bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent research advances in young-onset dementia
Authors: Loi Samantha M. , Pijnenburg Yolande , Velakoulis Dennis
Published: January 2023

Purpose of review

Young-onset dementia (YOD) refers to a dementia for which symptom onset occurs below the age of 65. This review summarizes the recent literature in this area, focusing on updates in epidemiology, diagnosis and service provision.

Recent findings

In the last year, internationally, the prevalence of YOD was reported as 119 per 100 000, but this may vary according to population types. Although the commonest causes of YOD are Alzheimer's disease (AD) and frontotemporal dementia (FTD), there is increasing recognition that YOD is diagnostically and phenotypically broader than AD and FTD. YOD may be due to many other diseases (e.g. Huntington's disease, vascular dementia) whereas accumulation of the same protein (e.g. amyloid protein) may lead to different phenotypes of Alzheimer's disease (such as posterior cortical atrophy and behavioural-variant/frontal-variant AD). This heterogeneity of phenotypic presentation is also seen in YOD due to known genetic mutations. Biomarkers such as plasma and cerebrospinal fluid proteins, neuroimaging and genetics have shown promise in the early identification of YOD as well as providing further understanding behind the overlap between psychiatric and neurodegenerative conditions occurring in younger people. The management of YOD needs to consider age-specific issues for younger people with dementia and their family networks together with better integration with other health services such as aged, disability and improved access to services and financial assistance.

These findings emphasize the need for early identification and appropriate age-specific and person-centred management for people with young-onset dementia.
Down syndrome regression disorder: updates and therapeutic advances
Authors: Santoro Jonathan D. , Filipink Robyn A. , Baumer Nicole T. , Bulova Peter D. , Handen Benjamin L.
Published: January 2023

Purpose of review

Down syndrome regression disorder (DSRD) is a symptom cluster consisting of neuropsychiatric regression without cause. Although knowledge of this condition has accelerated over the last decade, prior studies have been limited by heterogenous nomenclature, diagnostic approaches and therapeutic interventions. This review highlights recent advances in the diagnosis and clinical approach to DSRD and reviews the most up-to-date literature on therapeutic interventions for this condition.

Recent findings

Several multicentre studies have reported exciting findings on the presence of neurodiagnostic study abnormalities and responses to a variety of therapeutics, including psychotropics (including benzodiazepines), electroconvulsive therapy and immunotherapy. Differential response rates have been observed in the presence and absence of a variety of clinical and diagnostic factors.

Individuals with DSRD are responsive to a variety of psychiatric pharmacotherapy and immunotherapy underscoring this phenotype may have multiple causes. Multidisciplinary care is helpful in the evaluation and management of individuals with this condition.
Reclassification of Clostridium cocleatum, Clostridium ramosum, Clostridium spiroforme and Clostridium saccharogumia as Thomasclavelia cocleata gen. nov., comb. nov., Thomasclavelia ramosa comb. nov., gen. nov., Thomasclavelia spiroformis comb. nov. and Thomasclavelia saccharogumia comb. nov
Authors: Lawson Paul A. , Saavedra Perez Liz , Sankaranarayanan Krithivasan
Published: January 2023

The genus

Clostridium

is phenotypically and genotypically diverse, with many species phylogenetically located outside Clostridium sensu stricto. One such group consists of the species Clostridium cocleatum, Clostridium ramosum, Clostridium spiroforme and

Clostridium saccharogumia

(formally clostridial rRNA cluster XVIII) []. Sequencing of the 16S rRNA and, more recently, the results of genomic analyses have demonstrated that these species represent a coherent cluster separated from other closely related genera located in the family

Coprobacillaceae

within the order

Erysipelotrichales

[]. In addition to phenotypic, phylogenetic and genomic comparisons, chemotaxonomic features were consistent between all four species, the predominant fatty acids were C16 : 0 and C18 : 1ω9c, while glucose and ribose were the whole cell sugars present in the cell walls. Furthermore, he results of peptidoglycan analysis indicated that meso-2,6-diaminopimelic acid was present as the diagnostic diamino acid in all four species. Biochemical profiles were also concordant with them being closely related species. Therefore, on the basis of phylogenetic, genomic, phenotypic and chemotaxonomic information, a novel genus, Thomasclavelia gen. nov., is proposed. It is suggested that Clostridium cocleatum, Clostridium ramosum, Clostridium spiroforme and

Clostridium saccharogumia

be transferred to this genus as Thomasclavelia cocleata comb. nov., Thomasclavelia ramosa comb. nov., Thomasclavelia saccharogumia comb. nov. and Thomasclavelia spiroformis comb. nov. The type species of the genus is Thomasclavelia ramosa CCUG 24038T (=ATCC 25582T=DSM 1402T).
Transmembrane substrates of type three secretion system injectisomes
Authors: Godlee Camilla , Holden David W.
Published: January 2023

The type three secretion system injectisome of Gram-negative bacterial pathogens injects virulence proteins, called effectors, into host cells. Effectors of mammalian pathogens carry out a range of functions enabling bacterial invasion, replication, immune suppression and transmission. The injectisome secretes two translocon proteins that insert into host cell membranes to form a translocon pore, through which effectors are delivered. A subset of effectors also integrate into infected cell membranes, enabling a unique range of biochemical functions. Both translocon proteins and transmembrane effectors avoid cytoplasmic aggregation and integration into the bacterial inner membrane. Translocated transmembrane effectors locate and integrate into the appropriate host membrane. In this review, we focus on transmembrane translocon proteins and effectors of bacterial pathogens of mammals. We discuss what is known about the mechanisms underlying their membrane integration, as well as the functions conferred by the position of injectisome effectors within membranes.
TONSILS ARE MAJOR SITES OF PROLONGED SARS-COV-2 INFECTION IN CHILDREN
Authors: Lima Thais M. , Martins Ronaldo B. , Miura Carolina S. , Souza Maria V. O. , Cassiano Murilo H. A. , Rodrigues Tamara S. , Veras Flávio P. , Sousa Josane F. , Gomes Rogério , Almeida Glaucia M. , Melo Stella R. , Silva Gabriela C. , Dias Matheus , Capato Carlos F. , Silva Maria L. , Barros Veridiana E. D. , Carenzi Lucas R. , Zamboni Dario S. , Jorge Daniel M. M. , Tamashiro Edwin , Anselmo-Lima Wilma T. , Valera Fabiana C. P. , Arruda Eurico
Published: January 2023

In the present study, we show that SARS-CoV-2 can infect palatine tonsils and adenoids in children without symptoms of COVID-19, with no history of recent upper airway infection. We studied 48 children undergoing tonsillectomy due to snoring/OSA or recurrent tonsillitis between October 2020 and September 2021. Briefly, nasal cytobrush (NC), nasal wash (NW) and tonsillar tissue fragments obtained at surgery were tested by RT-PCR, immunohistochemistry (IHC), flow cytometry and neutralization assay. We detected the presence of SARS-CoV-2 in at least one specimen tested in 25% of patients (20% in palatine tonsils and 16.27% in adenoids, 10.41% of NC and 6.25% of NW). Importantly, in 2 of the children there was evidence of laboratory-confirmed acute infection 2 and 5 months before surgery. IHC revealed the presence of SARS-CoV-2 nucleoprotein in epithelial surface and in lymphoid cells in both extrafollicular and follicular regions, in adenoids and palatine tonsils. Flow cytometry showed that CD20+B lymphocytes were the most infected phenotypes by SARS-CoV-2 NP, followed by CD4+ and CD8+ T lymphocytes, and CD14+ macrophages and dendritic cells. Additionally, IF indicated that SARS-CoV-2-infected tonsillar tissues had increased expression of ACE2 and TMPRSS2. NGS sequencing demonstrated the presence of different SARS CoV-2 variants in tonsils from different tissues. SARS-CoV-2 antigen detection was not restricted to tonsils, but was also detected in nasal cells from the olfactory region. In conclusion, palatine tonsils and adenoids are sites of prolonged infection by SARS-CoV-2 in children, even without COVID-19 symptoms.
Predicting vasospasm risk using first presentation aneurysmal subarachnoid haemorrhage volume: a semi-automated CT image segmentation analysis in ITK-SNAP
Authors: Street James S , Pandit Anand S , Toma Ahmed K
Published: January 2023

Purpose

Cerebral vasospasm following aneurysmal subarachnoid haemorrhage (aSAH) is a significant complication associated with poor neurological outcomes. We present a novel, semi-automated pipeline in ITK-SNAP to segment subarachnoid blood volume from initial CT head (CTH) scans and use this to predict future radiological vasospasm.

Methods

42 patients were admitted between February 2020 and December 2021 to our tertiary neurosciences centre, and whose initial referral CTH scan was used for this retrospective cohort study. Blood load was segmented using a semi-automated random forest classifier and active contour evolution implemented in the open-source medical imaging analysis software ITK-SNAP. Clinical data were extracted from electronic healthcare records in order to fit models aimed at predicting radiological vasospasm risk.

Results

Semi-automated segmentations demonstrated excellent agreement with manual, expert-derived volumes (mean Dice coefficient=0.92). Total normalised blood volume, extracted from CTH images at first presentation, was significantly associated with greater odds of later radiological vasospasm, increasing by approximately 7% for each additional cm3of blood (OR=1.069, 95% CI: 1.021-1.120; p<.005). Greater blood volume was also significantly associated with vasospasm of a higher Lindegaard ratio, of longer duration, and a greater number of discrete episodes. Total blood volume predicted radiological vasospasm with a greater accuracy as compared to the modified Fisher scale (AUC= 0.86 vs 0.70), and was of independent predictive value.

Conclusion

Semi-automated methods provide a plausible pipeline for the segmentation of blood from CT head images in aSAH, and total blood volume is a robust, extendable predictor of radiological vasospasm, outperforming the modified Fisher scale. Greater subarachnoid blood volume significantly increases the odds of subsequent vasospasm, its time course and its severity.
Within-person Relationships of Sleep Duration with Next-Day Stress and Affect in the Daily Life of Adults with Type-1 Diabetes
Authors: Jin Haomiao , Gonzalez Jeffrey S , Pyatak Elizabeth , Schneider Stefan , Hoogendoorn Claire J , Hernandez Raymond , Lee Pey-Jiuan , Spruijt-Metz Donna
Published: January 2023

Objective

The objective of this study is to examine the within-person relationships between sleep duration and next-day stress and affect in the daily life of individuals with T1D.

Methods

Study participants were recruited in the Function and Emotion in Everyday Life with Type 1 Diabetes (FEEL-T1D) study. Sleep duration was derived by synthesizing objective (actigraphy) and self-report measures. General and diabetes-specific stress and positive and negative affect were measured using ecological momentary assessment. Multilevel regression was used to examine the within-person relationships between sleep duration and next-day stress and affect. Cross-level interactions were used to explore whether gender and baseline depression and anxiety moderated these within-person relationships.

Results

Adults with T1D (n=166) completed measurements for 14 days. The average age was 40.99 years, and 91 participants (54.82%) were female. The average sleep duration was 7.29 hours (SD=1.18 hours). Longer sleep was significantly associated with lower general stress (p<0.001) but not diabetes-specific stress (p=0.18) on the next day. There were significant within-person associations of longer sleep with lower levels on next-day negative affect (overall, p=0.002, disappoint, p=0.05; sad, p=0.05; tense, p<0.001; upset, p=0.008; anxious, p=0.04). There were no significant associations with positive affect. Examination of the interaction effects did not reveal significant differential relationships for men and women and for individuals with and without depression or anxiety at baseline.

Conclusion

Findings from this study suggest optimizing sleep duration as an important interventional target for better managing general stress and improving daily emotional wellbeing of individuals with T1D.
The impact of COVID-19 lockdown on a cohort of adults with recurrent major depressive disorder from Catalonia: a decentralized longitudinal study using remote measurement technology
Authors: Lavalle R. , Condominas E. , Haro JM , Giné-Vázquez I. , Bailon R , Laporta E , Garcia E , Kontaxis S , Riquelme G. , Lombardini F. , Preti A. , Peñarrubia-María MT , Coromina M. , Arranz B. , Vilella E. , Rubio E. ,   RADAR-MDD-Spain, Matcham F. , Lamers F , Hotopf M. , Penninx BWJH , Annas P. , Narayan V , Simblett S. , Siddi S
Published: January 2023

Background

The present study analyzes the effects of each containment phase of the first COVID-19 wave on depression levels in a cohort of adults with a history of major depressive disorder (MDD).

Methods

This analysis is part of the Remote Assessment of Disease and Relapse-MDD (RADAR-MDD) study. Individuals included had a diagnosis of DSM-5 major depressive disorder (MDD), at least two episodes of major depression (MDE), one of them in the previous two years. Depression was evaluated with the Patient Health Questionnaire-8 (PHQ-8) and anxiety with the Generalized Anxiety Disorder-7 (GAD-7). A total of 121 participants recruited from Catalonia were registered from November 1, 2019, to October 16, 2020. Levels of depression were explored across the phases (pre-lockdown, lockdown, four post-lockdown phases) of the restrictions imposed by the Spanish/Catalan governments. Then, a mixed model was fitted to estimate how depression varied over the phases.

Results

A small but statistically significant rise in the depressive severity was found during the lockdown and phase 0 (early post-lockdown), as compared with the pre-lockdown phase in this sample with a history of MDD. Those with low pre-lockdown depression experienced an increase in depression levels during the “new normality”. We observed a significant decrease in the depression levels during the “new normality” in those with high pre-lockdown depression, compared to the pre-lockdown period.

Conclusion

These findings suggest that COVID-19 restrictions impacted on the depression of individuals diagnosed with MDD, depending on their pre-lockdown depression severity. Furthermore, these subjects worsened when the restrictions were harder, during the lockdown and the early post-lockdown.
TERTexpression is associated with metastasis from thin primaries, exhausted CD4+ T cells in melanoma and with DNA repair across cancer entities
Authors: Kuhn Christina Katharina , Meister Jaroslawna , Kreft Sophia , Stiller Mathias , Puppel Sven-Holger , Zaremba Anne , Scheffler Björn , Ullrich Vivien , Schöneberg Torsten , Schadendorf Dirk , Horn Susanne
Published: January 2023

Telomerase reverse transcriptase (TERT) promoter mutations occur frequently in cancer, have been associated with increasedTERTexpression and cell proliferation, and could potentially influence therapeutic regimens for melanoma. As the role ofTERTexpression in malignant melanoma and the non-canonical functions of TERT remain understudied, we aimed to extend the current knowledge on both types ofTERTalterations with respect to survival, further clinical and molecular parameters. Using multivariate models,TERTalterations were not consistently associated with survival in melanoma cohorts under immune checkpoint inhibition. The presence of CD4+ T cells increased withTERTexpression and correlated with the expression of exhaustion markers. While the frequency of promoter mutations did not change with Breslow thickness,TERTexpression was increased in metastases arising from thinner primaries. Enrichment analyses of single-cell RNA-seq showedTERTexpression is associated with genes involved in cell migration and dynamics of the extracellular matrix, supporting the role ofTERTduring invasion and metastasis. Co-regulated genes in several bulk tumors and single-cell RNA-seq cohorts also indicated non-canonical functions ofTERTrelated to mitochondrial DNA stability and nuclear DNA repair in line with increasedTERTexpression during chromothripsis (PCAWG cohort) and under hypoxic conditions (PCAWG and SKCM cohorts). Also in glioblastoma (Klughammer and PCAWG cohorts),TERTwas co-expressed with DNA repair genes. Our results thus indicate a relevance ofTERTexpression in melanoma metastasis, T cell dysfunction and DNA repair across cancer entities.

Significance

In addition to the frequently occurringTERTpromoter mutations, we testTERTexpression with respect to clinical and molecular associates, extending the canonical role ofTERTin melanoma and other cancer entities.
A targeted isotope dilution mass spectrometry assay for Osteopontin quantification in plasma of metastatic breast cancer patients
Authors: Leslie Andrew , Teh Eve , Druker Arik , Pinto Devanand M.
Published: January 2023

Osteopontin (OPN) is a secreted glycophosphoprotein that derives its name from its high abundance in bone and secretion by osteoblasts. It is also secreted by a number of immune cells and, therefore, is present in human plasma at nanogram per millilitre levels where it affects cell adhesion and motility. These properties implicate OPN as a promotor of tumor progression. Plasma OPN is primarily measured by enzyme-linked immunosorbent assay (ELISA). However, due to the complexity of the various OPN isoforms, conflicting results have been obtained on the use of OPN as a biomarker even in the same disease condition. These discrepant results may result from the difficulty in comparing ELISA results obtained with different antibodies that target unique OPN epitopes. Mass spectrometry can be used to quantify proteins in plasma and, by targeting OPN regions that do not bear post-translational modifications, may provide more consistent quantification. However, the low (ng/mL) levels in plasma present a significant analytical challenge. In order to develop a sensitive assay for plasma OPN, we explored a single-step precipitation method using a recently developed spin-tube format. Quantification was performed using isotope-dilution mass spectrometry. The concentration detection limit of this assay was 39 ± 15 ng/mL. The assay was applied to the analysis of plasma OPN in metastatic breast cancer patients.
Homeostasis at different backgrounds: The roles of overlayed feedback structures in vertebrate photoadaptation
Authors: Grini Jonas V. , Nygård Melissa , Ruoff Peter
Published: January 2023

We have studied the resetting behavior of eight basic integral controller motifs with respect to different but constant backgrounds. We found that the controllers split symmetrically into two classes: one class, based on derepression of the compensatory flux, leads to more rapid resetting kinetics as backgrounds increase. The other class, which directly activates the compensatory flux, shows a slowing down in the resetting at increased backgrounds. We found a striking analogy between the resetting kinetics of vertebrate photoreceptors and controllers based on derepression, i.e. vertebrate rod or cone cells show decreased sensitivities and accelerated response kinetics as background illuminations increase. The central molecular model of vertebrate photoadaptation consists of an overlay of three negative feedback loops with cytosolic calcium, cyclic guanosine monophosphate (cGMP) and cyclic nucleotide-gated (CNG) channels as components. While in one of the feedback loops the extrusion ofby potassium-dependent sodium-calcium exchangers (NCKX) can lead to integral control with cGMP as the controlled variable, the expected robust perfect adaptation of cGMP is lost, because of the two other feedback loops. They avoid thatlevels become too high and toxic. Looking at psychophysical laws, we found that in all of the above mentioned basic controllers Weber’s law is followed when a “just noticeable difference” (threshold) of 1% of the controlled variable’s set-point was considered. Applying comparable threshold pulses or steps to the photoadaptation model we find, in agreement with experimental results, that Weber’s law is followed for relatively high backgrounds, while Stephens’ power law gives a better description when backgrounds are low. Limitations of our photoadaption model, in particular with respect to potassium/sodium homeostasis, are discussed. Finally, we discuss possible implication of background perturbations in biological controllers when compensatory fluxes are based on activation.
Using Mechanistic Models and Machine Learning to Design Single-Color Multiplexed Nascent Chain Tracking Experiments
Authors: Raymond William S. , Ghaffari Sadaf , Aguilera Luis U. , Ron Eric , Morisaki Tatsuya , Fox Zachary R. , May Michael P. , Stasevich Timothy J. , Munsky Brian
Published: January 2023

mRNA translation is the ubiquitous cellular process of reading messenger-RNA strands into functional proteins. Over the past decade, large strides in microscopy techniques have allowed observation of mRNA translation at a single-molecule resolution for self-consistent time-series measurements in live cells. Dubbed Nascent chain tracking (NCT), these methods have explored many temporal dynamics in mRNA translation uncaptured by other experimental methods such as ribosomal profiling, smFISH, pSILAC, BONCAT, or FUNCAT-PLA. However, NCT is currently restricted to the observation of one or two mRNA species at a time due to limits in the number of resolvable fluorescent tags. In this work, we propose a hybrid computational pipeline, where detailed mechanistic simulations produce realistic NCT videos, and machine learning is used to assess potential experimental designs for their ability to resolve multiple mRNA species using a single fluorescent color for all species. Through simulation, we show that with careful application, this hybrid design strategy could in principle be used to extend the number of mRNA species that could be watched simultaneously within the same cell. We present a simulated example NCT experiment with seven different mRNA species within the same simulated cell and use our ML labeling to identify these spots with 90% accuracy using only two distinct fluorescent tags. The proposed extension to the NCT color palette should allow experimentalists to access a plethora of new experimental design possibilities, especially for cell signalling applications requiring simultaneous study of multiple mRNAs.
Increments in Visual Motion Coherence are More Readily Detected than Decrements
Authors: Wei Lai , Mitchell Autumn O. , Maunsell John H.R.
Published: January 2023

Understanding the circuits that access and read out information in the cerebral cortex to guide behavior remains a challenge for systems-level neuroscience. Recent optogenetic experiments targeting specific cell classes in mouse primary visual cortex (V1) have shown that mice are sensitive to optically-induced increases in V1 spiking, but are relatively insensitive to decreases in neuronal spiking of similar magnitude and time course. This asymmetry suggests that the readout of signals from cortex depends preferentially on increases in spike rate. We investigated whether humans display a similar asymmetry by measuring thresholds for detecting changes in the motion coherence of dynamic random dot stimuli. The middle temporal visual area (MT) has been shown to play an important role in discriminating random dot stimuli, and the responses of its individual neurons to dynamic random dots are well characterized. While both increments and decrements in motion coherence have heterogeneous effects on MT responses, increments cause on average more increases in firing rates. Consistent with this, we found that subjects are far more sensitive to increments of random dot motion coherence than to decrements of coherence. The magnitude of the difference in detectability was largely consistent with the expected difference in effectiveness of coherence increments and decrements in producing increases in MT spike rates. The results add strength to the notion that the circuit mechanisms that read out cortical signals are relatively insensitive to decrements in cortical spiking.
AI-assisted selection of mating pairs through simulation-based optimized progeny allocation strategies in plant breeding
Authors: Hamazaki Kosuke , Iwata Hiroyoshi
Published: January 2023

Emerging technologies such as genomic selection have been applied to modern plant and animal breeding to increase the speed and efficiency of variety release. However, breeding requires decisions regarding parent selection and mating pairs, which significantly impact the ultimate genetic gain of a breeding scheme. The selection of appropriate parents and mating pairs to increase genetic gain while maintaining genetic diversity is still an urgent need that breeders are facing. This study aimed to determine the best progeny allocation strategies by combining future-oriented simulations and numerical black-box optimization for an improved selection of parents and mating pairs. In this study, we focused on optimizing the allocation of progenies, and the breeding process was regarded as a black-box function whose input is a set of parameters related to the progeny allocation strategies and whose output is the ultimate genetic gain of breeding schemes. The allocation of progenies to each mating pair was parameterized according to a softmax function of multiple selection criteria. Different selection criteria are weighted in the function to balance genetic gains and genetic diversity optimally. The weighting parameters were then optimized by the black-box optimization algorithm called StoSOO via future-oriented breeding simulations. Simulation studies to evaluate the potential of our novel method revealed that the breeding strategy based on optimized weights attained almost 10% higher genetic gain than that with an equal allocation of progenies to all mating pairs within just four generations. Among the optimized strategies, those considering the expected genetic variance of progenies could maintain the genetic diversity throughout the breeding process, leading to a higher ultimate genetic gain than those without considering it. These results suggest that our novel method can significantly improve the speed and efficiency of variety development through optimized decisions regarding the selection of parents and mating pairs. In addition, by changing simulation settings, our future-oriented optimization framework for progeny allocation strategies can be easily implemented into general breeding schemes, contributing to accelerated plant and animal breeding with high efficiency.
Astrocytic connection to engram neurons Increased after learning
Authors: Kim Jooyoung , Sung Yongmin , Park HyoJin , Choi Dong Il , Kim Ji-il , Lee Hoonwon , Jung Min Kyo , Noh Seulgi , Ye Sanghyun , Lee Jiah , Islam Md Ariful , Chun Heejung , Mun Ji Young , Kaang Bong-Kiun
Published: January 2023

Astrocytes directly participate in learning and memory. However, the structural association between astrocytes and memory-encoding engram neurons after learning remains to be elucidated. We developed astrocyte-enhanced green fluorescent protein reconstitution across synaptic partners (eGRASP) to examine tripartite synapses between astrocytes and engram neurons. Using astrocyte-eGRASP, we found that astrocytes had increased connections to engram neurons after learning. Dendritic spines with astrocytic contacts showed enhanced morphology. Live-cell imaging of astrocyte-eGRASP revealed that astrocytic connections are stabilized by neuronal activity. These results indicate that astrocytes distinguish contact between engram neurons and generate engram-specific contact patterns during learning.
Antagonistic regulation of salt and sugar chemotaxis plasticity by a single chemosensory neuron inCaenorhabditis elegans
Authors: Tomioka Masahiro , Umemura Yusuke , Ueoka Yutaro , Chin Risshun , Katae Keita , Uchiyama Chihiro , Ike Yasuaki , Iino Yuichi
Published: January 2023

The nematodeCaenorhabditis elegansmemorizes various external chemicals, such as ions and odorants, during feeding. Here we find thatC. elegansis attracted to the monosaccharides glucose and fructose after exposure to these monosaccharides in the presence of food; however, it avoids them without conditioning. The attraction to glucose requires a left-sided ASE gustatory neuron called ASEL. ASEL activity increases when glucose concentration decreases. Optogenetic ASEL stimulation promotes forward movements; however, after glucose conditioning, it promotes turning, suggesting that after glucose conditioning, the behavioral output of ASEL activation switches toward glucose. We previously reported that chemotaxis toward sodium ion (Na+), which is sensed by ASEL, increases after Na+conditioning in the presence of food. Interestingly, glucose conditioning decreases Na+chemotaxis, and conversely, Na+conditioning decreases glucose chemotaxis, suggesting the reciprocal inhibition of learned chemotaxis to distinct chemicals. The activation of PKC-1, an nPKC ε/η ortholog, in ASEL promotes glucose chemotaxis and decreases Na+chemotaxis after glucose conditioning. Furthermore, genetic screening identified ENSA-1, an ortholog of the protein phosphatase inhibitor ARPP-16/19, which functions in parallel with PKC-1 in glucose-induced chemotactic learning toward distinct chemicals. These findings suggest that kinase–phosphatase signaling regulates the balance between learned behaviors based on glucose conditioning in ASEL, which might contribute to migration toward chemical compositions where the animals were previously fed.

Author summary

Caenorhabditis elegansresponds to compounds that taste salty, bitter, sour, etc. However, its response to sweet compounds is unclear. Here, we show thatC. elegansresponds to glucose through a chemosensory neuron called ASEL.C. elegansavoids high concentrations of glucose and learns to approach glucose after feeding in the presence of high glucose, dependent on the action of ASEL. The ASEL neuron has been reported to respond to salt and promotes salt attraction after feeding in the presence of high salt. We find that the feeding-associated attractive responses to glucose and salt are antagonistic. When encountered with a mixture of salt and glucose during feeding,C. eleganschanges its chemotactic response toward those chemicals according to the balance of each chemical in the mixture.C. elegansmay memorize the concentrations of the chemical mixture during feeding and migrates to the chemical composition previously fed, which may promote opportunities obtaining food. Furthermore, we find that kinase–phosphatase signaling, which modulates neurotransmission, in ASEL is required for chemotaxis based on information processing of salt and glucose.
A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments
Authors: Chidley Christopher , Darnell Alicia M. , Gaudio Benjamin L. , Lien Evan C. , Barbeau Anna M. , Vander Heiden Matthew G. , Sorger Peter K.
Published: January 2023

Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here, we report a CRISPRi/a screening platform to systematically interrogate the contribution of specific nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumor models. We applied this platform to identify the transporters of amino acids in leukemia cells and found that amino acid transport is characterized by high bidirectional flux that is dependent on the composition of the microenvironment. While investigating the role of transporters in cystine starved cells, we uncovered a novel role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumors and found that levels of glucose and amino acids can restrain proliferation in that environment. This study provides a framework for the systematic identification of critical cellular nutrient transporters, characterizing the function of such transporters, and studying how the tumor microenvironment impacts cancer metabolism.
Age specific impacts of vegetation functional traits on gastro-intestinal nematode parasite burdens in a large herbivore
Authors: Wiersma Ellis , Pakeman Robin J. , Bal Xavier , Pilkington Jill G. , Pemberton Josephine M. , Nussey Daniel H. , Sweeny Amy R.
Published: January 2023

Gastro-intestinal nematode (GIN) parasites play an important role in the ecological dynamics of many animal populations. Recent studies suggest fine-scale spatial variation in GIN infection dynamics are important in wildlife systems, but the environmental drivers underlying this variation remain poorly understood.

We used data from over two decades of GIN parasite egg counts, host space use, and spatial vegetation data from a long-term study of Soay sheep on St Kilda to test how spatial autocorrelation and vegetation in an individual’s home range predict parasite burden across three age groups. We developed a novel approach to quantify the plant functional traits present in a home range to describe the quality of vegetation present.

Effects of space and vegetation varied between age classes. In immature lambs, strongyle parasite faecal egg counts (FEC) were spatially structured, being highest in the north and south of our study area. Independent of host body weight and spatial autocorrelation, plant functional traits predicted parasite egg counts. Higher egg counts were associated with more digestible and preferred plant functional traits, suggesting the association could be driven by host density and habitat preference.

In contrast, we found no evidence that parasite FEC were related to plant functional traits in the host home range in yearlings or adult sheep. Adult FEC were spatially structured, with highest burdens in the north-east of our study area, while yearling FEC showed no evidence of spatial structuring.

Our findings support the importance of fine-scale environmental variation for wildlife disease ecology and provides new evidence that such effects may vary across demographic groups within a population. Parasite burdens in immature individuals appear more readily influenced by fine-scale spatial variation in the environment, highlighting the importance of such heterogeneity for our understanding of wildlife epidemiology and health.
Single-molecule displacement mapping indicates unhindered intracellular diffusion of small (<~1 kDa) solutes
Authors: Choi Alexander A. , Xiang Limin , Li Wan , Xu Ke
Published: January 2023

While fundamentally important, the intracellular diffusion of small (<~1 kDa) solutes has been difficult to elucidate due to challenges in both labeling and measurement. Here we quantify and spatially map the translational diffusion patterns of small solutes in mammalian cells by integrating several recent advances. In particular, by executing tandem stroboscopic illumination pulses down to 400-μs separation, we extend single-molecule displacement/diffusivity mapping (SMdM), a super-resolution diffusion quantification tool, to small solutes with high diffusion coefficientsDof >300 μm2/s. We thus show that for multiple water-soluble dyes and dye-tagged nucleotides, intracellular diffusion is dominated by vast regions of high diffusivity ~60-70% of thatin vitro, up to ~250 μm2/s in the fastest cases. Meanwhile, we also visualize sub-micrometer foci of substantial slowdowns in diffusion, thus underscoring the importance of spatially resolving the local diffusion behavior. Together, these results suggest that the intracellular diffusion of small solutes is only modestly scaled down by the slightly higher viscosity of the cytosol over water, but otherwise not further hindered by macromolecular crowding. We thus lift a paradoxically low speed limit for intracellular diffusion suggested by previous experiments.

Abstract Graphic
Two conformations of the Tom20 preprotein receptor in the TOM holo complex
Authors: Ornelas Pamela , Bausewein Thomas , Martin Janosch , Morgner Nina , Nussberger Stephan , Kühlbrandt Werner
Published: January 2023

The TOM complex is the main entry point for precursor proteins into mitochondria. Precursor proteins containing targeting sequences are recognized by the TOM complex and imported into the mitochondria. We have determined the structure of the TOM core complex fromNeurospora crassaby single-particle cryoEM at 3.3 Å resolution, showing its interaction with a bound presequence at 4 Å resolution, and of the TOM holo complex including the Tom20 receptor at 6-7 Å resolution. TOM is a transmembrane complex consisting of two β-barrels, three receptor subunits and three short transmembrane subunits. Tom20 has a transmembrane helix and a receptor domain on the cytoplasmic side. We propose that Tom20 acts as a dynamic gatekeeper, guiding precursor proteins into the pores of the TOM complex. We analyze the interactions of Tom20 with other TOM subunits, present insights into the structure of the TOM holo complex, and suggest a translocation mechanism.
Homeostatic Reinforcement Theory Accounts for Sodium Appetitive State- and Taste-Dependent Dopamine Responding
Authors: Duriez Alexia , Bergerot Clemence , Cone Jackson J. , Roitman Mitchell F. , Gutkin Boris
Published: January 2023

Seeking and consuming nutrients is essential to survival and maintenance of life. Dynamic and volatile environments require that animals learn complex behavioral strategies to obtain the necessary nutritive substances. While this has been classically viewed in terms of homeostatic regulation, where complex nutrient seeking behaviors are triggered by physiological need, recent theoretical work proposed that such strategies are a result of reinforcement learning processes. This theory also proposed that phasic dopamine (DA) signals play a key role in signaling potentially need-fulfilling outcomes. To examine potential links between homeostatic and reinforcement learning processes, we focus on sodium appetite as sodium depletion triggers state and taste dependent changes in behavior and DA signaling evoked by sodium-related stimuli. We find that both the behavior and the dynamics of DA signaling underlying sodium appetite can be accounted for by extending principles of homeostatic regulation into a reinforcement learning framework (HRRL). We first optimized HRRL-based agents to model sodium-seeking behavior measured in rats. Agents successfully reproduced the state and the taste dependence of behavioral responding for sodium as well as for lithium and potassium salts. We then show that these same agents can account for the regulation of DA signals evoked by sodium tastants in a taste and state dependent manner. Our models quantitatively describe how DA signals evoked by sodium decrease with satiety and increase with deprivation suggesting that phasic DA signals and sodium consumption are down regulated prior to animals reaching satiety. Lastly, our HRRL agents also account for the behavioral and neurophysiological observations that suggest mice cannot distinguish between sodium and lithium containing salts. Our HRRL agents exhibited an equal preference for sodium versus lithium containing solutions, and underestimated the nutritional value of sodium when lithium was concurrently available. We propose that animals use orosensory signals as predictors of the internal impact of the consumed good and our results pose clear targets for future experiments. In sum, this work suggests that appetite-dirven behavior may be driven by reinforcement learning mechanisms that are dynamically tuned by homeostatic need.
Gallionellaceae pangenomic analysis reveals insight into phylogeny, metabolic flexibility, and iron oxidation mechanisms
Authors: Hoover Rene L. , Keffer Jessica L. , Polson Shawn W. , Chan Clara S.
Published: January 2023

The iron-oxidizing Gallionellaceae drive a wide variety of biogeochemical cycles through their metabolisms and biominerals. To better understand the environmental impacts of Gallionellaceae, we need to improve our knowledge of their diversity and metabolisms, especially any novel iron oxidation mechanisms. Here, we used a pangenomic analysis of 103 genomes to resolve Gallionellaceae phylogeny and explore the range of genomic potential. Using a concatenated ribosomal protein tree and key gene patterns, we determined Gallionellaceae has four genera, divided into two groups–iron-oxidizing bacteria (FeOB)Gallionella,Sideroxydans, andFerriphaseluswith known iron oxidases (Cyc2, MtoA) and nitrite-oxidizing bacteria (NOB)CandidatusNitrotoga with nitrite oxidase (Nxr). The FeOB and NOB have similar electron transport chains, including genes for reverse electron transport and carbon fixation. Auxiliary energy metabolisms including S oxidation, denitrification, and organotrophy were scattered throughout the Gallionellaceae FeOB. Within FeOB, we found genes that may represent adaptations for iron oxidation, including a variety of extracellular electron uptake (EEU) mechanisms. FeOB genomes encoded more predictedc-type cytochromes overall, notably more multihemec-type cytochromes (MHCs) with >10 CXXCH motifs. These include homologs of several predicted outer membrane porin-MHC complexes, including MtoAB and Uet. MHCs are known to efficiently conduct electrons across longer distances and function across a wide range of redox potentials that overlap with mineral redox potentials, which can help expand the range of usable iron substrates. Overall, the results of pangenome analyses suggest that the Gallionellaceae generaGallionella,Sideroxydans, andFerriphaselusare primarily iron oxidizers, capable of oxidizing dissolved Fe2+as well as a range of solid iron or other mineral substrates.

Importance

Neutrophilic iron-oxidizing bacteria (FeOB) produce copious iron (oxyhydr)oxides that can profoundly influence biogeochemical cycles, notably the fate of carbon and many metals. To fully understand environmental microbial iron oxidation, we need a thorough accounting of iron oxidation mechanisms. In this study we show the Gallionellaceae FeOB have both known iron oxidases as well as uncharacterized multiheme cytochromes (MHCs). MHCs are predicted to transfer electrons from extracellular substrates and likely confer metabolic capabilities that help Gallionellaceae occupy a range of different iron- and mineral-rich niches. Gallionellaceae appear to specialize in iron oxidation, so it makes sense that they would have multiple mechanisms to oxidize various forms of iron, given the many iron minerals on Earth, as well as the physiological and kinetic challenges faced by FeOB. The multiple iron/mineral oxidation mechanisms may help drive the widespread ecological success of Gallionellaceae.
HOS1 promotes plant tolerance to low-energy stressviathe SnRK1 protein kinase
Authors: Margalha Leonor , Elias Alexandre , Belda-Palazón Borja , Peixoto Bruno , Confraria Ana , Baena-González Elena
Published: January 2023

Plants need to integrate internal and environmental signals to mount adequate stress responses. The NUCLEAR PORE COMPLEX (NPC) component HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 1 (HOS1) is emerging as such an integrator, affecting responses to cold, heat, light and salinity. Stress conditions often converge in a low-energy signal that activates SUCROSE NON-FERMENTING 1-RELATED KINASE 1 (SnRK1) to promote stress tolerance and survival. Here, we explored the role of HOS1 in the SnRK1-dependent response to low-energy stress inArabidopsis thaliana, using darkness as a treatment and a combination of genetic, biochemical and phenotypic assays. We show that the induction of starvation genes and plant tolerance to prolonged darkness are defective in thehos1mutant. HOS1 interacts physically with the SnRK1α1 catalytic subunit in yeast-two-hybrid andin planta, and the nuclear accumulation of SnRK1α1 is reduced in thehos1mutant. Likewise, another NPC mutant,nup160, exhibits lower activation of starvation genes and decreased tolerance to prolonged darkness. Importantly, defects in low-energy responses in thehos1background are rescued by fusing SnRK1α1 to a potent nuclear localization signal, or by sugar supplementation during the dark treatment. Altogether, this work demonstrates the importance of HOS1 for the nuclear accumulation of SnRK1α1, which is key for plant tolerance to low-energy conditions.
Export of diverse and bioactive peptides through a type I secretion system
Authors: Kim Sun-Young , Parker Jennifer K. , Gonzalez-Magaldi Monica , Telford Mady S. , Leahy Daniel J. , Davies Bryan W.
Published: January 2023

Microcins are peptide antibiotics secreted by Gram-negative bacteria that inhibit the growth of neighboring microbes. They are exported from the cytosol to the environment in a one-step process through a specific type I secretion system (T1SS). While the rules governing export of natural or non-native substrates have been resolved for T1SSs that secrete large proteins, relatively little is known about substrate requirements for peptides exported through T1SSs that secrete microcins. Here, we investigate the prototypic microcin V T1SS fromEscherichia coliand show it can export a remarkably wide range of natural and synthetic peptides. We demonstrate that secretion through this system is not affected by peptide charge or hydrophobicity and appears only constrained by peptide length. A varied range of bioactive peptides, including an antibacterial peptide, a microbial signaling factor, a protease inhibitor, and a human hormone, can all be secreted and elicit their intended biological effect. Secretion through this system is not limited toE. coli, and we demonstrate its function in additional Gram-negative species that can inhabit the gastrointestinal tract. Our findings uncover the highly promiscuous nature of peptide export thorough the microcin V T1SS, which has implications for native cargo capacity and use of Gram-negative bacteria for peptide research and delivery.

Importance

Microcin type I secretion systems in Gram-negative bacteria transport antibacterial peptides from the cytoplasm to the extracellular environment in single step. In nature, each microcin secretion system is generally paired with a specific peptide. We know little about the export capacity of these transporters and how peptide sequence influences secretion. Here, we investigate the microcin V type I secretion system. Remarkably, our studies show this system can export diverse peptides and is only limited by peptide length. Furthermore, we demonstrate that various bioactive peptides can be secreted, and this system can be used in Gram-negative species that colonize the gastrointestinal tract. These finding expand our understanding of secretion through type I systems and their potential uses in peptide applications.