bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary protein splanchnic uptake and digestibility via stable isotope tracers
Authors: Cox Jake , Wilkinson Daniel James , Atherton Philip James , Smith Kenneth
Published: July 2024

Purpose of review

Dietary proteins are broken down into peptides across the gastrointestinal tract, with skeletal muscle being a primary deposition site for amino acids in the form of incorporation into, for example, metabolic and structural proteins. It follows that key research questions remain as to the role of amino acid bioavailability, of which protein digestibility and splanchnic sequestration (absorption and utilization) of amino acids are determining factors, impact upon muscle protein synthesis (MPS) in clinical states.

Recent findings

Elevated splanchnic amino acid uptake has been implicated in anabolic resistance (i.e. attenuated anabolic responses to protein intake) observed in ageing, though it is unclear whether this limits MPS. The novel ‘dual stable isotope tracer technique’ offers a promising, minimally invasive approach to quantify the digestion of any protein source(s). Current work is focused on the validation of this technique against established methods, with scope to apply this to clinical and elderly populations to help inform mechanistic and interventional insights.

Considerations should be made for all facets of protein quality; digestibility of the protein, absorption/utilization and subsequent peripheral bioavailability of amino acids, and resultant stimulation of MPS. Stable isotope tracer techniques offer a minimally invasive approach to achieve this, with wide-ranging clinical application.
Use of SATB2 and CDX2 Immunohistochemistry to Characterize and Diagnose Colorectal Cancer
Authors: Kato Shunsuke , Koshino Akira , Lasota Jerzy , Komura Masayuki , Wang Chengbo , Ebi Masahide , Ogasawara Naotaka , Kojima Kazuhisa , Tsuzuki Toyonori , Kasai Kenji , Takahashi Satoru , Miettinen Markku , Kasugai Kunio , Inaguma Shingo
Published: July 2024

SATB2 has been reported to be highly specific for lower gastrointestinal tract tumors. On the basis of its ileum–colon conversion effects, which involve the activation of colonic genes in cooperation with CDX2 and HNF4A, we hypothesized that SATB2 and CDX2 might define the characteristics of colorectal cancers (CRCs). In the present study, the clinicopathologic and immunohistochemical characteristics of 269 CRCs were analyzed according to SATB2 and CDX2 expression. CRCs with SATB2− and/or CDX2− phenotypes showed associations with poorly differentiated histotypes (P<0.00001), mucus production (P=0.0019), and mismatch repair-deficient phenotypes (P<0.00001). SATB2−/CDX2− CRCs were significantly associated with CK20-negativity, with or without CK7 expression (P<0.00001), as well as with MUC5AC-positivity (P<0.00001), and CD10-negativity (P=0.00047). Negativity for SATB2 or CDX2 was associated with the expression of PD-L1 in both all CRC (P<0.00001) and mismatch repair-proficient CRC (P=0.000091). Multivariate Cox hazard regression analysis identified negativity for SATB2 and/or CDX2 as potential independent risk factors for patients with CRC. Regarding the diagnostic utility of SATB2, all of the 44 CRC metastases could be diagnosed as colorectal in origin if the immunohistochemical phenotypes (including CK7, CK20, and p53) of the primary lesions and patient history were considered. Among the other 684 tumors, we were unable to distinguish a case of CK7−/CK20+/CDX2+/SATB2+ ovarian mucinous cystadenocarcinoma from metastatic CRC without the patient history and clinical information.
ODMAP: Stakeholder Perspectives on a Novel Public Health and Public Safety Overdose Surveillance System
Authors: Allen Bennett , Cohen-Serrins Julian
Published: July 2024

This pilot study explores the utilization of the Overdose Detection Mapping Application Program (ODMAP) as a tool for enhancing collaboration between the public health and public safety sectors to address the overdose epidemic in the United States. Through qualitative interviews with ODMAP users, key themes emerged, including the role of data sharing in facilitating collaboration, challenges posed by divergent data privacy standards, and the need for clearer guidance on cross-sector data sharing. Findings highlight ODMAP’s potential to integrate data for targeted interventions at individual and population levels. Future research directions include overcoming data sharing barriers, strategically utilizing data across sectors, and rigorously evaluating the impact of cross-sector partnerships on overdose morbidity and mortality. Overall, this study underscores the importance of ODMAP in fostering coordinated responses to the overdose crisis and provides valuable insights for improving overdose surveillance and intervention efforts.
Local-manifold-distance-based regression: an estimation method for quantifying dynamic biological interactions with empirical time series
Authors: Kawatsu Kazutaka
Published: July 2024

Quantifying species interactions based on empirical observations is crucial for ecological studies. Advancements in nonlinear time-series analyses, particularly S-maps, are promising for high-dimensional and non-equilibrium ecosystems. S-maps sequentially perform a local linear model fitting to the time evolution of neighbouring points on the reconstructed attractor manifold, and the coefficients can approximate the Jacobian elements corresponding to interaction effects. However, despite that the advantages in nonlinear forecasting with noise-contaminated data, these methodologies have a limitation in the Jacobian estimation accuracy owing to non-equidistantly stretched local manifolds in the state space. Herein, we therefore introduced a local manifold distance (LMD) concept, a non-equidistant measure based on the multi-faceted state dependency. By integrating LMD with advanced computation techniques, we presented a robust and efficient analytical method, LMD-based regression (LMDr). To validate its advantages in prediction and Jacobian estimation, we analysed synthetic time series of model ecosystems with different noise levels and applied it to an experimental protozoan predator–prey system with established biological information. The robustness to noise was the highest for LMDr, which also showed a better correspondence to expected predator–prey interactions in the protozoan system. Thus, LMDr can be applied to study complex ecological networks under dynamic conditions.
Validating the concept of top scavenger: the Andean Condor as a model species
Authors: Méndez Diego , Vargas Félix Hernán , Sarasola José Hernán , Olea Pedro P.
Published: July 2024

Vultures provide the key ecosystem service of quickly removing carrion, so they have recently been assumed to be top scavengers. To challenge the concept of top scavenger (i.e. the most influential in the scavenging community and process), between 2012 and 2019, we recorded the consumption of 45 equine carcasses available for two different avian scavenger guilds in the Tropical Andes; each guild included the Andean Condor, the alleged top scavenger. The carcasses eaten by Andean Condors were consumed, on average, 1.75 times faster than those they did not eat. Furthermore, the greater abundance of feeding condors shortened carcass consumption time more than a greater abundance of any other species by 1.65 to 5.96 times, on average. These findings support the hypothesis that the Andean Condor significantly drives scavenging dynamics and is, therefore, an unrestricted top scavenger. Additionally, we established a gradient of tolerance of avian scavengers to domestic dog disturbance at carcasses, from highest to lowest: vultures > caracaras > condors. Our study framework holds great potential for advancing in food webs’ comprehension through quantifying the relative functional role of scavenging communities’ members and for guiding efforts to weigh up the ecological contributions of top scavengers and foster their conservation.
Mitochondrial function is enhanced by thyroid hormones during zebra finch development
Authors: Oefele Marlene , Hau Michaela , Ruuskanen Suvi , Casagrande Stefania
Published: July 2024

An organism’s response to its environment is largely determined by changes in the energy supplied by aerobic mitochondrial metabolism via adenosine triphosphate (ATP) production. ATP is especially important under energy-demanding conditions, such as during rapid growth. It is currently poorly understood how environmental factors influence energy metabolism and mitochondrial functioning, but recent studies suggest the role of thyroid hormones (TH). TH are key regulators of growth and metabolism and can be flexibly adjusted to environmental conditions, such as environmental temperature or food availability. To test whether TH enhancement is causally linked to mitochondrial function and growth, we provided TH orally at physiological concentrations during the main growth phase in zebra finch (
Taeniopygia guttata
) nestlings reared in a challenging environment. TH treatment accelerated maximal mitochondrial working capacity—a trait that reflects mitochondrial ATP production, without affecting growth. To our knowledge, this is the first study to characterize the regulation of mitochondria by TH during development in a semi-naturalistic context and to address implications for fitness-related traits, such as growth.
Context-driven communication during deep-sea foraging in a social toothed whale
Authors: Hessing Sanne , Risser Nolwenn , Pichot Loanne , Oudejans Machiel G. , Guilpin Marie , Barcelos Luís M. D. , Curé Charlotte , Visser Fleur
Published: July 2024

Social deep-diving odontocetes face the challenge of balancing near-surface proximity to oxygen and group members with foraging in the deep sea. Individuals rely on conspecifics for critical life functions, such as predator defence, but disperse during foraging to feed individually. To understand the role of social acoustic mediation during foraging in deep-diving toothed whales, we investigated the context of social burst-pulse call production in Risso’s dolphin (
Grampus griseus
) using biologgers. Dolphins produced context-specific burst pulses predominantly during daytime foraging, preceding or following foraging dives and in the early descent of daytime deep dives. Individuals applied differential short and long burst-pulse calls intended for either near-surface receivers (horizontal transmission) or deep-foraging receivers (vertical transmission). Our results show that deep-diving toothed whales are reliant on acoustic communication during certain foraging contexts, to relay information including foraging conditions or an individual’s location. Moreover, they accentuate the importance of maintaining acoustic contact with conspecifics, specifically when dispersed during deeper foraging. It also signifies that our oceanic top predators may be specifically vulnerable to the current strong increase in anthropogenic noise. Potential masking of the signals from group members communicating at a distance could undermine their social cohesion, and hence their capacity to maintain vital life functions.
Rickettsia
induces strong cytoplasmic incompatibility in a predatory insect
Authors: Owashi Yuta , Arai Hiroshi , Adachi-Hagimori Tetsuya , Kageyama Daisuke
Published: July 2024

Rickettsia
, a group of intracellular bacteria found in eukaryotes, exhibits diverse lifestyles, with some acting as vertebrate pathogens transmitted by arthropod vectors and others serving as maternally transmitted arthropod endosymbionts, some of which manipulate host reproduction for their own benefit. Two phenotypes, namely male-killing and parthenogenesis induction are known as
Rickettsia
-induced host reproductive manipulations, but it remains unknown whether
Rickettsia
can induce other types of host manipulation. In this study, we discovered that
Rickettsia
induced strong cytoplasmic incompatibility (CI), in which uninfected females produce no offspring when mated with infected males, in the predatory insect
Nesidiocoris tenuis
(Hemiptera: Miridae). Molecular phylogenetic analysis revealed that the
Rickettsia
strain was related to
Rickettsia bellii
, a common insect endosymbiont. Notably, this strain carried plasmid-encoded homologues of the CI-inducing factors (namely
cifA
-like and
cifB
-like genes), typically found in
Wolbachia
, which are well-known CI-inducing endosymbionts. Protein domain prediction revealed that the
cifB
-like gene encodes PD-(D/E)XK nuclease and deubiquitinase domains, which are responsible for
Wolbachia
-induced CI, as well as ovarian tumour-like (OTU-like) cysteine protease and ankyrin repeat domains. These findings suggest that
Rickettsia
and
Wolbachia
endosymbionts share underlying mechanisms of CI and that CI-inducing ability was acquired by microbes through horizontal plasmid transfer.
Age dominates flight distance and duration, while body size shapes flight speed in
Bombus terrestris
L. (Hymenoptera: Apidae)
Authors: Gilgenreiner Milena , Kurze Christoph
Published: July 2024

Flight plays a crucial role in the fitness of insect pollinators, such as bumblebees. Despite their relatively large body size compared with their wings, bumblebees can fly under difficult ambient conditions, such as cooler temperatures. While their body size is often positively linked to their foraging range and flight ability, the influence of age remains less explored. Here, we studied the flight performance (distance, duration and speed) of ageing bumblebee workers using tethered flight mills. Additionally, we measured their intertegular distance and dry mass as proxies for their body size. We found that the flight distance and duration were predominantly influenced by age, challenging assumptions that age does not play a key role in foraging and task allocation. From the age of 7 to 14 days, flight distance and duration increased sixfold and fivefold, respectively. Conversely, the body size primarily impacted the maximum and average flight speed of workers. Our findings indicate that age substantially influences the flight distance and duration in bumblebee workers, affecting foraging performance and potentially altering task allocation strategies. This underscores the importance of considering individual age and physiological changes alongside body size/mass in experiments involving bumblebee workers.
Context-dependent effects of thermal acclimation on physiological correlates of animal personality in Asiatic toads
Authors: Tan Song , Li Juan , Chen Jingfeng , Fu Jinzhong
Published: July 2024

Persistent individual variation in behaviour, or ‘personality’, is a widespread phenomenon in animals, and understanding the evolution of animal personality is a key task of current biology. Natural selection has been proposed to promote the integration of personality with animal ‘intrinsic states’, such as metabolic or endocrine traits, and this integration varies with ecological conditions. However, these external ecological modulatory effects have rarely been examined. Here, we investigate the effects of thermal acclimation on between-individual covariations between physiology and behaviour in Asiatic toads (
Bufo gargarizans
) along an altitudinal gradient. Our results reveal that the thermal modulatory effects on the covariations depend on the altitudinal population. Specifically, at low altitudes, between-individual covariations are highly plastic, with risk-taking behaviour covarying with baseline glucocorticoids (GCs) under warm acclimation, but risk-taking and exploration behaviour covarying with resting metabolic rate (RMR) under cold acclimation. In contrast, between-individual covariations are relatively fixed at high altitudes, with risk-taking behaviour consistently covarying with baseline GCs. Furthermore, at low altitudes, changes in covariations between RMR and personality are associated with adjustment of energy management models. Evidently, animal physiological states that determine or covary with personality can adapt according to the seasonal thermal environment and the thermal evolutionary background of populations. Our findings highlight the importance of a multi-system physiological approach to understand the evolution of animal personality.
Mesorhizobium retamae sp. nov., a novel non-nodulating and non-nitrogen-fixing species isolated from the root nodules of Retama raetam sampled in Tunisia
Authors: Ben Gaied Roukaya , Sbissi Imed , Tarhouni Mohamed , Huber Katharina , Wolf Jacqueline , Neumann-Schaal Meina , Nouioui Imen , Ghodhbane-Gtari Faten , Gtari Maher
Published: July 2024

A comprehensive polyphasic taxonomic investigation integrating taxongenomic criteria was conducted on strain IRAMC:0171T isolated from the root nodules of Retama raetam in Tunisia. This Gram-stain-negative and aerobic bacterium thrived within a temperature range of 5–45 °C, optimal at 28 °C, and tolerated salt concentrations from 0–6 % NaCl, with an optimal range of 0–3 %. It displayed pH tolerance from pH 4 to 10, thriving best at pH 6.8–7.5. Chemotaxonomically, strain IRAMC:0171T was characterized by diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, and phosphatidylethanolamine as polar lipids. Its predominant fatty acid composition was C18 : 1
 ω7c (61.2 %), and the primary ubiquinone was Q10 (97 %). Analysis of the 16S rRNA gene of strain IRAMC:0171T showed 99.08 % similarity to Mesorhizobium waimense ICMP 19557T, Mesorhizobium amorphae ACCC 19665T, and Mesorhizobium huakuii IAM 14158. However, digital DNA–DNA hybridization and average nucleotide identity analyses revealed values ranging from 21.1 to 25.2 % and 77.05 to 82.24 %, respectively, signifying significant deviation from established species demarcation thresholds. Phylogenetic studies, encompassing 16S rRNA, whole-genome-based tree reconstruction, and core protein analysis, positioned strain IRAMC:0171T closest to Mesorhizobium terrae KCTC 72278T and ‘Mesorhizobium hungaricum’ UASWS1009T, forming together a distinct branch within the genus Mesorhizobium. In consideration of this comprehensive data, we propose strain IRAMC:0171T (=DSM 112841T=CECT 30767T) as the type strain of a new species named Mesorhizobium retamae sp. nov.
Artificial Intelligence Algorithms in Nailfold Capillaroscopy Image Analysis: A Systematic Review
Authors: Emam Omar S. , Ebadi Jalal Mona , Garcia-Zapirain Begonya , Elmaghraby Adel S.
Published: July 2024

Background

Non-invasive imaging modalities offer a great deal of clinically significant information that aid in the diagnosis of various medical conditions. Coupled with the never-before-seen capabilities of Artificial Intelligence (AI), uncharted territories that offer novel innovative diagnostics are reached. This systematic review compiled all studies that utilized AI in Nailfold Capillaroscopy as a future diagnostic tool.

Methods and Findings

Five databases for medical publications were searched using the keywords artificial intelligence, machine learning, deep learning and nailfold capillaroscopy to return 105 studies. After applying the eligibility criteria, 10 studies were selected for the final analysis. Data was extracted into tables that addressed population characteristics, AI model development and nature and results of their respective performance. We found supervised deep learning approaches to be the most commonly used (n= 8). Systemic Sclerosis was the most commonly studied disease (n= 6). Sample size ranged from 17,126 images obtained from 289 participants to 50 images from 50 participants. Ground truth was determined either by experts labelling (n= 6) or known clinical status (n= 4). Significant variation was noticed in model training, testing and feature extraction, and therefore the reporting of model performance. Recall, precision and Area Under the Curve were the most used metrics to report model performance. Execution times ranged from 0.064 to 120 seconds per image. Only two models offered future predictions besides the diagnostic output.

Conclusions

AI has demonstrated a truly remarkable potential in the interpretation of Nailfold Capillaroscopy by providing physicians with an intelligent decision-supportive tool for improved diagnostics and prediction. With more validation studies, this potential can be translated to daily clinical practice.
Paternal genome elimination creates contrasting evolutionary trajectories in male and female citrus mealybugs
Authors: Mongue Andrew J. , Woodman Tamsin , Marshall Hollie , Garber Arkadiy , Franco José C. , McCutcheon John P. , Ross Laura
Published: July 2024

Most studies of sex-biased genes explore their evolution in familiar chromosomal sex determination systems, leaving the evolution of sex differences under alternative reproductive systems unknown. Here we explore the system of paternal genome elimination employed by mealybugs (Hempitera: Pseudococcidae) which have no sex chromosomes. Instead, all chromosomes are autosomal and inherited in two copies, but sex is determined by the ploidy of expression. Females express both parental alleles, but males reliably silence their paternally inherited chromosomes, creating genome-wide haploid expression in males and diploid expression in females. Additionally, sons do not express alleles directly inherited from their fathers, potentially disrupting the evolution of male-benefitting traits. To understand how these dynamics impact molecular evolution, we generated sex-specific RNAseq, a new gene annotation, and whole-genome population sequencing of the citrus mealybug,Planococcus citri. We found that genes expressed primarily in females hold more variation and evolve more quickly than those expressed in males or both sexes. Conversely, more adaptation occurs in genes expressed mainly in males than those expressed in females. Put together, paternal genome elimination appears to slow change on the male side but, by increasing selective scrutiny, increase the amount of adaptation in these genes. These results expand our understanding of evolution in a non-mendelian genetic system and the data we generated should prove useful for future research on this pest insect.
Artifacts in single-cell mitochondrial DNA mutation analyses misinform phylogenetic inference
Authors: Lareau Caleb A. , Chapman Michael S. , Penter Livius , Nawy Tal , Pe’er Dana , Ludwig Leif S.
Published: July 2024

Sequencing mitochondrial DNA (mtDNA) variants from single cells has resolved clonality and lineage in native human samples and clinical specimens. Prior work established that heteroplasmic mtDNA variants can be used to delineate clonality in hematopoiesis, but they have limited ability to reconstruct cellular phylogenies. However, a recent report by Wenget al. challenges the current paradigm by describing an unprecedented number of shared mtDNA variants between cells that reportedly resolve high-resolution phylogenetic trees. We re-examined the claims of Wenget al., and identified two major points of concern regarding this unprecedented connectedness. First, shared variants between cells are disproportionately detected in a single molecule per cell, and second, these variants are enriched 10–20-fold at the edges of mtDNA molecules, reminiscent of artifacts reported in other sequencing approaches. Further, our analyses show that pruning low support and likely artificial mtDNA variants removes nearly all of the reported phylogenetic structure. Thus, we strongly caution against using mtDNA variant calling workflows that rely on minimal evidence, including the computational pipeline introduced in Wenget al., as variants with high connectedness and low evidence are likely artifacts that lead to the construction of false phylogenies.
Biomarker Discovery in Alzheimer’s and Neurodegenerative Diseases using Nucleic Acid-Linked Immuno-Sandwich Assay
Authors: Ashton Nicholas J. , Benedet Andrea L. , Di Molfetta Guglielmo , Pola Ilaria , Anastasi Federica , Fernández-Lebrero Aida , Puig-Pijoan Albert , Keshavan Ashvini , Schott Jonathan , Tan Kubra , Montoliu-Gaya Laia , Isaacson Richard , Bongianni Matilde , Tolassi Chiara , Cantoni Valentina , Alberici Antonella , Padovani Alessandro , Zanusso Gianluigi , Pilotto Andrea , Borroni Barbara , Suárez-Calvet Marc , Blennow Kaj , Zetterberg Henrik
Published: July 2024

INTRODUCTION

Recent advancements in immunological methods accurately quantify biofluid biomarkers for identifying Alzheimer’s pathology and neurodegeneration. Despite this progress, more biomarkers, ideally in blood, are needed for effective patient management and disease monitoring for Alzheimer’s disease (AD) and other neurodegenerative proteinopathies.

METHODS

We employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system (CNS) panel for biomarker quantification in plasma, serum and cerebrospinal fluid (CSF) of patients with AD, mild cognitive impairment, Lewy body dementia, progranulin (GRN) mutation carriers and matched controls.

RESULTS

NULISA™ identified p-tau217 and NfL as the most significantly deregulated plasma biomarkers in the AD continuum andGRNmutation carriers, respectively. Importantly, numerous novel and significant proteomic changes were observed in each disease comparison, which included proteins involved in synaptic processing, inflammation, microglial reactivity, TDP-43 and α-synuclein pathology. Plasma and serum act as complimentary biofluids.

CONCLUSION

We highlight the potential of next-generation biomarker identification tools, such as NULISA™, to detect novel proteomic features that incorporate established biomarkers like p-tau217 and NfL. These findings highlight the importance of continued biomarker discovery to enhance patient management, improve treatment decisions, and better understand the complexities of neurodegenerative disorders.
Evaluation of Hepatitis B core related antigen (HBcrAg) as a biomarker in cohorts from the United Kingdom and South Africa
Authors: Downs Louise O , Delphin Marion , Schalwyk Marije van , Hugo Susan , Gabriel Shiraaz , Lumley Sheila F , Waddilove Elizabeth , Wang Tingyan , Lara Catherine de , Babbs Arran , Wareing Sue , Fengou Polyxeni , Andersson Monique I , Glashoff Richard , Martin Jacqueline , Ansari M. Azim , Agarwal Kosh , Dusheiko Geoffrey , Taljaard Jantjie , Preiser Wolfgang , Barnes Eleanor , Kelly Gavin , Carey Ivana , Shimakawa Yusuke , Maponga Tongai , Matthews Philippa C
Published: July 2024

Introduction

Better understanding of hepatitis B virus (HBV) biomarkers is needed. We evaluated Hepatitis B core related antigen (HBcrAg), in the United Kingdom (UK) and South Africa (SA).

Methods

We undertook a cross-sectional retrospective observational study of adults with chronic HBV infection from the UK (n=142) and SA (n=211). We recorded clinical and laboratory parameters and quantified HBcrAg. We report HBcrAg distribution, relationship with other biomarkers, and performance in risk stratification based on point of care test (POCT) thresholds.

Results

SA and UK cohorts were similar in sex and age (p>0.05), but significantly different in ethnicity, HIV coinfection, HBeAg-positivity and proportion with HBV viral load (VL) >200,000 IU/ml (all p<0.001). More of the untreated SA population had HBcrAg >5.3 log10U/ml compared to the UK (33% vs 9% respectively, p<0.0001). HBcrAg ≥4.3 log10U/ml (corresponding to a positive POCT) was 100% sensitive and 92% specific for predicting VL >200,000 IU/ml in the UK, but not SA. HBcrAg positively correlated with alanine transferase (ALT) (p<0.001 in UK, p<0.01 in SA), and fibrosis/cirrhosis by APRI score (p = 0.03 in UK and p=0.008 in SA), but not by elastography or FIB-4 scores.

Discussion

HBcrAg distribution and relationship with other biomarkers differs between settings. HBcrAg (including POCT) may be a useful proxy for VL, but less so as a marker of disease progression, Its use needs tailoring to represent diverse populations.
Lung function may recover after coal mine fire smoke exposure: a longitudinal cohort study
Authors: Holt Nicolette R , Smith Catherine L , Gao Caroline X , Borg Brigitte , Lane Tyler J , Brown David , Ikin Jillian F , Makar Annie , McCrabb Thomas , Thomas Mikayla , Nilsen Kris , Thompson Bruce R , Abramson Michael J
Published: July 2024

Background and objective

The 2014 Hazelwood coalmine fire exposed residents in nearby Morwell to high concentrations of particulate matter <2·5 µm (PM2·5) for approximately 6 weeks. This analysis aimed to evaluate the long-term impact on respiratory health.

Methods

Adults from Morwell and the unexposed town of Sale completed validated respiratory questionnaires and performed spirometry, gas transfer and oscillometry 3·5-4 years (Round 1) and 7·3-7·8 years (Round 2) after the fire. Individual PM2·5exposure levels were estimated using chemical transport models mapped onto participant-reported time-location data. Mixed-effects regression models were fitted to analyse associations between PM2·5exposure and outcomes, controlling for key confounders.

Results

From 519 (346 exposed) Round 1 participants, 329 (217 exposed) participated in Round 2. Spirometry and gas transfer in Round 2 were mostly lower compared with Round 1, excepting FVC (increased) and FEV1(minimal change). The effect of mine fire-related PM2·5exposure changed from a negative effect in Round 1 to no effect in Round 2 for both pre-(p=0·005) and post-bronchodilator FVC (p=0·032). PM2·5was not associated with gas transfer in either round. For post-bronchodilator reactance and area under the curve, a negative impact of PM2·5in Round 1 showed signs of recovery in Round 2 (both p<0·001).

Conclusion

In this novel study evaluating long-term respiratory outcomes after medium-duration high concentration PM2·5exposure, the attenuated associations between exposure and respiratory function may indicate some recovery in lung function. With increased frequency and severity of landscape fires observed globally, these results inform public health policies and planning.

KEY MESSAGES

Evidence is currently lacking on the long-term sequelae of high concentration PM2·5exposure, from extreme wildfire events lasting weeks to months, on lung physiology and function. We found that previously observed deficits in adult lung function, measured using spirometry, gas transfer and oscillometry 3.5 years after a prolonged coal mine fire, may recover in the longer-term. With increased frequency of prolonged landscape fires observed globally, these results inform public health policies and planning.
Ototoxicity-related Changes in GABA Immunolabeling Within the Rat Inferior Colliculus
Authors: Holt Avril Genene , Griffith Ronald D. , Lee Soo D. , Asako Mikiya , Buras Eric , Yalcinoglu Selin , Altschuler Richard A.
Published: July 2024

Several studies suggest that hearing loss results in changes in the balance between inhibition and excitation in the inferior colliculus (IC). The IC is an integral nucleus within the auditory brainstem. The majority of ascending pathways from the lateral lemniscus (LL), superior olivary complex (SOC), and cochlear nucleus (CN) synapse in the IC before projecting to the thalamus and cortex. Many of these ascending projections provide inhibitory innervation to neurons within the IC. However, the nature and the distribution of this inhibitory input have only been partially elucidated in the rat.The inhibitory neurotransmitter, gamma aminobutyric acid (GABA), from the ventral nucleus of the lateral lemniscus (VNLL), provides the primary inhibitory input to the IC of the rat with GABA from other lemniscal and SOC nuclei providing lesser, but prominent innervation. There is evidence that hearing related conditions can result in dysfunction of IC neurons. These changes may be mediated in part by changes in GABA inputs to IC neurons. We have previously used gene micro-arrays in a study of deafness-related changes in gene expression in the IC and found significant changes in GAD as well as the GABA transporters and GABA receptors (Holt 2005). This is consistent with reports of age and trauma related changes in GABA (Bledsoe et al, 1995; Mossop et al, 2000; Salvi et al, 2000). Ototoxic lesions of the cochlea produced a permanent threshold shift. The number, intensity, and density of GABA positive axon terminals in the IC were compared in normal hearing and deafened rats. While the number of GABA immunolabeled puncta was only minimally different between groups, the intensity of labeling was significantly reduced. The ultrastructural localization and distribution of labeling was also examined. In deafened animals, the number of immuno gold particles was reduced by 78% in axodendritic and 82% in axosomatic GABAergic puncta. The affected puncta were primarily associated with small IC neurons. These results suggest that reduced inhibition to IC neurons contribute to the increased neuronal excitability observed in the IC following noise or drug induced hearing loss. Whether these deafness-diminished inhibitory inputs originate from intrinsic or extrinsic CNIC sources awaits further study.
Chemical genetics reveals cross-activation of plant developmental signaling by the immune peptide-receptor pathway
Authors: Herrmann Arvid , Sepuru Krishna Mohan , Endo Hitoshi , Nakagawa Ayami , Kusano Shuhei , Bai Pengfei , Ziadi Asraa , Kato Hiroe , Sato Ayato , Liu Jun , Shan Libo , Kimura Seisuke , Itami Kenichiro , Uchida Naoyuki , Hagihara Shinya , Torii Keiko U.
Published: July 2024

Cells sense and integrate multiple signals to coordinate development and defence. A receptor-kinase signaling pathway for plant stomatal development shares components with the immunity pathway. The mechanism ensuring their signal specificities remains unclear. Using chemical genetics, here we report the identification of a small molecule, kC9, that triggers excessive stomatal differentiation by inhibiting the canonical ERECTA receptor-kinase pathway. kC9 binds to and inhibits the downstream MAP kinase MPK6, perturbing its substrate interaction. Strikingly, activation of immune signaling by a bacterial flagellin peptide nullified kC9’s effects on stomatal development. This cross-activation of stomatal development by immune signaling depends on the immune receptor FLS2 and occurs even in the absence of kC9 if the ERECTA-family receptor population becomes suboptimal. Furthermore, proliferating stomatal-lineage cells are vulnerable to the immune signal penetration. Our findings suggest that the signal specificity between development and immunity can be ensured by MAP Kinase homeostasis reflecting the availability of upstream receptors, thereby providing a novel view on signal specificity.
Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment
Authors: Sapudom Jiranuwat , Tipay Paul , Teo Jeremy CM
Published: July 2024

The tumor microenvironment (TME), which is composed of various cell types and the extracellular matrix (ECM), plays crucial roles in cancer progression and treatment outcomes. However, the impact of the mechanical properties of the ECM, specifically collagen fibril alignment and crosslinking, on macrophage behavior and polarization is less understood. To investigate this, we reconstituted 3D collagen matrices to mimic the physical characteristics of the TME. Our results demonstrated that stiffening the matrix through the alignment or crosslinking of collagen fibrils promotes macrophage polarization toward the anti-inflammatory M2 phenotype. This phenotype is characterized by increased expression of CD105 and CD206 and a distinct cytokine secretion profile. The increased stiffness and aligned fibrils activate mechanotransduction pathways, notably integrin β1 and PI3K signaling, leading to increased IL-4 secretion, which acts in an autocrine manner to further promote M2 polarization. Interestingly, these stiffened microenvironments also suppressed the proinflammatory response. In coculture experiments with breast cancer cell lines (MDA-MB-231 and MCF-7), macrophages within stiffened or aligned matrices significantly increased cancer cell proliferation and invasion. These findings suggest that the mechanical properties of the ECM, specifically its alignment and crosslinking, create a more favorable environment for tumor progression by modulating macrophage activity. Overall, our study underscores the critical role of ECM mechanics in shaping immune cell behavior within the TME, highlighting the potential for therapies that target ECM properties and macrophage polarization to inhibit cancer progression and enhance treatment efficacy.
Narrow window data-independent acquisition on the Orbitrap Astral Mass Spectrometer enables fast and deep coverage of the plasma glycoproteome
Authors: Jager Shelley , Zeller Martin , Pashkova Anna , Schulte Douwe , Damoc Eugen , Reiding Karli R. , Makarov Alexander A. , Heck Albert J.R.
Published: July 2024

Recently, a conceptually new mass analyzer was introduced by pairing a quadrupole Orbitrap mass spectrometer with an asymmetric track lossless (Astral™) analyzer. This system provides >200-Hz MS/MS scanning speed, high resolving power and sensitivity, and low-ppm mass accuracy. This instrument allows a narrow-window data-independent (nDIA) strategy, improving sensitivity and reproducibility even when using very short LC gradients. Although this represents a new technical milestone in peptide-centric proteomics, this new system has not yet been evaluated for the analyses of very complex and clinically important proteomes, such as represented by the plasma glycoproteome. Here, we evaluated the Orbitrap Astral mass spectrometer for the analysis of the plasma glycoproteome, and pioneer a dedicated nDIA workflow, themed nGlycoDIA. With substantially adjusted parameters and varying collision energies, nGlycoDIA has clear benefits for plasma glycoproteomics. We tested our method both in glycopeptide enriched and crude plasma, leading to the identification of more than 3000 unique glycoPSMs from 181 glycoproteins, covering a dynamic range of 7 orders of magnitude in the enriched plasma sample in just 40 minutes. In addition, we detect for the first time several glycosylated cytokines that have a reported plasma concentration in the ng/L range. Furthermore, shortening the gradient to 10 min still allows the detection of almost 2500 unique glycoPSMs from enriched plasma, indicating that high-throughput indepth clinical plasma glycoproteomics may be within reach.
Harnessingin vivoSynthesis of Bioactive Multiarylmethanes inEscherichia colivia Oxygen-Mediated Free Radical Reaction Induced by Simple Phenols
Authors: Wang Donglou , He Jiangbo , Chen Yonghong , Liu Boran , Wu Zhuang , Pan Xuerong , Niu Xuemei
Published: July 2024

Background

Xanthenes and multi-aryl carbon core containing compounds represent different types of complex and condensed architectures that have impressive wide range of pharmacological, industrial and synthetic applications. Moreover, indoles as building blocks were only found in naturally occurring metabolites with di-aryl carbon cores and in chemically synthesized tri-aryl carbon core containing compounds. Up to date, rare xanthenes with indole bearing multicaryl carbon core have been reported in natural or synthetic products. The underlying mechanism of fluores-cein-like arthrocolins with tetra-arylmethyl core were synthesized in an engineeredEscherichia colifed with toluquinol remained unclear.

Results

In this study, the Keio collection of single gene knockout strains of 3901 mutants ofE. coliBW25113, together with 14 distinctE. colistrains, was applied to explore the origins of endoge-nous building blocks and the biogenesis for arthrocolin assemblage. Deficiency in bacterial res-piratory and aromatic compound degradation genesubiX,cydB,sucAandssuEinhibited the mu-tant growth fed with toluquinol. Metabolomics of the cultures of 3897 mutants revealed that only disruption oftnaAinvolving in transforming tryptophan to indole, resulted in absence of arthro-colins. Further media optimization, thermal cell killing and cell free analysis indicated that a non-enzyme reaction was involved in the arthrocolin biosynthesis inE. coli. Evaluation of redox potentials and free radicals suggested that an oxygen-mediated free radical reaction was respon-sible for arthrocolins formation inE. coli. Regulation of oxygen combined with distinct phenol derivatives as inducer, 31 arylmethyl core containing metabolites including 13 new and 8 biolog-ical active, were isolated and characterized. Among them, novel arthrocolins withp-hydroxylbenzene ring from tyrosine were achieved through large scale of aerobic fermentation and elucidated x-ray diffraction analysis. Moreover, most of the known compounds in this study were for the first time synthesized in a microbe instead of chemical synthesis. Through feeding the rat with toluquinol after colonizing the intestines of rat withE. coli, arthrocolins also ap-peared in the rat blood.

Conclusion

Our findings provide a mechanistic insight intoin vivosynthesis of complex and condensed ar-throcolins induced by simple phenols and exploits a quinol based method to generate endoge-nous aromatic building blocks, as well as a methylidene unit, for the bacteria-facilitated synthesis of multiarylmethanes.
Effect of curcumin and 5-bromoindole-3-carboxaldehyde on the inhibition of Quorum sensing-dependent virulence factors inPseudomonas aeruginosa
Authors: González Gabriel Martínez , Contreras Rodolfo García , Alvarado-Salazar Juan Andres , García Valdés Israel , Valdés Nilda García , Lugo Gutiérrez Denisse Alejandra , Bustamante Martínez Ingrid Lizeth , Tescucano Alonso Alonso Ruben , Ramirez-Villalva Alejandra , Almeida Villegas Jorge Angel
Published: July 2024

Pseudomonas aerugoinosais a bacterium that causes important nosocomial diseases with high mortality and is classified within the bacteria of the acronym ESKAPE. The virulence ofPsuedomonas aeruginosais mediated by Quorum sensing, a cellular communication system that allows it to modulate the expression of virulence factors such as elastase, protease, siderophores, biofilm, alginate among others, through the LasI / LasR, RhlI / RhlR and PQS systems. Quorum inhibition allows an antivirulence strategy, where it has been shown that molecules such as curmunin and carboxaldehydes have considerable activity for this purpose. In the present work, the ability to inhibit Quorum Sensing-dependent virulence factors inPseudomonas aeruginosawas evaluated using curcumin and 5- bromoindole-3-carboxaldehyde. The strains evaluated are Pa01, Pa14 and ATCC 27853 at concentrations (1 and 5 µg/ml) for curcumin and (30, 50 and 100 µg/ml) for 5-bromoindole-3-carboxaldehyde. 5-Bromoindole-3-carboxaldehyde significantly inhibited the production of pyocyanin in Pa01 (92.5% at 100 µg/ml), elastase in Pa01 (79.85% at 100 µg/ml), protease in Pa01 (92.8% at 50 µg/ml) and alginate in ATCC 27853 (76.16% at 100 µg/ml). Curcumin showed substantial inhibition of pyocyanin in ATCC 27853 (100% at 5 µg/ml), elastase in Pa14 (56.19% at 5 µg/ml), protease in Pa01 (87.04% at 5 µg/ml) and alginate in Pa01 (48.26% at 5 µg/ml). These findings suggest the potential of these compounds as antivirulence agents, to combatP. aeruginosainfections.
A trimeric USP11/USP7/TCEAL1 complex stabilizes RNAPII during early transcription to sustain oncogenic gene expression
Authors: Dehmer Markus , Gallant Peter , Herold Steffi , Cossa Giacomo , Conte Francesca , Koster Jan , Sauer Florian , Schülein-Völk Christina , Ade Carsten P. , Vidal Raphael , Kisker Caroline , Versteeg Rogier , Beli Petra , Vos Seychelle M. , Eilers Martin , Büchel Gabriele
Published: July 2024

During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. Whether protein ubiquitylation and proteasomal degradation affect the fate of RNAPII close to promoters is less well understood. Here we show that the deubiquitylating enzyme USP11 and its heterodimeric partner USP7 form a trimeric complex with TCEAL1, a member of the poorly understood TCEAL (TCEA/TFIIS-like) protein family. TCEAL1 shares sequence homology with the RNAPII interaction domain of the TCEA/TFIIS elongation factor, which controls the fate of backtracked RNAPII. TCEAL1 stabilizes complexes of USP11 with USP7 and with RNAPII. TCEAL1 is recruited to core promoters when transcription elongation is blocked and globally enhances the chromatin association of RNAPII during early transcription. Mechanistically, the USP11/USP7/TCEAL1 complex competes with TFIIS for binding to core promoters and protects RPB8, an essential subunit of RNAPII, from degradation, likely preventing excessive TFIIS-mediated transcript cleavage and RNAPII disassembly. In neuroblastoma and other tumors, TCEAL1-dependent genes define a TGF beta-dependent gene expression program that is characteristic for mesenchymal and invasive tumor cell types, suggesting that the USP11/USP7/TCEAL1 trimer stabilizes RNAPII during early transcription to support a critical oncogenic gene expression program (190 words).
A bacterial TIR-based immune system senses viral capsids to initiate defense
Authors: Roberts Cameron G. , Fishman Chloe B. , Banh Dalton V. , Marraffini Luciano A.
Published: July 2024

Toll/interleukin-1 receptor (TIR) domains are present in immune systems that protect prokaryotes from viral (phage) attack. In response to infection, TIRs can produce a cyclic adenosine diphosphate-ribose (ADPR) signaling molecule, which activates an effector that depletes the host of the essential metabolite NAD+ to limit phage propagation. How bacterial TIRs recognize phage infection is not known. Here we describe the sensing mechanism for the staphylococcal Thoeris defense system, which consists of two TIR domain sensors, ThsB1 and ThsB2, and the effector ThsA. We show that the major capsid protein of phage Φ80α forms a complex with ThsB1 and ThsB2, which is sufficient for the synthesis of 1’’-3’ glycocyclic ADPR (gcADPR) and subsequent activation of NAD+ cleavage by ThsA. Consistent with this, phages that escape Thoeris immunity harbor mutations in the capsid that prevent complex formation. We show that capsid proteins from staphylococcal Siphoviridae belonging to the capsid serogroup B, but not A, are recognized by ThsB1/B2, a result that suggests that capsid recognition by Sau-Thoeris and other anti-phage defense systems may be an important evolutionary force behind the structural diversity of prokaryotic viruses. More broadly, since mammalian toll-like receptors harboring TIR domains can also recognize viral structural components to produce an inflammatory response against infection, our findings reveal a conserved mechanism for the activation of innate antiviral defense pathways.
Subtypes and proliferation patterns of small intestine neuroendocrine tumors revealed by single cell RNA sequencing
Authors: Someach Einav , Halder Debdatta , Spitzer Avishay , Barbolin Chaya , Tyler Michael , Halperin Reut , Biton Moshe , Tirosh Amit , Tirosh Itay
Published: July 2024

Neuroendocrine tumors (NETs) occur primarily in the small intestine, lung and pancreas. Due to their rarity compared to other malignancies in these organs, their complex biology remains poorly understood, including their oncogenesis, tumor composition and the intriguing phenomena of mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN). Here we profiled ten low-grade small intestine NET (SiNET) tumor samples as well as one mixed lung tumor by single-cell or single-nuclei RNA-seq. We find that SiNETs are largely separated into two distinct subtypes, in which the neuroendocrine cells upregulate epithelial or neuronal markers, respectively. Surprisingly, in both subtypes the neuroendocrine cells are largely non-proliferative while higher proliferation is observed in multiple non-malignant cell types. Specifically, B and plasma cells are highly proliferative in the epithelial-like SiNET subtype, potentially reflecting the outcome of high Migration Inhibitory Factor (MIF) expression in those tumors, which may constitute a relevant target. Finally, our analysis of a mixed lung neuroendocrine tumor identifies a population of putative progenitor cells that may give rise to both neuroendocrine and non-neuroendocrine (squamous) cells, potentially explaining the origin of the mixed histology. Taken together, our results provide important insights and hypotheses regarding the biology of neuroendocrine neoplasms.