bluuebunny/crossref_metadata_2025 huggingface dataset:
The Molecular Architecture of Variable Lifespan in Diversity Outbred Mice
Authors: Hackett Mohamed Sean R , Magzoub Majed Mohamed , Maile Tobias M , Vu Ngoc , Wright Kevin M , Melamud Eugene , Haas Wilhelm , McAllister Fiona E , Churchill Gary A , Bennett Bryson D
Published: November 2023

To unravel the causes and effects of aging we can monitor the time-evolution of the aging process and learn how it is structured by genetic and environmental variation before ultimately testing theories about the causal drivers of aging. Diverse Outbred (DO) mice provide widespread, yet controlled, genetic variation generating considerable variation in mouse lifespan - here, we explore the relationship between DO mouse aging and lifespan. We profiled the plasma multiome of 110 DO mice at three ages using liquid chromatography - mass spectrometry (LC-MS)-based metabolomics and lipidomics and proteomics. Individual mice varied more than two-fold in natural lifespan. The combination of known age and resulting lifespan allows us to evaluate alternative models of how molecules were related to chronological age and lifespan. The majority of the aging multiome shifts with chronological age highlighting the accelerating chemical stress of aging. In contrast, proteomic pathways encompassing both well-appreciated aspects of aging biology, such as dysregulation of proteostasis and inflammation, as well as lesser appreciated changes such as through toll-like receptor signaling, shift primarily with fraction of life lived (the ratio of chronological age to lifespan). This measure, which approximates biological age, varies greatly across DO mice creating a global disconnect between chronological and biological age. By sampling mice near their natural death we were able to detect loss-of-homeostasis signatures involving focal dysregulation of proteolysis and the secreted phosphoproteome which may be points-of-failure in DO aging. These events are succeeded by massive changes in the multiome in mice’s final three weeks as widespread cell death reshapes the plasma of near-death mice.
Introducing flocker: an R package for flexible occupancy modeling via brms and Stan
Authors: Socolar Jacob B. , Mills Simon C.
Published: November 2023

Occupancy models are a widespread tool for analyzing biological survey data, but packages for fitting these models offer a limited variety of effects structures.

We developedRpackageflockerto connect occupancy models (single- and multi- species; single- and multi-season) to the uniquely powerful formula syntax ofRpackagebrms.

Using familiar formula-based syntax,flockermodels can readily incorporate a wide array of effects structures, including phylogenetic random effects, splines, Gaussian processes, autoregressive structures, monotonic effects, and nonlinear predictors. These are available for use in formulas for occupancy, detection, colonization, extinction, and autologistic terms (as applicable to the model type).flockeradditionally provides functionality for data simulation, posterior prediction, and model comparison, following well-documented statistical decisions that we put forward as best practices.

We anticipate thatflockerwill facilitate the work of practitioners who seek added realism in occupancy models. We further hope thatflocker’s synthesis of these models will help inform best practices around occupancy modeling.
Criticality of resting-state EEG predicts perturbational complexity and level of consciousness during anesthesia
Authors: Maschke Charlotte , O’Byrne Jordan , Colombo Michele Angelo , Boly Melanie , Gosseries Olivia , Laureys Steven , Rosanova Mario , Jerbi Karim , Blain-Moraes Stefanie
Published: November 2023

1

Consciousness has been proposed to be supported by electrophysiological patterns poised at criticality, a dynamical regime which exhibits adaptive computational properties, maximally complex patterns and divergent sensitivity to perturbation. Here, we investigated dynamical properties of the resting-state electroencephalogram of healthy subjects undergoing general anesthesia with propofol, xenon or ketamine. We then studied the relation of these dynamic properties with the perturbational complexity index (PCI), which has shown remarkably high sensitivity in detecting consciousness independent of behavior. All participants were unresponsive under anesthesia, while consciousness was retained only during ketamine anesthesia (in the form of vivid dreams)., enabling an experimental dissociation between unresponsiveness and unconsciousness. We estimated (i) avalanche criticality, (ii) chaoticity, and (iii) criticality-related measures, and found that states of unconsciousness were characterized by a distancing from both the edge of activity propagation and the edge of chaos. We were then able to predict individual subjects’ PCI (i.e., PCImax) with a mean absolute error below 7%. Our results establish a firm link between the PCI and criticality and provide further evidence for the role of criticality in the emergence of consciousness.

2

Significance Statement

Complexity has long been of interest in consciousness science and had a fundamental impact on many of today’s theories of consciousness. The perturbational complexity index (PCI) uses the complexity of the brain’s response to cortical perturbations to quantify the presence of consciousness. We propose criticality as a unifying framework underlying maximal complexity and sensitivity to perturbation in the conscious brain. We demonstrate that criticality measures derived from resting-state electroencephalography can distinguish conscious from unconscious states, using propofol, xenon and ketamine anesthesia, and from these measures we were able to predict the PCI with a mean error below 7%. Our results support the hypothesis that critical brain dynamics are implicated in the emergence of consciousness and may provide new directions for the assessment of consciousness.
Signature Informed Sampling for Transcriptomic Data
Authors: Janakarajan Nikita , Graziani Mara , Martinez Maria Rodriguez
Published: November 2023

Working with transcriptomic data is challenging in deep learning applications due to its high dimensionality and low patient numbers. Deep learning models tend to overfit this data and do not generalize well on out-of-distribution samples and new cohorts. Data augmentation strategies help alleviate this problem by introducing synthetic data points and acting as regularisers. However, existing approaches are either computationally intensive or require parametric estimates. We introduce a new solution to an old problem - a simple, non-parametric, and novel data augmentation approach inspired by the phenomenon of chromosomal crossover. Based on the assumption that there exist non-overlapping gene signatures describing each phenotype of interest, we demonstrate how new synthetic data points can be generated by sampling gene signatures from different patients under certain phenotypic constraints. As a case study, we apply our crossover method to transcriptomic data of colorectal cancer. Through discriminative and generative experiments on two different datasets, we show that our method improves patient stratification by generating samples that mirror biological variability as well as the models' robustness to overfitting and distribution shift. Our approach requires little to no computation, and outperforms, or at the very least matches, the performance of established augmentation methods.
Neonicotinoids andVarroamites force the extending of longevity in a bee colony during overwintering to forget
Authors: Yamada Toshiro , Yamada Yasuhiro
Published: November 2023

A mathematical model that can estimate the apparent longevity of bee-colony proposed by the authors to clarify that the longevity normally changes with seasons as follows: The longevity maintains almost constant from at 20 to 30 days from late spring to late autumn, thereafter, it continues to extend till late spring up to 160 to 200 days. Immediately after overwintering, the longevity is shortened almost vertically from one sixth to one tenth. Such normal seasonal changes in longevity are shown when a pesticide-free food is administered to the bee-colony and when pesticide-containing sugar syrup is. However, abnormal seasonal changes in longevity, which does not extend even if winter approaches, are shown for the bee-colony ingesting neonicotinoid-containing pollen and for the colony infested withVarroamites.

Judging from the fact that pollen is the main food for the bee-brood, that mites parasitize larvae and pupae, and that the vital functions and organs of honeybees are created during the larval and pupal stages, it can be inferred that a neonicotinoid-containing pollen paste and parasitic mites cause serious damage to the bee ability to detect the arrival of winter. Such dysfunction in the larval and pupal stages probably interferes with extending the longevity of adult bees even as winter approaches.
Machine learning-based revelation of GABBR1 and IQGAP2 as candidate biomarkers of pulmonary arterial hypertension and their correlation with immune infiltration
Authors: Wang Bao , Cheng Ju , Li Zengyou , Peng Yanfeng
Published: November 2023

Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with complex pathogenesis, and its intrinsic molecular mechanisms remain unclear. The aim of this study was to screen gene expression data from PAH patients, identify possible diagnostic indicators of PAH and to investigate the role of immune cell infiltration in the progression of PAH.

This study made use of the gene expression dataset of PAH patients from the GEO database. R software was used to identify differentially expressed genes and perform functional enrichment analysis. The SVM-RFE, LASSO and Random Forest algorithms were then used to screen for PAH hub genes and validated in the peripheral blood and lung tissue datasets. Finally, the CIBERSORT algorithm was used to assess PAH lung tissue immune cell infiltration and to investigate the correlation between hub genes and immune cells.

A total of 132 DEGs were screened in this study, which were centrally involved in the neuroreceptor-ligand activity pathway and associated with neurotransmission and hemoglobin complex. A total of 2 pivotal genes, GABBR1 and IQGAP2, were obtained by machine learning algorithms. The 2 pivotal genes had good predictive power as verified by ROC curves. Further immune infiltration analysis showed a decrease in T cells and an increase in the proportion of macrophages and dendritic cells in the lung tissue of PAH patients. The expression of GABBR1 was positively correlated with T cells and negatively correlated with macrophages and dendritic cells.

In our study, we identified 2 potential diagnostic key genes: GABBR1 and IQGAP2. Our findings may provide a theoretical basis for the analysis of the underlying mechanisms of PAH and the development of targeted medicines.

Highlight Box

Key findings

We identified 2 potential key genes of PAH, GABBR1 and IQGAP2.

What is known and what is new?

Sympathetic hyperexcitability as well as immune responses are closely associated with the development of PAH, and pulmonary vascular hyperplasia is a key pathogenetic mechanism of PAH.

Important biomarkers related to neuroreceptors and immune responses in PAH lung tissue have not been identified, while our study identified GABBR1 as a key neuroreceptor and immune cell regulator in PAH. IQGAP2 could be a new hotspot direction for pulmonary vascular remodeling.

What is the implication, and what should change now?

GABBR1 and IQGAP2 may be potential therapeutic targets for PAH. The new horizon provided by this study will provide some reference for subsequent PAH studies.
A network-based methodology to reconstruct biodiversity based on interactions with indicator species
Authors: Bouderbala Ilhem , Fortin Daniel , Tremblay Junior A. , Allard Antoine , Desrosiers Patrick
Published: November 2023

The relationship between species presence, biodiversity reconstruction, and latitudinal gradients is a complex and multifaceted topic that has been the subject of extensive research in ecology. Recent studies have provided valuable insights into the patterns and drivers of these phenomena. Also, with the ongoing decline in biodiversity, there is a need for efficient field monitoring techniques. Indicator species (IS) emerged as a promising tool to monitor diversity because their presence indicates a maximum number of conditionally co-occurring species. We aim to assess the effectiveness of IS for biodiversity reconstruction implicitly based on their co-occurrence with other species through a network-based methodology. The IS are identified based on various network metrics and the likelihood of species’ occurrences is computed based on (1) their conditional occurrence probability with IS and (2) the occurrence probability of IS. We test the approach with field observations of birds in the Côte-Nord region of Québec. From our methodology, the climate latitudinal gradient plays a significant role on the alternation in composition of IS with an almost complete turnover between northern and southern networks. The latitudinal gradient impacts also the nature of the inter-specific interactions with more avoidance relationship toward the Tropics and more cooperation liaisons toward the north. Regarding the effectiveness in the reconstruction of assemblages occurrence, we observe a strong negative correlation (r ≤ −0.95) between the percentage of sites occupied and the dissimilarity between the original and the estimated occurrences. More precisely, species must be present in more than 29% and 33% of northern and southern sites to recover well from its co-occurrence with IS. Therefore, it is more challenging to reconstruct biodiversity in communities closet to Tropics due to higher complex interactions and interspecific competition in these areas, which make it more difficult to infer community composition. In conclusion, our method demonstrates that it is possible to predict local species assemblages based on their implicit interactions with local IS. Nevertheless, the relatively low success of less present species illustrates the need for further theoretical development to reconstruct biodiversity, mainly to recover the occurrence of rare species.
Coenzyme-Protein Interactions since Early Life
Authors: Sanchez-Rocha Alma Carolina , Makarov Mikhail , Pravda Lukáš , Novotný Marian , Hlouchová Klára
Published: November 2023

Recent findings in protein evolution and peptide prebiotic plausibility have been setting the stage for reconsidering the role of peptides in the early stages of life’s origin. Ancient protein families have been found to share common themes and proteins reduced in composition to prebiotically plausible amino acids have been reported capable of structure formation and key functions, such as binding to RNA. While this may suggest peptide relevance in early life, their functional repertoire when composed of a limited number of early residues (missing some of the most sophisticated functional groups of today’s alphabet) has been debated.

Cofactors enrich the functional scope of about half of extant enzymes but whether they could also bind to peptides lacking the evolutionary late amino acids remains speculative. The aim of this study was to resolve the early peptide propensity to bind organic cofactors by analysis of protein-coenzyme interactions across the Protein Data Bank (PDB). We find that the prebiotically plausible amino acids are more abundant in the binding sites of the most ancient coenzymes and that such interactions rely more frequently on the involvement of the protein backbone atoms and metal ion cofactors. Moreover, we have identified a few select examples in today’s enzymes where coenzyme binding is supported solely by prebiotically available amino acids. These results imply the plausibility of a coenzyme-peptide functional collaboration preceding the establishment of the Central Dogma and full protein alphabet evolution.
Sequence-ensemble-function relationships for disordered proteins in live cells
Authors: Emenecker Ryan J. , Guadalupe Karina , Shamoon Nora M. , Sukenik Shahar , Holehouse Alex S.
Published: November 2023

Intrinsically disordered protein regions (IDRs) are ubiquitous across all kingdoms of life and play a variety of essential cellular roles. IDRs exist in a collection of structurally distinct conformers known as an ensemble. An IDR’s amino acid sequence determines its ensemble, which in turn can play an important role in dictating molecular function. Yet a clear link connecting IDR sequence, its ensemble properties, and its molecular function in living cells has not been directly established. Here, we set out to test this sequence-ensemble-function paradigm using a novel computational method (GOOSE) that enables the rational design of libraries of IDRs by systematically varying specific sequence properties. Using ensemble FRET, we measured the ensemble dimensions of a library of rationally designed IDRs in human-derived cell lines, revealing how IDR sequence influences ensemble dimensionsin situ.Furthermore, we show that the interplay between sequence and ensemble can tune an IDR’s ability to sense changes in cell volume - ade novomolecular function for these synthetic sequences. Our results establish biophysical rules for intracellular sequence-ensemble relationships, enable a new route for understanding how IDR sequences map to function in live cells, and set the ground for the design of synthetic IDRs withde novofunction.
Combined Bioinformatic and Splicing Analysis of Likely Benign Intronic and Synonymous Variants Reveals Evidence for Pathogenicity
Authors: Hirschi Owen R. , Felker Stephanie A. , Rednam Surya P. , Vallance Kelly L. , Williams Parsons D. , Roy Angshumoy , Cooper Gregory M. , Plon Sharon E.
Published: November 2023

Background

Current clinical variant analysis pipelines focus on coding variants and intronic variants within 10-20 bases of an exon-intron boundary that may affect splicing. The impact of newer splicing prediction algorithms combined within vitrosplicing assays on rare variants currently considered Benign/Likely Benign (B/LB) is unknown.

Methods

Exome sequencing data from 576 pediatric cancer patients enrolled in the Texas KidsCanSeq study were filtered for intronic or synonymous variants absent from population databases, predicted to alter splicing via SpliceAI (>0.20), and scored as potentially deleterious by CADD (>10.0). Total cellular RNA was extracted from monocytes and RT-PCR products analyzed. Subsequently, rare synonymous or intronic B/LB variants in a subset of genes submitted to ClinVar were similarly evaluated. Variants predicted to lead to a frameshifted splicing product were functionally assessed using anin vitrosplicing reporter assay in HEK-293T cells.

Results

KidsCanSeq exome data analysis revealed a rare, heterozygous, intronic variant (NM_177438.3(DICER1):c.574-26A>G) predicted by SpliceAI to result in gain of a secondary splice acceptor site. The proband had a personal and family history of pleuropulmonary blastoma consistent withDICER1syndrome but negative clinical sequencing reports. Proband RNA analysis revealed alternativeDICER1transcripts including the SpliceAI-predicted transcript.

Similar bioinformatic analysis of synonymous or intronic B/LB variants (n=31,715) in ClinVar from 61 Mendelian disease genes yielded 18 variants, none of which could be scored by MaxEntScan. Eight of these variants were assessed (DICER1n=4,CDH1n=2,PALB2n=2) usingin vitrosplice reporter assay and demonstrated abnormal splice products (mean 66%; range 6% to 100%). Available phenotypic information from submitting laboratories demonstratedDICER1phenotypes in 2 families (1 variant) and breast cancer phenotypes forPALB2in 3 families (2 variants).

Conclusions

Our results demonstrate the power of newer predictive splicing algorithms to highlight rare variants previously considered B/LB in patients with features of hereditary conditions. Incorporation of SpliceAI annotation of existing variant data combined with either direct RNA analysis orin vitroassays has the potential to identify disease-associated variants in patients without a molecular diagnosis.
The WD Domain OfAtg16l1Crucial For LC3-Associated Phagocytosis Is Not Required For Preserving Skin Homeostasis In Mice
Authors: Conway Shannon , Jefferson Matthew , Warren Derek T. , Wileman Thomas , Morris Christopher J.
Published: November 2023

The skin is a multifunctional organ, forming a barrier between the external and internal environment, thereby functioning as an initial safeguard against foreign and harmful environmental and biological factors. The barrier function is governed by the epidermis, a stratified epithelium composed of an outermost cornified envelope, several differentiated layers, and an innermost basal layer, anchored to the basement membrane (BM). Below the BM lies the dermis, which is composed of an extracellular matrix (ECM), formed by the dermal fibroblasts and dermal adipose tissue. The skin is subject to constant cellular turnover (terminal differentiation) that maintains the homeostatic state of the skin. Recently, autophagy has been implicated in epidermal differentiation and in preserving homeostasis in the skin. The AKT/mTORC1 pathway is a key regulator for epidermal development and differentiation, and conditions (e.g., psoriasis) are linked to the hyperactivation of these key autophagy regulators. A further process known as LC3-associated phagocytosis (LAP) uses some but not all components of autophagy. The Atg16l1 E230 mouse model (E230), deficient for LAP, has been widely used to study the effects of LAP-deficiency and autophagy in tissue homeostasis.

Here, the E230 model was used to study the relationship between skin homeostasis and LAP and to determine whether LAP-deficient mice (WD) display a cutaneous skin phenotype. Histological analysis of male 1-year-old Wild Type (WT) and WD mice skin revealed morphological differences in dorsal and tail skin. qPCR analysis of key keratins showed no differences (p > 0.05) when compared between genotypes. This was confirmed by western blotting studies. In addition, the expression of general proliferation markers (Akt & ERK2) showed a small reduction (p < 0.05) in the WD mice skin. General skin barrier formation was assessed by dye permeation assays, which demonstrated full and proper formation of the skin barrier at E18.5 in both WT and WD. Notable dermal thinning in the WD mice skin (p < 0.0001), led us to examine the biomechanical properties to dismiss any abnormalities relating to biomechanical functionality. Results indicate that WT and WD mouse skin show identical biomechanical properties at these ages (p < 0.05 and p < 0.01, respectively). In summary, the noted differences in the dermal and epidermal histology of WD skin were shown to be functionally insignificant in terms of epidermal permeability and dermal biomechanics.
Exploring the local field potential signal from the subthalamic nucleus for phase-targeted auditory stimulation in Parkinson’s disease
Authors: Krugliakova Elena , Karpovich Artyom , Stieglitz Lennart , Huwiler Stephanie , Lustenberger Caroline , Imbach Lukas , Bujan Bartosz , Jedrysiak Piotr , Jacomet Maria , Baumann Christian R. , Fattinger Sara
Published: November 2023

Background

Enhancing slow waves, the electrophysiological (EEG) manifestation of non-rapid eye movement (NREM) sleep, might offer therapeutic benefits for patients with Parkinson’s disease (PD) by improving sleep quality and slowing disease progression. Phase-targeted auditory stimulation (PTAS) is an approach to enhance slow waves, which are detected in the surface EEG signal in real-time.

Objective

We aimed to test whether the local-field potential of the subthalamic nucleus (STN-LFP) can be used to detect frontal slow waves and evaluate the PTAS-related electrophysiologic changes.

Methods

We enrolled patients diagnosed with PD and undergoing Percept™ PC neurostimulator (Medtronic) implantation for the deep brain stimulation of STN (STN-DBS) in a two-step surgery. Patients participated in 3 full-night recordings, including one between-surgeries recording and two recordings during rehabilitation, one with DBS+ (on) and one with DBS-(off). Surface EEG and STN-LFP signals from Percept PC were recorded simultaneously, and PTAS was applied during sleep in all three recording sessions.

Results

Our results show that during NREM sleep, slow waves of the cortex and STN are time-locked. We observed the effects of PTAS in STN-LFP in all types of analyses, including spectral, coherence, and event-related potentials.

Conclusion

Our findings suggest that PTAS could be implemented using STN-LFP signal for slow wave detection. Additionally, we propose options for better STN-LFP signal preprocessing, including different referencing and filtering that could make the detection of the cortical slow waves in STN-LFP more reliable.
Ethnicity as a predictor of nonmotor symptoms impact on quality of life in patients with Parkinson’s disease: A systematic review
Authors: Aldeen Huda Shujaa , Houlden Henry , Rizig Mie
Published: November 2023

Background

Parkinson’s disease (PD) is a chronic progressive hypokinetic movement disorder characterised by rigidity, tremor, and bradykinesia in addition to multiple non-motor features. It is increasingly recognised that NMS have a substantial impact on the quality of life (QoL) of people with PD, more than motor features. The prevalence and types of these NMS vary among PD patients from different ethnic groups. Ethnicity has been postulated as a determinant of PD symptoms and quality of life of people with PD. There is paucity of data on the effect of ethnicity on (QoL) of people with PD.

Aim

The aim of this review is to critically evaluate the literature to (1) identify the variability of NMS that affect QoL of people with PD from different ethnicities, and (2) to examine if ethnicity could determine the impact of these NMS on the QoL of people with PD.

Methods

This review was conducted according to recommendations in preferred reporting Items for Systematic Review and Meta-Analysis (PRISMA). Search was conducted in three databases (PubMed, Ovid Embase and Scopus) in the period between March & July 2023. NMS were assessed by four scales: NMSS, NMQT, MDS-UDPRS I, and HADS. QoL was assessed by PDQ39. Ethnicity has been defined based on the country where the study has been conducted. A best-evidence synthesis was used to summarise the demographics, study designs, NMS features in each ethnic group. The impact of NMS features on QoL in different ethnic groups was assessed by comparing the power of correlations measures between NMS domains and QoL in all studies.

Results

Twenty-one studies with 4246 patients were deemed suitable to be included. Patients in the selected studies were grouped to eight ethnic populations: Caucasian, East Asian, Indian, North African, West African, Hispanic, Mediterranean, and Middle Eastern ethnicities. Heterogeneous protocols and varied statistical methodologies were used in most studies to assess the relation between NMS and QoL of people with PD. Overall depression, fatigue, and sleep and memory problems are the symptoms with the most significant impact on QoL of majority of ethnic populations. Other NMS including cardiovascular, gastrointestinal and urinary Symptoms exhibited a variability in their impact on QoL in different ethnic groups.

Conclusion

Our study demonstrates that ethnicity may have a significant impact on the correlation between NMS and QoL of patients with PD. There is deficiency in studies assessing the impact of PD NMS on QoL in Africans, Latin Americans, and Middle Eastern populations. Ethnicity is poorly defined and frequently unaddressed in PD studies. Large multicentre, multinational multi-ethnic studies using rigorous unified protocols are required to properly evaluate the effect of ethnicity on PD NMS. Identification of these variabilities is crucial to aid efficient health policy planning based on each population needs and optimize use of local resources.
Warm temperature suppresses plant systemic acquired resistance by interceptingN-hydroxypipecolic acid biosynthesis
Authors: Shields Alyssa , Yao Lingya , Rossi Christina A.M. , Cordon Paula Collado , Kim Jong Hum , Abu AlTemen Wasan Mudher , Li Sha , Marchetta Eric J. R. , Shivnauth Vanessa , Chen Tao , He Sheng Yang , Xin Xiu-Fang , Castroverde Christian Danve M.
Published: November 2023

Climate warming influences disease development by targeting critical components of the plant immune system, including pattern-triggered immunity (PTI), effector-triggered immunity (ETI) and production of the central defence hormone salicylic acid (SA) at the primary pathogen infection site. However, it is not clear if and/or how temperature impacts systemic immunity. Here we show that pathogen-triggered systemic acquired resistance (SAR) inArabidopsis thalianais suppressed at elevated temperature. This was accompanied by global downregulation of SAR-induced genes at elevated temperature. Abolished SAR under warmer conditions was associated with reduced biosynthesis of the SAR metaboliteN-hydroxypipecolic acid (NHP) inArabidopsisand other plant species (such as tomato and rapeseed), as demonstrated by downregulation of NHP biosynthetic genes (ALD1andFMO1) and reduced NHP and pipecolic acid (Pip) levels. Although multiple SAR signals have been shown previously, exogenous NHP or Pip was sufficient to restore disease protection at elevated temperature, indicating that heat-mediated SAR suppression is due to downregulation of the NHP pathway. Along withALD1andFMO1, local and systemic expression of the SA biosynthetic geneICS1were also suppressed at warm temperature. Finally, we define a transcriptional network controlling thermosensitive NHP pathway via the master transcription factors CBP60g and SARD1. Our findings demonstrate that warm temperatures impact not only local but also systemic immunity by impinging on NHP biosynthesis, providing a roadmap towards engineering climate-resilient plant immune systems.
Atypical cortical feedback underlies failure to process contextual information in the superior colliculus of Scn2a+/-autism model mice
Authors: Ferrarese Leiron , Asari Hiroki
Published: November 2023

Atypical sensory integration and contextual learning are common symptoms in autism, but how sensory circuits are affected remains elusive. Here we performedin vivotwo-photon calcium imaging and pupillometry of mice engaged in an implicit learning task in stable and volatile visual contexts. Wild-type and Scn2a-haploinsufficient autism-model mice exhibited distinct patterns of context-dependent modulation in pupil and neuronal dynamics in the superior colliculus, while retinal outputs showed no contextual modulation. A hierarchical Bayesian learning model showed that the superior colliculus largely represented expectations on the task volatility in wild-type mice, but rather on the outcome itself in Scn2a+/-mice, much as suggested in autism. Chemogenetic perturbation revealed that the cortical feedback signals mediated the observed contextual modulation, both at the neurophysiological and behavioral levels. These results suggest that the corticotectal input is critical for contextual sensory integration in the superior colliculus, and its anomaly underlies abnormal sensory learning in autism.
Seizure cycles in paediatric epilepsy
Authors: Kamitakahara Hannah , Karoly Philippa J. , Stirling Rachel E. , Eden Dominique , Nurse Ewan S. , Dabscheck Gabriel , Freestone Dean , Cook Mark J. , D’Souza Wendyl , Naim-Feil Jodie
Published: November 2023

Multiday cyclic patterns underlying the timing of seizures are well-established in adults with epilepsy and are critical to the development of seizure risk forecasting models. As cycles underpinning these models are yet to be explored in paediatric cohorts, the current study applies methods drawn from seizure risk forecasting to identify and compare multiday seizure cycles between paediatric and adult cohorts. This is followed by the first validation of personalised forecasts of seizure likelihood in a paediatric cohort. Multiday seizure cycles were extracted retrospectively from 325 (71 paediatric) electronic seizure diary users (more than 28 days of app use) with confirmed epilepsy. Cycles were grouped (k-means clustering), and seizure cycles quantified (synchronisation index), with significant cycles identified by Rayleigh test of periodicity (p<0.05). Wilcoxon rank-sum test assessed differences in prevalence and strength of cycle groups between paediatric and adult cohorts. 34,402 seizures (paediatric:M=101,SD=103, adult:M=107,SD=156) were analysed and seizure cycles were grouped according to circadian (0.5-1.5 days), about-weekly (2-12 days), about-fortnightly (13-22 days) and about-monthly (23-32 days) periodicities. Significant cycles were identified in each cycle group, with no differences in prevalence or cycle strength between paediatric and adult cohorts for any multiday cycle group. Similar effects were observed across clinical and demographic features (sex, epilepsy-type, medication). These multiday patterns formed the basis for cycle-based estimates of seizure likelihood. Receiver operating characteristic (area under the curve: AUC) was applied and demonstrated that these seizure forecasts performed better than chance (i.e. shuffled seizure times). Multiday seizure cycles are therefore similar in paediatric and adult cohorts, and this study provides the first validation of cycle-based seizure risk forecasting models as a promising approach for paediatric epilepsy.
Manipulating condensation of thermo-sensitive SUF4 protein tunes flowering time in Arabidopsis thaliana
Authors: Meyer Heather M. , Hotta Takashi , Malkovskiy Andrey , Zheng Yixian , Ehrhardt David W.
Published: November 2023

Intrinsically disordered proteins (IDP) lack stable tertiary structures, which allows them to change conformation and function under different physicochemical conditions. This may be highly advantageous for plants, which often use changes in their environment to elicit a variety of responses, including developmental events. For instance, some plants delay flowering in the fall and require exposure to winter temperatures as a cue to initiate flowering the following spring. Many of the genes involved in temperature-dependent flowering have been extensively studied inArabidopsis, yet how plants coordinate their molecular states with seasonal temperature change is poorly understood. Here, we explore the role of temperature-sensitive phase separation of the IDP and flowering-time regulator, SUPPRESSOR OF FRIGIDA 4 (SUF4), in modulating flowering time. SUF4 has a well-defined role in regulating temperature-dependent flowering time by activating the master floral suppressorFLOWERING LOCUS C (FLC). We show that in plant nuclei, SUF4 is a temperature-sensitive protein that assembles into biomolecular condensates in warm temperatures (20°C). When temperatures cool (4°C), SUF4 nuclear condensates disassemble, causing SUF4 to disperse within the nucleoplasm. Additionally, we demonstrate that the number of SUF4 condensates quantitatively correlates with flowering time. Progressive alterations to the amino acid composition of SUF4’s disordered region cause likewise progressive changes in temperature-dependent condensation bothin vitroandin vivo,FLCtranscription, and the onset of flowering. Lastly, we observe that SUF4 condensates coincide with the accumulation of other key flowering-time proteins (FRIGIDA and ELF7). These findings indicate that condensation of SUF4 likely plays a pivotal role in promoting flowering, possibly by concentrating and stabilizing regulatory factors needed for the transcriptional activation ofFLCthrough temperature-dependent phase separation. This research suggests that in plants, IDPs can sense environmental cues and regulate critical developmental processes.

One-Sentence Summary

Evidence suggest thatArabidopsisuses temperature-sensitive condensation to regulateFLCtranscription and flowering time.
Exploring phenotypic and genetic variability in hemp (Cannabis sativa)
Authors: Trubanová Nina , Pender Grace , McCabe Paul F. , Melzer Rainer , Schilling Susanne
Published: November 2023

Hemp (Cannabis sativaL.) is a high-value multi-purpose crop with applications ranging from the medicinal use of its secondary metabolites to carbon-sequestering building materials. To fully capitalise on the potential of hemp as a crop for more sustainable agriculture, detailed phenotypic and genotypic characterizations are required in order to inform targeted breeding programmes.

Here, we present a detailed morphological and genomic analysis of 10 hemp cultivars. We found high variability in agronomically important traits such as flowering time, plant height, and biomass in most of the hemp cultivars tested. Additionally, genotyping by sequencing demonstrates that genetic differences are pervasive, both between hemp cultivars as well as between individuals of a single cultivar. The significant genetic and phenotypic variability we observe in hemp contrasts with other crops, where cultivars are often phenotypically and genetically relatively uniform. We argue that the variability of hemp is an asset for breeding and increases the potential for further improvement of the crop but is also a challenge for today’s highly automated agriculture that relies on phenotypic uniformity.

Author summary

Hemp (Cannabis sativaL.) stands as one of the earliest domesticated crops. This remarkable plant is a sustainable crop with high carbon sequestration capacity which can be cultivated for soil remediation. Furthermore, hemp oil and fibre are used for many applications ranging from cooking to manufacturing bioplastics, textiles, or building materials of superb characteristics, and its secondary metabolites are sought after because of their medicinal properties. However, in contrast to many modern crops, hemp exhibits extensive variability in key agricultural traits, such as plant height and flowering time. This variability presents a challenge for both farmers and processors. To unravel the fundamentals of hemp diversity we conducted a comprehensive study of phenotypic and genetic characterisation of ten diverse hemp cultivars. We present findings confirming substantial variability not only among individuals of different cultivars but also within the same cultivar. Additionally, we explore heterozygosity in the context of other hemp studies and other crops. Understanding this variability in the context of a single hemp cultivar and across multiple cultivars is paramount for breeding novel, more uniform hemp varieties which will allow us to unlock the full potential of hemp as a crop of the future.
Imaging the binding of MECP2 to DNA
Authors: West Anne E.
Published: November 2023

Mutations in the methyl-DNA binding domain of MECP2 cause Rett syndrome; however, distinct mutations are associated with different severity of the disease. Live-cell imaging and single-molecule tracking are sensitive methods to quantify the DNA binding affinity and diffusion dynamics of nuclear proteins. In this issue ofGenes & Development, Zhou and colleagues (pp. 883–900) used these imaging methods to quantitatively describe the partial loss of DNA binding resulting from a novel pathologicalMECP2mutation with intermediate disease severity. These data demonstrate how single-molecule tracking can advance understanding of the molecular mechanisms connectingMECP2mutations with Rett syndrome pathophysiology.
Modeling of Ca/P and deposit size responses of electrodeposited calcium-phosphate coating using full factorial design
Authors: Amirnejad Mohabbat , Rajabi Mohammad , Jamaati Roohollah
Published: November 2023

Purpose

This study aims to investigate the effect of electrodeposition parameters (i.e. time and voltage) on the properties of hydroxyapatite (HA) coating fabricated on Ti6Al4V surface.

Design/methodology/approach

A full factorial design along with response surface methodology was utilized to evaluate the main effect of independent variables and their relative interactions on response variables. The effect of electrodeposition voltage and deposition time on HA coatings Ca/P molar ratio and the size of deposited HA crystals were examined by structural equation modeling (SEM). The formation of plate-like and needle-like HA crystals was observed for all experiments.

Findings

The results obtained showed that the higher electrodeposition voltage leads to lower Ca/P values for HA coatings. This is more significant at lower deposition times, where at a 20-minute deposition time, the voltage increased from 2 to 3 V and the Ca/P decreased from 2.27 to 1.52. Full factorial design results showed that electrodeposition voltage has a more significant effect on the size of the deposited HA crystal. With increasing the voltage from 2 to 3 V at a deposition time of 20 min, the HA crystal size varied from 99 to 36 µm.

Originality/value

The investigation delved into the impact of two critical parameters, deposition time and voltage, within the electrodeposition process on two paramount properties of HA coatings. Analyzing the alterations in coating characteristics relative to variations in these process parameters can serve as a foundational guide for subsequent research in the domain of calcium-phosphate deposition for implants.
Supply chain risk management to achieve healthcare supply chain operational excellence: a fsQCA and PLS-SEM approach
Authors: Senna Pedro , Guimarães Marujo Lino , Santos Ana Carla de Souza Gomes dos , Freitag Alberto Eduardo Besser , França Sergio Luiz Braga
Published: November 2023

Purpose

Healthcare supply chains (HCSCs) face severe challenges when compared to regular chains. Besides avoiding bankruptcy, they must accomplish their goal which is to save lives. Since 2019 the COVID-19 pandemic evidenced that a HCSC disruption generates disruptions to other SCs. Therefore, the objective of this paper is threefold: conduct a systematic literature review to build a HCSC operational excellence (HSCOE) definition; build a conceptual framework by mapping the antecedents of HSCOE and formulate hypotheses; test the hypotheses using a fuzzy-Set Qualitative Comparative Analysis (fsQCA) combined with partial least squares structural equation modeling (PLS-SEM) techniques to obtain empirical validation.

Design/methodology/approach

Given this context, this paper conducted a systematic literature review to build a HSCOE conceptual framework and used a fsQCA combined with PLS-SEM techniques to obtain empirical validation.

Findings

The paper revealed a relationship between important variables to achieve HSCOE, such as Supply chain 4.0, SC risk management, SC integration, SC resilience (antecedents) and HSCOE (consequent).

Originality/value

The literature contributions of this paper are as follows: validating a new scale for each of the constructs; finding evidence of the causal relationships between the latent variables; measuring how the constructs influence the HSCOE; in addition, the results address important literature gaps identified by researchers and serve as a guide to organizations that need to implement these practices. Furthermore, this study recommends that HCSC managers consider the implementation of robust initiatives concerning the latent variables presented in this work.
Tying the knot – linking bootstrapping and working capital management in established enterprises
Authors: Fitzsimons Margaret , Hogan Teresa , Hayden Michael Thomas
Published: November 2023

Purpose

Bootstrapping is a practitioner-based term adopted in entrepreneurship to describe the techniques employed in micro, small and medium-sized enterprises (MSMEs) to minimise the need for external funding by securing resources at little or no cost and applying strategies to effectively use resources. Working capital management (WCM) is a term used in financial management to define a set of practices used to manage business resources, including cash management. This paper explores the overlap and divergence between these two disciplinary distinct concepts.

Design/methodology/approach

A dual methodology is employed. First, the usage of the two terms in prior literature is analysed and synthesised. Second, the study uses factor analysis to explore how bootstrapping practices described by owners of 167 established MSMEs relate to the components of WCM in financial management.

Findings

The factor analysis identifies two main bootstrapping practices employed by MSMEs: (1) delaying payments and owner-related bootstrapping and (2) customer-related bootstrapping. Delaying payments is an integral practice in trade payables management and customer-related bootstrapping includes practices that are integral to trade receivables management. Therefore, links between bootstrapping practices and WCM practices are firmly established.

Research limitations/implications

The study is not without limitations. Based on cross-sectional evidence for established firms in Ireland only, future studies could explore cross-country longitudinal panel data to fully examine life cycle and sectoral effects, as well as other external shocks (for example, COVID-19) on bootstrapping and WCM practices. This study does not explain why some factors (for example, joint utilisation and inventory management) are present in some bootstrapping studies and not in others; further case study research might help explain this. Finally, changes in the business environment facing start-ups and established enterprise, including increased digitalisation, online trading, self-employment, remote hub working and sustainability, offer new avenues for bootstrapping research.

Originality/value

This is the first study to comprehensively explore the conceptual and empirical links between bootstrapping and WCM. This study will enable researchers and practitioners in these two distinct disciplines to learn from each other. Accounting researchers and practitioners can broaden their understanding of how WCM “works” in MSME settings. Similarly, entrepreneurship researchers and practitioners can deepen their understanding of how bootstrapping can be adopted by businesses to manage resources effectively.