bluuebunny/crossref_metadata_2025 huggingface dataset:
A deep-learning workflow to predict upper tract urothelial cancer subtypes supporting the prioritization of patients for molecular testing
Authors: Angeloni Miriam , Doeveren Thomas van , Lindner Sebastian , Volland Patrick , Schmelmer Jorina , Foersch Sebastian , Matek Christian , Stoehr Robert , Geppert Carol I. , Heers Hendrik , Wach Sven , Taubert Helge , Sikic Danijel , Wullich Bernd , van Leenders Geert J. L. H. , Zaburdaev Vasily , Eckstein Markus , Hartmann Arndt , Boormans Joost L. , Ferrazzi Fulvia , Bahlinger Veronika
Published: June 2023

Background

Urothelial carcinoma of the bladder (UBC) comprises several molecular subtypes, which are associated with different targetable therapeutic options. However, if and how these associations extend to the rare upper tract urothelial carcinoma (UTUC) remains unclear.

Objective

Identifying UTUC protein-based subtypes and developing a deep-learning (DL) workflow to predict these subtypes directly from histopathological H&E slides.

Design, Setting, and Participants

Subtypes in a retrospective cohort of 163 invasive samples were assigned on the basis of the immunohistochemical expression of three luminal (FOXA1, GATA3, CK20) and three basal (CD44, CK5, CK14) markers. DL model building relied on a transfer-learning approach.

Outcome Measurements and Statistical Analysis

Classification performance was measured via repeated cross-validation, including assessment of the area under the receiver operating characteristic (AUROC). The association of the predicted subtypes with histological features, PD-L1 status, andFGFR3mutation was investigated.

Results and Limitations

Distinctive luminal and basal subtypes were identified and could be successfully predicted by the DL (AUROC 95thCI: 0.62-0.99). Predictions showed morphology as well as presence ofFGFR3-mutations and PD-L1 positivity that were consistent with the predicted subtype. Testing of the DL model on an independent cohort highlighted the importance to accommodate histological subtypes.

Conclusions

Our DL workflow is able to predict protein-based UTUC subtypes directly from H&E slides. Furthermore, the predicted subtypes associate with the presence of targetable genetic alterations.

Patient Summary

UTUC is an aggressive, yet understudied, disease. Here, we present an artificial intelligence algorithm that can predict UTUC subtypes directly from routine histopathological slides and support the identification of patients that may benefit from targeted therapy.
“Non-Invasive Imaging Modalities in Coronary Artery Disease:A meta analysiscomparingCCTAandStandard of Care (SOC)”
Authors: Dani Avichal , Shah Pari , Desai Dev
Published: June 2023

Introduction

Coronary Artery Disease has become a global pandemic and a major cause of death especially among Older population. The risk factor calculation or the degree of Coronary artery damage is usually an invasive procedure. A paradigm change has occurred in the last ten years regarding the assessment of coronary artery disease (CAD) utilising coronary computed tomography angiography (CCTA).

Aims and Objectives

To Comapre CCTA with Standard Care to calculate the need of revascularization, invasive coronary angiography as well as to compare both for MI and All cause mortality

Results

CCTA was found to be associated with a significant increase in revascularizations (RR =1.401, 95% CI =1.315-1.492, p<0.001) as well as invasive coronary angiography procedures (RR =1.304, 95% CI =1.208-1.409, p<0.001). However, it was associated with decreased incidences of MI (RR =0.752, 95% CI =0.578-1.409, p<0.033). There was no significant association with all-cause mortality.

Conclusion

CCTA is significantly correlated with a reduction in MI episodes and an increase in revascularizations and ICA procedures. However, it was found that it had no effect on all-cause mortality. On the contrary, standard care approaches were associated with greater rates of MI but lesser referrals for invasive coronary angiography and revascularization.
Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases
Authors: Wójcik Magdalena , Juhas Ulana , Mohammadi Elyas , Mattisson Jonas , Drężek-Chyła Kinga , Rychlicka-Buniowska Edyta , Bruhn-Olszewska Bożena , Davies Hanna , Chojnowska Katarzyna , Olszewski Paweł , Bieńkowski Michał , Jankowski Michał , Rostkowska Olga , Hellmann Andrzej , Pęksa Rafał , Kowalski Jacek , Zdrenka Marek , Kobiela Jarek , Zegarski Wojciech , Biernat Wojciech , Szylberg Łukasz , Remiszewski Piotr , Mieczkowski Jakub , Filipowicz Natalia , Dumanski Jan P.
Published: June 2023

Male sex is a risk factor for colorectal cancer (CRC) with higher illness burden and earlier onset. Thus, we hypothesized that loss of chromosome Y (LOY) in the tumor micro-environment (TME) might be involved in oncogenesis. Previous studies show that LOY in circulating leukocytes of aging men was associated with shorter survival and non-hematological cancer, as well as higher LOY in CD4+ T-lymphocytes in men with prostate cancer vs. controls. However, nothing is known about LOY in leukocytes infiltrating TME and we address this aspect here. We studied frequency and functional effects of LOY in blood, TME and non-tumorous tissue. Regulatory T-lymphocytes (Tregs) in TME had the highest frequency of LOY-cells (22%) in comparison to CD4+ T-lymphocytes and cytotoxic CD8+ T-lymphocytes. Using scRNA-seq LOY was also linked to higher expression ofPDCD1, TIGITandIKZF2in Tregs.PDCD1andTIGITencode immune checkpoint receptors involved in the regulation of Tregs function. Our study sets the direction for further functional research regarding a probable role of LOY in intensifying features related to the suppressive phenotype of Tregs in TME and consequently a possible influence on immunotherapy response in CRC patients.
Light-exercise-induced dopaminergic and noradrenergic stimulation in the dorsal hippocampus: using a rat physiological exercise model
Authors: Hiraga Taichi , Hata Toshiaki , Soya Shingo , Shimoda Ryo , Takahashi Kanako , Soya Mariko , Inoue Koshiro , Johansen Joshua P. , Okamoto Masahiro , Soya Hideaki
Published: June 2023

Exercise activates the dorsal hippocampus, which triggers the synaptic and cellar plasticity and ultimately promotes memory formation. For decades, these benefits have been explored using demanding and stress-response-inducing exercise at moderate-to-vigorous intensities. In contrast, our translational research with animals and humans has focused on light exercise below the lactate threshold (LT), which almost anyone can safely perform with minimal stress, and found that even light exercise can stimulate hippocampal activity and enhance memory performance. Although the circuit mechanism of this boost remains unclear, arousal promotion even with light exercise implies the involvement of the ascending monoaminergic system, which is essential to modulate hippocampal activity and impact memory. To examine this hypothesis, we employed our physiological exercise model based on the LT of rats that can be applied to human and immunohistochemically assessed the neuronal activation of the dorsal hippocampal sub-regions and brainstem monoaminergic neurons. Also, we monitored the dynamics of monoamine release at the dorsal hippocampus usingin vivomicrodialysis. We found that even light exercise increased neuronal activity in the dorsal hippocampal sub-regions and induced noradrenaline and dopamine release. Furthermore, we found that tyrosine hydroxylase-positive neurons in the locus coeruleus (LC) and the ventral tegmental area (VTA) were activated even by light exercise and were both positively correlated with the dorsal hippocampal activation. In conclusion, our findings demonstrate that light exercise stimulates hippocampal neurons, possibly through the LC-noradrenergic and/or VTA-dopaminergic neurons. This sheds light on the circuit mechanisms responsible for hippocampal neural activation during exercise, consequently enhancing memory function.

Graphical abstract

Our previous research with animals and humans has demonstrated that even light exercise can boost neuronal activity in the dorsal hippocampus and improve memory. While the mechanism underlying this remains undetermined, recent studies suggest the involvement of the ascending monoaminergic system. Here, we examined this hypothesis and found a possible contribution of noradrenergic neurons in the locus coeruleus and dopaminergic neurons in the ventral tegmental area to dorsal hippocampal activation during light exercise, implying a circuit mechanism for light-exercise-enhanced memory.
Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes
Authors: Milenkovic Dusanka , Misic Jelena , Hevler Johannes F , Molinié Thibaut , Chung Injae , Atanassov Ilian , Li Xinping , Filograna Roberta , Mesaros Andrea , Mourier Arnaud , Heck Albert J R , Hirst Judy , Larsson Nils-Göran
Published: June 2023

The mammalian respiratory chain complexes I, III2and IV (CI, CIII2and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI- CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate thein vivorole of the respirasome, we generated homozygous knock-in mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in the mouse, but raises questions about their alternate functions, such as relating to regulation of protein stability and prevention of age-associated protein aggregation.
Robust axis elongation by Nodal-dependent restriction of BMP signaling
Authors: Schauer Alexandra , Pranjic-Ferscha Kornelija , Hauschild Robert , Heisenberg Carl-Philipp
Published: June 2023

Embryogenesis is brought about by the coordinated activities of different signaling pathways controlling cell fate specification and morphogenesis. In vertebrate gastrulation, both Nodal and BMP signaling play key roles in germ layer specification and morphogenesis, yet their interplay to coordinate embryo patterning with morphogenesis is still insufficiently understood. Here, we took a reductionist approach using zebrafish embryonic explants to study the coordination of Nodal and BMP signaling for embryo patterning and morphogenesis. We show that Nodal signaling not only triggers explant elongation by inducing mesendodermal progenitors but also by suppressing BMP signaling activity at the site of mesendoderm induction. Ectopic BMP signaling in the mesendoderm blocks cell alignment and oriented mesendoderm intercalations, key processes to drive explant elongation. Translating theseex vivoobservations to the intact zebrafish embryo showed that, similar to explants, Nodal signaling renders the dorsal domain less sensitive towards BMP signaling to allow effective cell intercalations and thus robust embryonic axis elongation. These findings suggest a dual function of Nodal signaling in embryonic axis elongation by both inducing mesendoderm and maintaining low levels of BMP signaling activity in the dorsal portion of the mesendoderm.
Androgen exposure impairs neutrophil maturation and function within the infected kidney
Authors: Hreha Teri N. , Collins Christina A. , Hunstad David A.
Published: June 2023

Urinary tract infections (UTIs) in men are uncommon but carry increased risk for severe pyelonephritis and other complications. In models ofEscherichia coliUTI, male C3H/HeN mice uniformly develop high-titer pyelonephritis (most with renal abscesses) in a testosterone-dependent manner, but the mechanisms underlying this phenotype are unknown. Here, using female mouse models, we show that androgen exposure impairs neutrophil maturation in the upper and lower urinary tract, compounded by an additional reduction of neutrophil function specifically within the infected kidney, enabling persistent high-titer infection and promoting abscess formation. Following intravesical inoculation with uropathogenicE. coli(UPEC), kidneys of androgen-exposed C3H mice showed delayed local pro-inflammatory cytokine responses while robustly recruiting neutrophils. These were enriched for an end-organ-specific population of aged but immature neutrophils (CD49d+, CD101–). Compared to their mature counterparts, these aged immature kidney neutrophils exhibited reduced functionsin vitro, including impaired degranulation and diminished phagocytic activity, while splenic, bone marrow, and bladder neutrophils did not display these alterations. Further, aged immature neutrophils exhibited little phagocytic activity within intratubular UPEC communitiesin vivo. Experiments with B6 conditional androgen receptor (AR)-deficient mice indicated rescue of the maturation defect when AR was deleted in myeloid cells. We conclude that the recognized enhancement of UTI severity by androgens reflects urinary tract-specific impairment of neutrophil maturation (largely via cell-intrinsic AR signaling) and kidney-specific reduction in neutrophil antimicrobial capacity, resulting in failure to control renal bacterial infection.
Unraveling the Genomic Diversity and Admixture History of Captive Tigers in the United States
Authors: Armstrong Ellie E. , Mooney Jazlyn A. , Solari Katherine A. , Kim Bernard Y. , Barsh Gregory S. , Grant Victoria B. , Greenbaum Gili , Kaelin Christopher B. , Panchenko Katya , Pickrell Joseph K. , Rosenberg Noah , Ryder Oliver A. , Yokoyama Tsuya , Ramakrishnan Uma , Petrov Dmitri A. , Hadly Elizabeth A.
Published: June 2023

Genomic studies of rare and endangered species have focused broadly on describing diversity patterns and resolving phylogenetic relationships, with the overarching goal of informing conservation efforts. However, few studies have investigated the genomic diversity potentially housed in captive populations. For tigers (Panthera tigris) in particular, captive individuals vastly outnumber those in the wild, yet the diversity of the captive population remains largely unexplored. Here, we present the first large-scale genetic study of the private (non-zoo) captive tiger population in the United States (U.S.), also known as ‘Generic’ tigers. We find that the U.S. Generic tiger population has an admixture fingerprint comprising all six extant wild tiger subspecies (P. t. altaica, Amur;P. t. tigris, Bengal;P. t. corbetti, Indochinese;P. t. jacksoni, Malayan;P. t. amoyensis, South China;P. t. sumatrae, Sumatran). We show that the Generic tiger population has a comparable amount of genetic diversity to most wild subspecies, relatively few private variants, and fewer deleterious mutations. We also observe inbreeding coefficients that are similar to wild populations, suggesting that inbreeding in captive populations is not pervasive, although there are some individuals within the Generic population that are substantially inbred. Our results elucidate the admixture history of the Generic tiger population in the U.S. Additionally, we develop a reference panel for tigers and show that it can be used with imputation to accurately distinguish individuals and assign ancestry even with ultra-low coverage (0.25×) data. The study and reference panel will provide a resource to assist in tiger conservation efforts.
Astrocyte Ca2+signalling mediates long-distance metaplasticity in the hippocampal CA1
Authors: Jones Owen D. , Singh Anurag , Logan Barbara J. , Abraham Wickliffe C.
Published: June 2023

Astrocytes play an increasingly recognised role in regulating synaptic plasticity, but their contribution to metaplasticity is poorly understood. We have previously described a long-distance form of metaplasticity whereby priming stimulation in stratum oriens inhibits subsequent LTP in the neighbouring stratum radiatum of the hippocampal CA1 region of both rats and mice. Using genetic and pharmacological strategies to manipulate astrocytic Ca2+signalling, we now show this form of metaplasticity requires inositol triphosphate receptor-dependent Ca2+release in these cells. Blocking Ca2+signalling or inositol triphosphate receptors in single radiatum astrocytes abolishes the metaplasticity at nearby synapses. We also show the relevant Ca2+release in astrocytes is driven by adenosine A2Breceptors, and stimulation of these receptors elicits the metaplasticity effect bothin vitroandin vivo. Further, the metaplasticity requires signalling via tumor necrosis factor, but this cytokine is required to act on astrocytes, not neurons. Instead, glutamate, acting on GluN2B-containing NMDA receptors, is the likely gliotransmitter that signals to neurons to inhibit LTP. Together these data reveal a novel role for astrocytes in hippocampal LTP regulation across broader spatiotemporal scales than previously recognised.

Main points

In hippocampal CA1, “priming” activity inhibits subsequent LTP at synapses hundreds of microns away.

This effect requires astrocytic Ca2+signaling, and a molecular cascade involving adenosine A2Breceptors, tumor necrosis factor and GluN2B-containing NMDA receptors.

The metaplasticity effect is evidentin vitroandin vivo.

Long-distance astrocyte signaling is a mechanism for regulating neural activity over broad spatiotemporal scales.
Uncovering the association mechanism between two intrinsically flexible proteins
Authors: Dávalos Angy L. , Rivera José D. , Favaro Denize C. , Oliveira Ronaldo J. , Carretero Gustavo PB. , Lacerda Caroline D. , Cuccovia Iolanda M. , Cardoso Marcus V. C. , Farah Chuck S. , Salinas Roberto K.
Published: June 2023

The understanding of protein-protein interaction mechanisms is key to the atomistic description of cell signalling pathways and for the development of new drugs. In this context, the mechanism of intrinsically disordered proteins folding upon binding has attracted attention. The VirB9 C-terminal domain (VirB9Ct) and the VirB7 N-terminal motif (VirB7Nt) associate with VirB10 to form the outer membrane core complex of the Type IV Secretion System injectisome. Despite forming a stable and rigid complex, VirB7Ntbehaves as a random coil while VirB9Ctis intrinsically dynamic in the free state. Here we combined NMR, stopped-flow fluorescence and computer simulations using structure-based models to characterize the VirB9Ct-VirB7Ntcoupled folding and binding mechanism. Our data indicated that VirB9Ctbinds to VirB7Ntby way of a conformational selection mechanism. However, at higher temperatures energy barriers between different VirB9Ctconformations are more easily surpassed. Under these conditions the formation of non-native initial encounter complexes may not be neglected, providing alternative pathways towards the native complex conformation. These observations highlight the intimate relationship between folding and binding, calling attention to the fact that the two molecular partners must search for the most favored intramolecular and intermolecular interactions on a rugged and funnelled conformational energy landscape, along which multiple intermediates may lead to the final native state.
Pharmacokinetic profile of the synthetic mu-opioid receptor agonist [Lys7]Dermorphin-IRDye®800CW and its feasibility as a biomarker for opioid use disorder
Authors: Samkoe Kimberley S. , Strawbridge Rendall R. , Spaller Mark R. , Pletnev Alexandre A. , Wirth Dennis J. , Byrd Brook K. , Meng Boyu , Sottosanti J. Scott , Davis Scott C. , Elliott Jonathan T.
Published: June 2023

Background

Opioid use disorder (OUD) affects more than 14 million Americans and poses a high risk of relapse, overdose, and death. Current treatments are not tailored to individual needs and do not monitor the effectiveness of the medication. We propose a novel method to measure the occupancy of mu opioid receptors (MOR), which are key targets for opioid pharmacotherapy, in peripheral tissues with high MOR density. We developed a fluorescent peptide agonist that binds to MOR and can be detected by non-invasive point-of-care techniques. We presentin vitroandin vivoresults that demonstrate the feasibility and potential of this method to assess MOR availability and treatment efficacy in OUD patients.

Methods

A new fluorescent-labeled synthetic peptide agonist [Lys7]Dermorphin-IRDye800CW, called DRM-800, was synthesized and characterizedin vitroto evaluate binding and internalization. Wildtype and MOR knock-out mice were used to quantify plasma kinetics and, using a cyromacrotome, fluorescence images were acquired post-mortem on whole-body sections 150 um apart. These volumes were used to comparein vivoenhancement of MOR-rich structures.

Results

In vitro assays and microscope visualization of DRM-800 showed high MOR-affinity and rapid, robust internalization. Plasma half-life following intravenous injection in mice was 8-12 minutes. Specific binding by tissue structures of interest, measured by the ratio of relative fluorescent units in wild-type vs. MOR knockout mice showed high binding in dorsal root ganglia, spiral ganglia and trigeminal ganglion, as well as in the small and large intestine.

Conclusions

The pharmacokinetics and distribution, binding kinetics and rapid internalization suggests that MOR-specific fluorescence enhancement corresponding to opioid rich structures could serve as a potential biomarker in opioid use disorder.
Can higher-order interactions resolve the species coexistence paradox?
Authors: Gibbs Theo , Gellner Gabriel , Levin Simon A. , McCann Kevin S. , Hastings Alan , Levine Jonathan M.
Published: June 2023

Most ecological models are based on the assumption that species interact in pairs. Emerging in diverse communities, however, are higher-order interactions, in which two or more species jointly impact the growth of a third species. A pitfall of the pairwise approach is that it misses the higher-order interactions potentially responsible for maintaining diversity in nature. Here, we explore how well higher-order interactions enable coexistence when pairwise interactions are insufficient to do so. Specifically, we explore the stability properties of systems where higher-order interactions guarantee that a specified set of abundances are a feasible equilibrium of the dynamics. Even these higher-order interactions do not necessarily produce robust coexistence. We find that facilitative higher-order interactions that counter pairwise competitive interactions are less likely to generate stable equilibria than competitive interactions countering pairwise facilitation. In both cases the system is more likely to be stable when the pairwise interactions are weak, and when the equilibrium abundances are near those produced by the pairwise interactions. Last, we show that correlations between the pairwise and higher-order interactions permit robust coexistence in diverse systems. Our work reveals the challenges in generating stable coexistence through higher-order interactions, but also uncovers higher-order interaction patterns that can enable diversity.
Current sampling and sequencing biases of Lassa mammarenavirus limit inference from phylogeography and molecular epidemiology in Lassa Fever endemic regions
Authors: Arruda Liã Bárbara , Free Hayley Beth , Simons David , Ansumana Rashid , Elton Linzy , Haider Najmul , Honeyborne Isobella , Asogun Danny , McHugh Timothy D , Ntoumi Francine , Zumla Alimuddin , Kock Richard
Published: June 2023

Lassa fever (LF) is a potentially lethal viral haemorrhagic infection of humans caused byLassa mammarenavirus(LASV). It is an important endemic zoonotic disease in West Africa with growing evidence for increasing frequency and sizes of outbreaks. Phylogeographic and molecular epidemiology methods have projected expansion of the Lassa fever endemic zone in the context of future global change. The Natal multimammate mouse (Mastomys natalensis) is the predominant LASV reservoir, with few studies investigating the role of other animal species. To explore host sequencing biases, all LASV nucleotide sequences and associated metadata available on GenBank (n = 2,298) were retrieved. Most data originated from Nigeria (54%), Guinea (20%) and Sierra Leone (14%). Data from non-human hosts (n = 703) were limited and only 69 sequences encompassed complete genes. We found a strong positive correlation between the number of confirmed human cases and sequences at the country level (r= 0.93 (95% Confidence Interval = 0.71 - 0.98),p< 0.001) but no correlation exists between confirmed cases and the number of available rodent sequences (r= -0.019 (95% C.I. -0.71 - 0.69),p =0.96). Spatial modelling of sequencing effort highlighted current biases in locations of available sequences, with increased effort observed in Southern Guinea and Southern Nigeria. Phylogenetic analyses showed geographic clustering of LASV lineages, suggestive of isolated events of human-to-rodent transmission and the emergence of currently circulating strains of LASV from the year 1498 in Nigeria. Overall, the current study highlights significant geographic limitations in LASV surveillance, particularly, in non-human hosts. Further investigation of the non-human reservoir of LASV, alongside expanded surveillance, are required for precise characterisation of the emergence and dispersal of LASV. Accurate surveillance of LASV circulation in non-human hosts is vital to guide early detection and initiation of public health interventions for future Lassa fever outbreaks.
CLOCI:Unveiling cryptic gene clusters with generalized detection
Authors: Konkel Zachary , Kubatko Laura , Slot Jason C.
Published: June 2023

Gene clusters are genomic loci that contain multiple genes that are functionally and genetically linked. Gene clusters collectively encode diverse functions, including small molecule biosynthesis, nutrient assimilation, metabolite degradation, and production of proteins essential for growth and development. Identifying gene clusters is a powerful tool for small molecule discovery and provides insight into the ecology and evolution of organisms. Current detection algorithms focus on canonical “core” biosynthetic functions many gene clusters encode, while overlooking uncommon or unknown cluster classes. These overlooked clusters are a potential source of novel natural products and comprise an untold portion of overall gene cluster repertoires. Unbiased,function-agnosticdetection algorithms therefore provide an opportunity to reveal novel classes of gene clusters and more precisely define genome organization. We presentCLOCI(Co-occurrence Locus and Orthologous Cluster Identifier), an algorithm that identifies gene clusters using multiple proxies of selection for coordinated gene evolution. Our approach generalizes gene cluster detection and gene cluster family circumscription, improves detection of multiple known functional classes, and unveils noncanonical gene clusters.CLOCIis suitable for genome-enabled small molecule mining, and presents an easily tunable approach for delineating gene cluster families and homologous loci.
Phantom oscillations in principal component analysis
Authors: Shinn Maxwell
Published: June 2023

Principal component analysis (PCA) is a dimensionality reduction technique that is known for being simple and easy to interpret. Principal components are often interpreted as low-dimensional patterns in high-dimensional data. However, this simple interpretation of PCA relies on several unstated assumptions that are difficult to satisfy. When these assumptions are violated, non-oscillatory data may have oscillatory principal components. Here, we show that two common properties of data violate these assumptions and cause oscillatory principal components: smooth-ness, and shifts in time or space. These two properties implicate almost all neuroscience data. We show how the oscillations that they produce, which we call “phantom oscillations”, impact data analysis. We also show that traditional cross-validation does not detect phantom oscillations, so we suggest procedures that do. Our findings are supported by a collection of mathematical proofs. Collectively, our work demonstrates that patterns which emerge from high-dimensional data analysis may not faithfully represent the underlying data.
The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults
Authors: Nakhe Arya Y , Dadi Prasanna K , Kim Jinsun , Dickerson Matthew T. , Behera Soma , Dobson Jordyn R. , Shrestha Shristi , Cartailler Jean-Philippe , Sampson Leesa , Magnuson Mark A , Jacobson David A
Published: June 2023

The gain–of–function mutation in the TALK–1 K+channel (p.L114P) is associated with maturity–onset diabetes of the young (MODY). TALK–1 is a key regulator of β–cell electrical activity and glucose–stimulated insulin secretion (GSIS). TheKCNK16gene encoding TALK–1, is the most abundant and β-cell–restricted K+channel transcript. To investigate the impact ofKCNK16L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing theKcnk16L114P mutation was generated. Heterozygous and homozygousKcnk16L114P mice exhibit increased neonatal lethality in the C57BL/6J and the mixed C57BL/6J:CD–1(ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygousKcnk16L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment.Kcnk16L114P increased whole–cell β-cell K+currents resulting in blunted glucose-stimulated Ca2+entry and loss of glucose-induced Ca2+oscillations. Thus, adultKcnk16L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impaired glucose homeostasis. Taken together, this study shows that the MODY–associatedKcnk16L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet hormone secretion during development. These data strongly suggest that TALK–1 is an islet–restricted target for the treatment of diabetes.
Integration of eQTL and Machine Learning Methods to Dissect Causal Genes with Pleiotropic effects in Genetic Regulation Networks of Seed Cotton Yield
Authors: Zhao Ting , Wu Hongyu , Wang Xutong , Zhao Yongyan , Wang Luyao , Pan Jiaying , Mei Huan , Han Jin , Wang Siyuan , Lu Kening , Li Menglin , Gao Mengtao , Cao Zeyi , Zhang Hailin , Wan Ke , Li Jie , Zhang Tianzhen , Guan Xueying
Published: June 2023

Expression quantitative trait loci (eQTL) provide a powerful means of investigating the biological basis of genome-wide association study (GWAS) results and exploring complex traits or phenotypes. In addition to identifying the causal gene incis, eQTL analysis also reveals a large number of trans-regulated genes located on different chromosomes, which form a gene regulatory network (GRN) that complements the GWAS locus. However, the dissection of a GRN and the crosstalk underlying multiple agronomical traits, along with prioritizing important genes in eQTL-derived GRNs, remains a major challenge. In this study, we generated 558 transcriptional profiles of lint-bearing ovules at one day post-anthesis (DPA) from a selective core cotton germplasm, from which we identified 12,207 eQTLs. By integrating with a GWAS catalog, we found that 66 out of 187 (35.29%) known phenotypic GWAS loci are colocalized with 1,090 eQTLs, forming 38 major functional GRNs predominantly (30 out of 38) associated with seed size-related phenotypes. Of the eGenes, 34 were shared between at least two functional GRNs, exhibiting pleiotropic effects, such asNF-YB3,GRDP1, andIDD7. Narrow-sense heritability analysis showed that the heritability increased with combining the eQTLs with GRNs compared to those with previous yield trait GWAS loci. The extreme gradient boosting (XGBoost) machine learning approach was then applied to predict seed cotton yield phenotypes based on gene expression. Top-ranking eGenes (NF-YB3,FLA2, andGRDP1) derived by XGBoost with pleiotropic effects on yield traits were validated, along with their potential roles by correlation analysis, domestication selection analysis, and transgenic plants. This study provides insights into the mining of GRNs in relation to the pleiotropy of phenotype. The combination of eQTL and machine learning approaches is efficient in improving the genetic dissection of agricultural traits.
Group or solitary dispersal: worker presence and number favour the success of colony foundation in ants
Authors: Finand Basile , Loeuille Nicolas , Bocquet Céline , Fédérici Pierre , Monnin Thibaud
Published: June 2023

Dispersal strategies are highly variable. Any strategy is associated to costs and benefits, and understanding which factors favour or disfavour a strategy is a key issue in ecology and evolution. Ants exhibit different dispersal and colony foundation strategies. Some species have winged queens that disperse solitarily and far by flight, and that found new colonies alone. Others have apterous queens that disperse with workers over short walking distances, and found new colonies as a group (colony fission). The putative benefits conferred by workers have been little studied and quantified, because comparing the costs and benefits of solitary vs. group dispersal and foundation is difficult when comparing different species. We did this using the antMyrmecina graminicola, one of the few species that use both strategies. Young queens were mated and allowed to found new colonies in the laboratory, with either zero, two or four workers. We monitored the survival and growth of foundations over one year. The presence of workers increased both survival and growth, with more workers yielding higher growth. These results show the benefit of dispersing and founding in a group. The presence of few workers (as little as two workers) was sufficient to provide benefits, suggesting group foundation does not require a dramatic decrease in the number of propagules produced inM. graminicola. Our results support the hypothesis that the two strategies coexist along a competition-colonization trade-off, where solitary foundation offers a colonization advantage while group foundation has a competitive advantage.
Opportunistic bacteria of grapevine crown galls are equipped with the genomic repertoire for opine utilization
Authors: Faist Hanna , Ankenbrand Markus J. , Sickel Wiebke , Hentschel Ute , Keller Alexander , Deeken Rosalia
Published: June 2023

Young grapevines (Vitis vinifera) suffer and eventually can die from the crown gall (CG) disease caused by the plant pathogenAllorhizobium vitis (Rhizobiaceae). Virulent members ofA. vitisharbour a tumor-inducing (Ti) plasmid and induce formation of crown galls (CGs) due to the oncogenes encoded on the transfer-DNA (T-DNA). Expression of oncogenes in transformed host cells induce unregulated cell proliferation, metabolic and physiological changes. The CG produces opines uncommon to plants, which provide an important nutrient source forA. vitisharbouring opine catabolism enzymes. CGs host a distinct bacterial community and the mechanisms establishing a CG-specific bacterial community are currently unknown. Thus, we were interested in whether genes homologous to those of the Ti-plasmid coexist in the genomes of the microbial species coexisting in CGs.

We isolated eight bacterial strains from grapevine CGs, sequenced their genomes and tested their virulence and opine utilization ability in bioassays. In addition, the eight genome sequences were compared to 34 published bacterial genomes, including closely related plant associated bacteria not from CGs. Homologous genes for virulence and opine anabolism were only present in the virulent Rhizobiaceae. By contrast, homologs of the opine catabolism genes were present in all strains including the non-virulent members of the Rhizobiaceae and non-Rhizobiaceae. Gene neighbourhood and sequence identity of the opine degradation cluster of virulent and non-virulent strains together with the results of the opine utilization assay support the important role of opine utilization for co-colonization in CGs, thereby shaping the CG community.

Significance statement

VirulentAllorhizobium vitiscauses crown galls on grapevines which reduce plant vigour, yield, and cannot be cured. Non-virulent agrobacteria have been used as biocontrol agents to reduce the virulence potential within a crown gall and disease symptoms. We wanted to know if and how in nature this biocontrol concept is accomplished. We found virulentAllorhizobiumalong with non-virulentAgrobacterium, orPseudomonasin the same tumours. Both harboured the catabolism genes in their genomes and metabolized thequorum sensingmolecule opine. Thus, in nature it seems common that virulent and non-virulent species coexist in a crown gall and that the avirulent members control the virulence potential of the crown gall community by reducing the opine levels.
FSCN1 is critical for HNSCC
Authors: Wei Xin
Published: June 2023

Background

The study of molecular markers for diagnosis and prognosis is of great clinical significance for HNSCC patients. In this study, we proposed that FSCN1 has a potential indication for prognosis and is essential for the migration of HNSCC.

Methods

We analyzed the expression and survival association of FSCN1 in HNSCC using TCGA data. We compared the expression of FSCN1 in tumors from primary and metastasis HNSCC patients using QPCR, western blotting, and immunochemistry staining. We determined the migration velocity of multiple HNSCC cell lines using a chemotaxis migration assay. We analyzed the correlation between FSCN1 expression and HNSCC cell migration. We also test the effect of FSCN1 knockdown and overexpression on HNSCC cell migration.

Results

FSCN1 was overexpressed in HNSCC than pair normal tissues and metastasis HNSCC than primary HNSCC. FSCN1 expression was associated with significantly poorer overall survival of HNSCC patients. FSCN1 was potentially associated with immune cell infiltration and migration-associated genes. FSCN1 level was correlated with the migration in HNSCC cell lines. Knockdown of FSCN1 reduced the migration and the overexpression of FSCN1 promoted the migration of HNSCC cell lines.

Conclusion

FSCN1 is a potential prognostic marker and a critical biomolecule for the migration of HNSCC
Accommodation and wavelength: the effect of longitudinal chromatic aberration on the stimulus-response curve
Authors: Fernandez-Alonso Maydel , Finch Abigail P. , Love Gordon D. , Read Jenny C. A.
Published: June 2023

The longitudinal chromatic aberration (LCA) of the eye creates a chromatic blur on the retina that is an important cue for accommodation. While this mechanism can work optimally in broadband illuminants such as daylight, it is not clear how the system responds to the narrowband illuminants used by many modern displays. Here, we measured pupil and accommodative responses as well as visual acuity under narrowband LED illuminants of different peak wavelengths. Observers were able to accommodate under narrowband light and compensate for the LCA of the eye, with no difference in the variability of the steady-state accommodation response between narrowband and broadband illuminants. Intriguingly, our subjects compensated more fully for LCA at nearer distances. That is, the difference in accommodation to different wavelengths became larger when the object was placed nearer the observer, causing the slope of the accommodation response curve to become shallower for shorter wavelengths and steeper for longer ones. Within the accommodative range of observers, accommodative errors were small and visual acuity normal. When comparing between illuminants, when accommodation was accurate, visual acuity was worst for blue narrowband light. This cannot be due to the sparser spacing for S-cones, since our stimuli had equal luminance and thus activated M-cones roughly equally. It is likely because ocular LCA changes more rapidly at shorter wavelength, and so the finite spectral bandwidth of LEDs corresponds to a greater dioptric range at shorter wavelengths. This effect disappears for larger accommodative errors, due to the increased depth-of-focus of the eye.
The impact of ROI extraction method for MEG connectivity estimation: practical recommendations for the study of resting state data
Authors: Brkić Diandra , Sommariva Sara , Schuler Anna-Lisa , Pascarella Annalisa , Belardinelli Paolo , Isabella Silvia L. , Di Pino Giovanni , Zago Sara , Ferrazzi Giulio , Rasero Javier , Arcara Giorgio , Marinazzo Daniele , Pellegrino Giovanni
Published: June 2023

Magnetoencephalography and electroencephalography (M/EEG) seed-based connectivity analysis requires the extraction of measures from regions of interest (ROI). M/EEG ROI-derived source activity can be treated in different ways. It is possible, for instance, to average each ROI’s time series prior to calculating connectivity measures. Alternatively, one can compute connectivity maps for each element of the ROI prior to dimensionality reduction to obtain a single map. The impact of these different strategies on connectivity results is still unclear.

Here, we address this question within a large MEG resting state cohort (N=113) and within simulated data. We consider 68 ROIs (Desikan-Kiliany atlas), two measures of connectivity (phase locking value-PLV, and its imaginary counterpart- ciPLV), three frequency bands (theta 4-8 Hz, alpha 9-12 Hz, beta 15-30 Hz). We compare four extraction methods: (i) mean, or (ii) PCA of the activity within the seed or ROIbeforecomputing connectivity, map of the (iii) average, or (iv) maximum connectivityaftercomputing connectivity for each element of the seed. Hierarchical clustering in then applied to compare connectivity outputs across multiple strategies, followed by direct contrasts across extraction methods. Finally, the results are validated by using a set of realistic simulations.

We show that ROI-based connectivity maps vary remarkably across strategies in terms of connectivity magnitude and spatial distribution. Dimensionality reduction procedures conductedaftercomputing connectivity are more similar to each-other, while PCA before approach is the most dissimilar to other approaches. Although differences across methods are consistent across frequency bands, they are influenced by the connectivity metric and ROI size. Greater differences were observed for ciPLV than PLV, and in larger ROIs. Realistic simulations confirmed thatafteraggregation procedures are generally more accurate but have lower specificity (higher rate of false positive connections). Though computationally demanding,afterdimensionality reduction strategies should be preferred when higher sensitivity is desired. Given the remarkable differences across aggregation procedures, caution is warranted in comparing results across studies applying different methods.
SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome
Authors: Stamenkovic Vera , Lautz Jonathan D. , Harsh Felicia M. , Smith Stephen E.P.
Published: June 2023

Glutamatergic synapses encode information from extracellular inputs using dynamic protein interaction networks (PINs) that undergo widespread reorganization following synaptic activity, allowing cells to distinguish between signaling inputs and generate coordinated cellular responses. Here, we investigated how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN. In cultured cortical neurons or acute cortical slices from P7, P17 and P60 FMR1-/ymice, the unstimulated protein interaction networks state resembled that of wildtype littermates stimulated with neurotransmitter agonists, demonstrating resting state pre-activation of signaling networks. We identified the Src family kinase (SFK) Fyn as a network hub, because many interactions involving Fyn were pre-activated. We tested whether targeting Fyn in FMR1-/ymice could modify disease phenotypes, and found that Saracatinib (AZD-0530), an SFK inhibitor, normalized elevated basal protein synthesis, novel object recognition memory and social behavior in FMR1-/ymice. However, SCB treatment did not normalize the PIN to a wild-type-like statein vitroorin vivo, but rather induced extensive changes to protein complexes containing Shank3, NMDARs and Fyn. We conclude that targeting abnormal nodes of a PIN can identify potential disease-modifying drugs, but behavioral rescue does not correlate with PIN normalization.
Architecture of the vertebrate egg coat and structural basis of the ZP2 block to polyspermy
Authors: Nishio Shunsuke , Emori Chihiro , Wiseman Benjamin , Fahrenkamp Dirk , Dioguardi Elisa , Zamora-Caballero Sara , Bokhove Marcel , Han Ling , Stsiapanava Alena , Lu Yonggang , Kodani Mayo , Bainbridge Rachel E. , Komondor Kayla M. , Carlson Anne E. , Landreh Michael , de Sanctis Daniele , Yasumasu Shigeki , Ikawa Masahito , Jovine Luca
Published: June 2023

Post-fertilization cleavage of glycoprotein ZP2, a major subunit of egg zona pellucida (ZP) filaments, is crucial for mammalian reproduction by irreversibly blocking polyspermy. ZP2 processing is thought to inactivate a sperm-binding activity located upstream of the protein’s cleavage site; however, its molecular consequences and connection with ZP hardening are unknown. Here we report X-ray crystallographic, cryo-EM and biochemical studies showing that cleavage of ZP2 triggers its oligomerization. Deletion of the ZP-N1 domain that precedes the cleavage site of mouse ZP2 allows it to homodimerize even without processing, and animals homozygous for this variant are subfertile by having a semi-hardened ZP that allows sperm attachment but hinders penetration. Combined with the structure of a native egg coat filament, which reveals the molecular basis of heteromeric ZP subunit interaction, this suggests that oligomerization of cleaved ZP2 cross-links the ZP, rigidifying it and making it physically impenetrable to sperm.
Ryanodine Receptor Stabilization Therapy Suppresses Ca2+-Based Arrhythmias in a Novel Model of Metabolic HFpEF
Authors: Kaplan Aaron D. , Boyman Liron , Ward Christopher W. , Lederer W. Jonathan , Greiser Maura
Published: June 2023

Heart Failure with preserved ejection fraction (HFpEF) is the most prevalent form of heart failure worldwide and its significant mortality is associated with a high rate of sudden cardiac death (SCD; 30% - 40%). Chronic metabolic stress is an important driver of HFpEF, and clinical data show metabolic stress as a significant risk factor for ventricular arrhythmias in HFpEF patients. The mechanisms of SCD and ventricular arrhythmia in HFpEF remain critically understudied and empirical treatment is ineffective. To address this important knowledge gap, we developed a novel preclinical model of metabolic-stress induced HFpEF using Western diet (High fructose and fat) and hypertension induced by nitric oxide synthase inhibition (with L-NAME) in wildtype C57BL6/J mice. After 5 months, mice display all clinical characteristics of HFpEF and present with stress-induced sustained ventricular tachycardia (VT). Mechanistically, we found a novel pattern of arrhythmogenic intracellular Ca2+handling that is distinct from the well-characterized changes pathognomonic for heart failure with reduced ejection fraction. In addition, we show that the transverse tubular system remains intact in HFpEF and that arrhythmogenic, intracellular Ca2+mobilization becomes hyper-sensitive to ß- adrenergic activation. Finally, in proof-of-concept experiments we showin vivothat the clinically used intracellular calcium stabilizer dantrolene, which acts on the Ca2+release channels of the sarcoplasmic reticulum (SR), the ryanodine receptors, acutely prevents stress-induced VT in HFpEF mice. Therapeutic control of SR Ca2+leak may present a novel mechanistic treatment approach in metabolic HFpEF.