inhabiting distinct subsurface ecosystems
Authors: Esser Sarah P. , Turzynski Victoria , Plewka Julia , Moore Carrie J. , Banas Indra , Soares André R. , Lee Janey , Woyke Tanja , Probst Alexander J.
Published: November 2023

CandidatusAltiarchaea are widespread across aquatic subsurface ecosystems and possess a highly conserved core genome, yet adaptations of this core genome to different biotic and abiotic factors based on gene expression remain unknown. Here, we investigated the metatranscriptome of twoCa. Altiarchaeum populations that thrive in two substantially different subsurface ecosystems. In Crystal Geyser, a high-CO2groundwater system in the USA,Ca. Altiarchaeum crystalense co-occurs with the symbiontCa. Huberiarchaeum crystalense, while in the Muehlbacher sulfidic spring in Germany, an artesian spring high in sulfide concentration,Ca. A. hamiconexum is heavily infected with viruses. We here mapped metatranscriptome reads against their genomes to analyze thein situexpression profile of their core genomes. Out of 537 shared gene clusters, 331 were functionally annotated and 130 differed significantly in expression between the two sites. Main differences were related to genes involved in cell defense like CRISPR-Cas, virus defense, replication, and transcription as well as energy and carbon metabolism. Our results demonstrate that altiarchaeal populations in the subsurface are likely adapted to their environment while influenced by other biological entities that tamper with their core metabolism. We consequently posit that viruses and symbiotic interactions can be major energy sinks for organisms in the deep biosphere.

(Originality-Significance Statement

Organisms of the uncultivated phylumCa. Altiarchaeota are globally widespread and fulfill essential roles in carbon cycling,e.g., carbon fixation in the continental subsurface. Here, we show that the transcriptional activity of organisms in the continental subsurface differ significantly depending on the geological and microbial setting of the ecosystem explaining many of the previously observed physiological traits of this organism group.)
Binary Discriminator Facilitates GPT-based Protein Design
Authors: Zeng Zishuo , Xu Rufang , Guo Jin , Luo Xiaozhou
Published: November 2023

Generative pre-trained transformers (GPT) models provide powerful tools for de novo protein design (DNPD). GPT-based DNPD involves three procedures: a) finetuning the model with proteins of interest; b) generating sequence candidates with the finetuned model; and c) prioritizing the sequence candidates. Existing prioritization strategies heavily rely on sequence identity, undermining the diversity. Here, we coupled a protein GPT model with a custom discriminator, which enables selecting candidates of low identity to natural sequences while highly likely with desired functions. We applied this framework to creating novel antimicrobial peptides (AMPs) and malate dehydrogenases (MDHs). Experimental verification pinpointed four broad-spectrum AMPs from 24 candidates. Comprehensive computational analyses on the prioritized MDHs candidates provide compelling evidence for the anticipated function. During experimental validation, 4/10 and 3/10 natural MDHs and generated-prioritized novel candidates, respectively, were expressed and soluble. All the soluble candidates (3/3) are functional in vitro. This framework is time- and data-efficient and may therefore considerably expedite the DNPD process.
Induction of apoptosis by double-stranded RNA was present in the last common ancestor of cnidarian and bilaterian animals
Authors: Kozlovski Itamar , Jaimes-Becerra Adrian , Sharoni Ton , Lewandowska Magda , Karmi Ola , Moran Yehu
Published: November 2023

Apoptosis, a major form of programmed cell death, is an essential component of host defense against invading intracellular pathogens. Viruses encode inhibitors of apoptosis to evade host responses during infection, and to support their own replication and survival. Therefore, hosts and their viruses are entangled in a constant evolutionary arms race to control apoptosis. Until now, apoptosis in the context of the antiviral immune system has been almost exclusively studied in vertebrates. This limited phyletic sampling makes it impossible to determine whether a similar mechanism existed in the last common ancestor of animals. Here, we established assays to probe apoptosis in the sea anemoneNematostella vectensis, a model species of Cnidaria, a phylum that diverged approximately 600 million years ago from the rest of animals. We show that polyinosinic:polycytidylic acid (poly I:C), a synthetic long double-stranded RNA mimicking viral RNA and a primary ligand for the vertebrate RLR melanoma differentiation-associated protein 5 (MDA5), is sufficient to induce apoptosis inN. vectensis. Furthermore, at the transcriptomic level, apoptosis related genes are significantly enriched upon poly(I:C) exposure inN. vectensisas well as bilaterian invertebrates. Our phylogenetic analysis of caspase family genes inN. vectensisreveals conservation of all four caspase genes involved in apoptosis in mammals and revealed a cnidarian-specific caspase gene which was strongly upregulated. Altogether, our findings suggest that apoptosis in response to a viral challenge is a functionally conserved mechanism that can be traced back to the last common ancestor of Bilateria and Cnidaria.
Mouse Genome Editing from Scratch
Authors: Popova J.V. , Bets V.D. , Omelina E.S. , Boldyreva L.V. , Kozhevnikova E.N.
Published: November 2023

Mouse genome modification requires costly equipment and highly skilled personnel to manipulate zygotes. A number of zygote electroporation techniques were reported to be highly efficient in gene delivery. One of these methods called i-GONAD (improved Genome-editing via Oviductal Nucleic Acids Delivery) describes electroporation-based gene transfer to zygotesin utero. Here we adopted this technology for mouse genome-editing from scratch minimizing the cost of equipment, operator skill and animal use. We chose the CRISPR/Cas9 system as a genome editing tool and i-GONAD as a gene delivery method to produceIL10gene knockout in C57BL/6 mice. Four animals out of 13 delivered pups (30.8%) were genetically compromised atIL10gene locus suggesting the feasibility of the approach. This report provides one of the possible technical settings for those who aim at establishing in-house mouse transgenesis pipeline at minimal cost from scratch.

For citation

Popova J.V., Bets V.D., Omelina E.S., Boldyreva L.V., Kozhevnikova E.N. Mouse Genome Editing from Scratch. Journal of Experimental Biology.Year; issue (number): page. DOI
FORAGING MECHANISMS IN EXCAVATE FLAGELLATES SHED NEW LIGHT ON THE FUNCTIONAL ECOLOGY OF EARLY EUKARYOTES
Authors: Suzuki Sei , Miano Federica , Asadzadeh Seyed Saeed , Simpson Alastair G.B. , Kiørboe Thomas
Published: November 2023

The phagotrophic flagellates described as ‘typical excavates’ have been hypothesized to be morphologically similar to the Last Eukaryotic Common Ancestor and understanding the functional ecology of excavates may therefore help shed light on the ecology of these early eukaryotes. Typical excavates are characterized by a posterior flagellum equipped with a vane that beats in a ventral groove. Here, we combined flow visualization and observations of prey capture in representatives of the three clades of excavates with computational fluid dynamic modelling, to understand the functional significance of this cell architecture. We record substantial differences amongst species in the orientation of the vane and the beat plane of the posterior flagellum. Clearance rate magnitudes estimated from flow visualization and modelling are like that of other similarly sized phagotrophic flagellates. The interaction between a vaned flagellum beating in a confinement is modelled to produce a very efficient feeding current at low energy costs, irrespective of the beat plane and vane orientation and of all other morphological variations. Given this predicted uniformity of function, we suggest that the foraging systems of typical excavates studied here may be good proxies to understand those potentially used by our distant ancestors more than 1 billion years ago.

Significance

Human sperm reminds us of our ancestry: flagellates, unicellular organisms equipped with a flagellum. The last common eukaryotic ancestor (LECA) was a flagellate. Phylogenetic analyses suggest that Excavates, an assemblage of flagellates, are the living organisms most similar to LECA. They have distinct characteristics in common: a ventral groove within which a vaned flagellum is beating. We show how the shared morphology and foraging behavior among 3 excavate clades is fluid dynamically efficient. A similar flagellar arrangement, potentially homologous to that found in the excavates, is found among flagellates from other deep branches of the eukaryotic tree, suggesting that the typical excavate foraging system studied here may have been used by our distant ancestors more than 1 billion years ago.
Double dissociation of visuomotor interaction mediated by visual feedback during continuousde novomotor learning
Authors: Kim Junghyun , Park Sungbeen , Yoo Kwangsun , Kim Sungshin
Published: November 2023

While the sensorimotor cortices are central neural substrates for motor control and learning, how the interaction between their subregions with visual cortices contributes to acquiringde novovisuomotor skills is poorly understood. We designed a continuous visuomotor task in fMRI where participants learned an arbitrary visuomotor mapping. To dissociate motor and somatosensory cortices functions, we manipulated visual feedback of a cursor such that they learned to control using fingers under two alternating conditions: online cursor feedback is available or unavailable except when a target is reached. We found double dissociation of fMRI activity in subregions of the sensorimotor and visual cortices and their interaction, which were mediated by the visual feedback. We also found a significant reduction in functional connectivity between somatosensory cortices and early visual cortices, which was highly correlated with performance improvement. These findings support the distinct interaction between subregions of sensorimotor cortices and visual cortices while highlighting the more dominant role of somatosensory cortices over motor cortices duringde novomotor learning.
Analysis of different strains of the turquoise killifishNothobranchius furzeriidentifies transcriptomic signatures associated with heritable lifespan differences
Authors: Mazzetto Mariateresa , Reichwald Kathrin , Sacramento Erika Kelmer , Koch Philipp , Ori Alessandro , Groth Marco , Cellerino Alessandro
Published: November 2023

The killifishNothobranchius furzeriis the shortest-lived vertebrate model organism and is characterized by laboratory strains differing in lifespan by more than a factor of two. The genetic architecture underlying this difference is complex and the pathways responsive remain elusive. We performed an analysis inN. furzeriof public transcritomic datasets comprehensive of four different tissues and one embryonic stage in two strains: the shorter-lived GRZ and the longer-lived MZM0410. Remarkably, the two strains differ in their transcriptome profile already at the embryonic stage. The short-lived strain GRZ shows an anticipated aging profile consistently in all tissues investigated, with differences in expression of aging-related genes detected already at sexual maturity. In addition, analysis of a longitudinal dataset revealed that genes whose expression is prognostic of longer lifespan at the individual level are also differentially expressed between strains at an early adult age, suggesting antagonistic pleiotropism.
OM2Seq: Learning retrieval embeddings for optical genome mapping
Authors: Nogin Yevgeni , Sapir Danielle , Zur Tahir Detinis , Weinberger Nir , Belinkov Yonatan , Ebenstein Yuval , Shechtman Yoav
Published: November 2023

Motivation

Genomics-based diagnostic methods that are quick, precise, and economical are essential for the advancement of precision medicine, with applications spanning the diagnosis of infectious diseases, cancer, and rare diseases. One technology that holds potential in this field is optical genome mapping (OGM), which is capable of detecting structural variations, epigenomic profiling, and microbial species identification. It is based on imaging of linearized DNA molecules that are stained with fluorescent labels, that are then aligned to a reference genome. However, the computational methods currently available for OGM fall short in terms of accuracy and computational speed.

Results

This work introduces OM2Seq, a new approach for the rapid and accurate mapping of DNA fragment images to a reference genome. Based on a Transformer-encoder architecture, OM2Seq is trained on acquired OGM data to efficiently encode DNA fragment images and reference genome segments to a common embedding space, which can be indexed and efficiently queried using a vector database. We show that OM2Seq significantly outperforms the baseline methods in both computational speed (by two orders of magnitude) and accuracy.

Availability and implementation

https://github.com/yevgenin/om2seq

Contact

yoavsh@bm.technion.ac.il
Mechanisms of infection and response of the fungal wheat pathogenZymoseptoria triticiduring compatible, incompatible and non-host interactions
Authors: Gomez-Gutierrez Sandra V. , Million Cassidy R. , Jaiswal Namrata , Gribskov Michael , Helm Matthew , Goodwin Stephen B.
Published: November 2023

Zymoseptoria triticiincites Septoria tritici blotch, a disease causing significant annual yield losses in wheat. To investigate infection phase-specific gene expression in the pathogen we analyzed gene expression during infection of susceptible (Taichung 29) and resistant (Veranopolis and Israel 493) wheat cultivars, plus the non-host species barley at 1, 3, 6, 10, 17 and 23 days post-inoculation (DPI). There were dramatic differences in pathogen gene expression at 10 DPI in the compatible compared to both incompatible interactions. The largest differences in pathogen gene expression occurred at 3 DPI in both compatible and incompatible interactions compared to the non-host interaction. Thirty-one putative effectors had early expression in the compatible interaction. Subsequent subcellular localization studies usingAgrobacterium-mediated transient expression inNicotiana benthamianarevealed that most candidate effectors localized to the nucleus and cytosol, and two localized to mobile cytosolic bodies, suggesting involvement in intracellular signaling or host gene regulation. Mycgr3109710, which localized to cytosolic bodies, belongs to the non-plant PR-1-like protein family implicated in virulence in other pathogens. Comparison of pathogen gene expression in resistant and susceptible hosts, in which an initial colonization is established, versus in the non-host species, allowed us to identify genes involved in establishing infection. Comparison of the compatible and incompatible interactions identified pathogen genes involved in transition from biotrophic to necrotrophic growth at 10 DPI. In addition, we contribute to the understanding of candidate effectors that are activated early during infection and might be involved in the initial plant immunity suppression.
Comparative analysis of gene regulatory networks identifies conserved regulators in seed plants
Authors: Wulf Donat , Bräutigam Andrea
Published: November 2023

Gene regulatory networks based on transcription factors control development and environmental responses in plants. Networks calculated by the machine learning algorithm random forest decision tree-based regression for the grasses barley, maize, wheat, Brachypodium, sorghum, and rice compared with Arabidopsis and an alga show substantial conservation. The degree of conservation depends on phylogenetic closeness. The processes, which are conserved between all species include basic cellular functions while the processes conserved in the grasses also more specific gene ontology terms. In the three species with a carbon concentration mechanism, photorespiration is partially disassociated from photosynthetic regulation. In contrast, in the C4 species, the regulation of C4 genes associates with photosynthetic regulation. The comparative analyses reveal conserved transcription factors, which control photosynthesis in seed plants but not in the alga. An analysis pipeline for the general transfer of information between the small weed Arabidopsis and the commercially relevant grasses is presented.
Prenatal inflammation reprograms hyperactive ILC2s that promote allergic lung inflammation and airway dysfunction
Authors: López Diego A. , Griffin Aleah , Aguilar Lorena Moreno , Rice Cassandra-Deering , Myers Elizabeth J. , Warren Kristi J. , Welner Robert , Beaudin Anna E.
Published: November 2023

Allergic asthma is a chronic respiratory disease that initiates in early life, but causal mechanisms are poorly understood. Here we examined how prenatal inflammation shapes allergic asthma susceptibility by reprogramming lung immunity from early development. Induction of Type I interferon-mediated inflammation during development provoked expansion and hyperactivation of group 2 innate lymphoid cells (ILC2s) seeding the developing lung. Hyperactivated ILC2s produced increased IL-5 and IL-13, and were associated with acute Th2 bias, eosinophilia, and decreased Tregs in the lung. The hyperactive ILC2 phenotype was recapitulated by adoptive transfer of a fetal liver precursor following exposure to prenatal inflammation, indicative of developmental programming. Programming of ILC2 function and subsequent lung immune remodeling by prenatal inflammation led to airway dysfunction at baseline and in response to papain, indicating increased asthma susceptibility. Our data provide a link by which developmental programming of progenitors by early-life inflammation drives lung immune remodeling and asthma susceptibility through hyperactivation of lung-resident ILC2s.

One Sentence Summary

Prenatal inflammation programs asthma susceptibility by inducing the production of hyperactivated ILC2s in the developing lung.
The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities
Authors: Zhang Xingyuan , Joseph Sayali , Wu Di , Bowser Jessica L. , Vaziri Cyrus
Published: November 2023

Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therapy-induced genotoxicity. Neoplastic cells also deploy mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA- based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC yet have distinct characteristics based on conventional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist.
Unexpected suppression of neural responses to natural foreground versus background sounds in auditory cortex
Authors: Hamersky Gregory R. , Shaheen Luke A. , Espejo Mateo López , Wingert Jereme C. , David Stephen V.
Published: November 2023

In everyday hearing, listeners encounter complex auditory scenes containing overlapping sounds that must be grouped into meaningful sources, or streamed, to be perceived accurately. A common example of this problem is the perception of a behaviorally relevant foreground stimulus (speech, vocalizations) in complex background noise (environmental, machine noise). Studies using a foreground/background contrast have shown that high-order areas of auditory cortex in humans pre-attentively form an enhanced representation of the foreground over background stimulus. Achieving this invariant foreground representation requires identifying and grouping the features that comprise the background noise so that they can be removed from the representation of the foreground. To study the cortical computations underlying representation of concurrent background (BG) and foreground (FG) stimuli, we recorded single unit responses in the auditory cortex (AC) of ferrets during presentation of natural sound excerpts from these two categories. In primary and secondary AC, we found overall suppression of responses when BGs and FGs were presented concurrently relative to the sum of responses to the same stimuli in isolation. Surprisingly, and in contrast to percepts that emphasize dynamic FGs, responses to FG sounds were suppressed relative to the paired BG sound. The degree of relative FG suppression could be explained by spectro-temporal statistics unique to each natural sound. Moreover, systematic degradation of the same spectro-temporal features decreased FG suppression as the sound categories became progressively less statistically distinct. The strongly suppressed representation of FG sounds in single units of AC in the presence of BG sound reveals a novel insight into how complex acoustic scenes are encoded at early stages of auditory processing.
Smell and Aftersmell: Fast Calcium Imaging Dynamics of Honey Bee Olfactory Coding
Authors: Paoli Marco , Wystrach Antoine , Ronsin Brice , Giurfa Martin
Published: November 2023

Odour processing exhibits multiple parallels between vertebrate and invertebrate olfactory systems. Insects, in particular, have emerged as relevant models for olfactory studies because of the tractability of their olfactory circuits. Here, we used fast calcium imaging to track the activity of projection neurons in the honey bee antennal lobe (AL) during olfactory stimulation at high temporal resolution. We observed a heterogeneity of response profiles and an abundance of inhibitory activities, resulting in various response latencies and stimulus- specific post-odour neural signatures. Recorded calcium signals were fed to a mushroom body (MB) model constructed implementing the fundamental features of connectivity between olfactory projection neurons, Kenyon cells (KC), and MB output neurons (MBON). The model accounts for the increase of odorant discrimination in the MB compared to the AL and reveals the recruitment of two distinct KC populations that represent odorants and their aftersmell as two separate but temporally coherent neural objects. Finally, we showed that the learning- induced modulation of KC-to-MBON synapses can explain both the variations in associative learning scores across different conditioning protocols used in bees and the bees’ response latency. Thus, it provides a simple explanation of how the time contingency between the stimulus and the reward can be encoded without the need for time tracking. This study broadens our understanding of olfactory coding and learning in honey bees. It demonstrates that a model based on simple MB connectivity rules and fed with real physiological data can explain fundamental aspects of odour processing and associative learning.
iLAM: imaging Locomotor Activity Monitor for circadian phenotyping of large-bodied flying insects
Authors: Dayton Jacob N. , Owens Avalon C.S.
Published: November 2023

Practical Tools

Historically, most insect chronoecological research has used direct observations, cameras, or infrared beam-based monitors to quantify movement across timed intervals. Although some alternative DIY systems are cheaper than the current standard locomotor activity monitor, these options remain complicated to build and/or computationally intensive.

We developed theimagingLocomotorActivityMonitor (iLAM), an affordable (∼ $75 USD/unit) system for activity quantification. The iLAM utilizes a Raspberry Pi Zero W computer and night-vision camera inside a flight cage to photograph a population of insects at user-defined intervals. Open-source, modular R-scripts process the images and output a file containing the number, size, coordinate location, and timing for all movements (blobs) identified between consecutive images. Output can be analyzed directly or converted into the standard TriKinetics DAM format.

We demonstrated the flexibility and power of the iLAM system by comparing diel and circadian activity of different insect species (fireflies:Photinus marginellus, P. greeni, P. obscurellus), ecotypes (moths:Ostrinia nubilalis), and sexes (moths:O. nubilalis). Data captured by only six iLAMs ($450) identified that peak activity ofO. nubilalisfemales (AZT: 19.2 hr) occurs significantly earlier than males (22.0 hr). Additionally, male moths from a univoltine population exhibited a significantly shorter endogenous period length (AZT: 21.3 hr) than males from a bivoltine genetic background (22.6 hr).

The iLAM will serve as a valuable tool for future researchers seeking to measure locomotor activity across diverse species, sexes, and populations in constant and changing environments.
Structure and mechanism of the human CTDNEP1-NEP1R1 membrane protein phosphatase complex necessary to maintain ER membrane morphology
Authors: Gao Shujuan , Rodríguez Jake W. Carrasquillo , Bahmanyar Shirin , Airola Michael V.
Published: November 2023

C-terminal Domain Nuclear Envelope Phosphatase 1 (CTDNEP1) is a non-canonical protein serine/threonine phosphatase that regulates ER membrane biogenesis. Inactivating mutations in CTDNEP1 correlate with development of medulloblastoma, an aggressive childhood cancer. The transmembrane protein Nuclear Envelope Phosphatase 1 Regulatory Subunit 1 (NEP1R1) binds CTDNEP1, but the molecular details by which NEP1R1 regulates CTDNEP1 function are unclear. Here, we find that knockdown of CTDNEP1 or NEP1R1 in human cells generate identical phenotypes, establishing CTDNEP1-NEP1R1 as an evolutionarily conserved membrane protein phosphatase complex that restricts ER expansion. Mechanistically, NEP1R1 acts as an activating regulatory subunit that directly binds and increases the phosphatase activity of CTDNEP1. By defining a minimal NEP1R1 domain sufficient to activate CTDNEP1, we determine high resolution crystal structures of the CTDNEP1-NEP1R1 complex bound to a pseudo-substrate. Structurally, NEP1R1 engages CTDNEP1 at a site distant from the active site to stabilize and allosterically activate CTDNEP1. Substrate recognition is facilitated by a conserved Arg residue that binds and orients the substrate peptide in the active site. Together, this reveals mechanisms for how NEP1R1 regulates CTDNEP1 and explains how cancer-associated mutations inactivate CTDNEP1.
Impact of customers' needs on online information search of upscale restaurant attributes and customer satisfaction
Authors: Lo Siu-Kam Jamie , Tavitiyaman Pimtong , Tsang Wing-Sze Lancy
Published: November 2023

Purpose

This research investigates the effects of consumers' online information searching on their dining satisfaction in upscale restaurants during the pandemic. Customers frequently rely on online sources to gather information about upscale restaurants prior to their visits.

Design/methodology/approach

Data from 307 diners across the top ten popular upscale restaurants in Hong Kong were analysed by using SEM to explore the links between customers' needs, information search, restaurant attributes and customer satisfaction.

Findings

This study uncovers customers' online search behaviours and identifies restaurant attributes that are associated with customer satisfaction, which were not typically emphasised before the COVID-19 pandemic. Driven by their social and psychological needs, customers devoted more time to reading written comments by other consumers compared to visual images or self-descriptions from restaurants. Only service attribute significantly influenced customer satisfaction, while food and price attributes were not significant.

Research limitations/implications

The findings of this study provide valuable insights for researchers and practitioners, shedding light on the altered needs and preferences of consumers following the unprecedented health crisis.

Originality/value

This study contributes to the development of expectancy disconfirmation theory and needs theory through the investigation of consumers' online information searching behaviours and dining satisfaction in upscale restaurants during the pandemic. By identifying the most important attributes influencing customer satisfaction, this research can aid upscale restaurants in developing effective marketing strategies and enhancing customer experiences.
Is a critical mass of women always enough to improve firm performance? The importance of the institutional context
Authors: Zaccone Maria Cristina , Argiolas Alessia
Published: November 2023

Purpose

This paper aims to present a comprehensive theoretical framework that seeks to explore the impact of cultural, legal and social factors within the external environment on the relationship between women on corporate boards and firm performance. By investigating these boundary conditions, the paper aims to shed light on how these pressures influence the aforementioned relationship.

Design/methodology/approach

To build the sample of companies, the authors selected companies listed on the stock exchanges of countries that represent a diverse range of institutional contexts. These contexts encompass countries with individualistic cultures, collectivist cultures, environments with mandatory gender quotas, environments without gender quotas, contexts with substantial progress toward gender equality and contexts with limited progress in achieving gender equality. To test the hypotheses, the authors used linear regression analysis as a primary analytical approach. Furthermore, they used the propensity score matching technique to address potential issues of reverse causality and unobserved heterogeneity.

Findings

The findings indicate that the positive influence of a critical mass of women on corporate boards on firm performance is contingent upon the institutional context. Specifically, the authors observed that this relationship is strengthened in institutional contexts characterized by an individualistic culture, whereas it is not as pronounced in collectivist cultural contexts. Furthermore, this research provides compelling evidence that the presence of a critical mass of women on boards leads to enhanced firm performance in institutional settings where gender quotas are not binding, as opposed to settings where such quotas are enforced. Lastly, the results demonstrate that the presence of a critical mass of women on boards is associated with improved firm performance in institutional settings characterized by low progress in achieving gender equality. However, the authors did not observe the same effect in institutional contexts that have made significant strides toward gender equality.

Originality/value

This research offers a unique perspective by investigating the relationship between women’s presence on corporate boards and firm performance across different institutional contexts. In this investigation, the authors recognize that gender diversity on corporate boards is not a one-size-fits-all solution and that its effects can be shaped by the unique institutional contexts in which companies operate.