bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Resilience-Promoting Interventions on Cancer Patients’ Positive Adaptation and Quality of Life
Authors: Wang Qing , Zhou Miao , Zhao Di , Lv Gaorong , Zhang Yunxue , Xie Zihui , Li Ping
Published: July 2022

Background

Resilience-promoting interventions (RPIs) are increasingly used for cancer patients. However, there are few comprehensive reports on the efficacy of RPIs in cancer patients.

Objective

A meta-analysis of randomized controlled trials (RCTs) was conducted to systematically evaluate the effects of RPIs on resilience, posttraumatic growth (PTG), and quality of life in cancer patients.

Methods

Two authors conducted independent literature searches in electronic databases (PubMed, Scopus, Web of Science, MEDLINE, EBSCO [ASC], Cochrane library, China National Knowledge Infrastructure, Wan Fang Data, and Chinese Scientific and Technological Journal Database) from the first available date to February 2021. Then, eligible studies were selected, data for meta-analysis were extracted, and the risk of bias was evaluated.

Results

Sixteen independent randomized controlled trials with 1620 participants were included. Meta-analysis showed that RPIs significantly improved the level of resilience and PTG among cancer patients. Further analysis indicated that both group and individual interventions could enhance resilience and PTG levels. However, RPIs did not significantly enhance the quality of life in cancer patients.

Conclusions

Clinical evidence from current randomized controlled trials shows that RPIs can improve the positive adaptation in cancer patients through either group intervention or individual intervention methods. In the future, the impact of RPIs on the quality of life needs further validation.

Implications for Practice

Interventions to enhance the positive adaptation for patients with cancer are needed. Considering that both group and individual forms of RPIs can improve resilience and PTG, future clinical intervention methods can be considered in combination with the specific situation of research implementation.
100 years of mathematical cosmology: Models, theories and problems, Part B
Authors: Cotsakis Spiros , Yefremov Alexander P.
Published: July 2022

We continue our overview of mathematical cosmology with a survey of the third and fourth periods of the development of the subject. The first Part includes the first two periods and is published separately. The third period (1980–2000) continues here with brief descriptions of the main ideas of inflation, the multiverse, quantum, Kaluza–Klein, and string cosmologies, wormholes and baby universes, cosmological stability and modified gravity. The last period, which ends today, includes various more advanced topics such as M-theoretic cosmology, braneworlds, the landscape, topological issues, the measure problem, genericity, dynamical singularities and dark energy. We emphasize certain threads that run throughout the whole period of development of theoretical cosmology and underline their importance in the overall structure of the field. We end this outline with an inclusion of the abstracts of all papers contributed to the second part of thePhilosophical Transactions of the Royal Society A, theme issue ‘The future of mathematical cosmology’.

This article is part of the theme issue ‘The future of mathematical cosmology, Volume 2’.
Aether, dark energy and string compactifications
Authors: Townsend Paul K.
Published: July 2022

The nineteenth-century aether died with special relativity but was resurrected by general relativity in the form of dark energy; a tensile material with tension equal to its energy density. Such a material is provided by the D-branes of string-theory; these can support the fields of supersymmetric particle-physics, although their energy density is cancelled by orientifold singularities upon compactification. Dark energy can still arise from supersymmetry-breaking anti-D-branes but it is probably time-dependent. Recent results on time-dependent compactifications to an FLRW universe with late-time accelerated expansion are reviewed.

This article is part of the theme issue ‘The future of mathematical cosmology, Volume 2’.
Intracellular carbon storage by microorganisms is an overlooked pathway of biomass growth
Authors: Mason-Jones Kyle , Breidenbach Andreas , Dyckmans Jens , Banfield Callum C. , Dippold Michaela A.
Published: July 2022

The concept of microbial biomass growth is central to microbial carbon (C) cycling and ecosystem nutrient turnover. Growth is usually assumed to occur by cellular replication, despite microorganisms’ capacity to increase biomass by synthesizing storage compounds. Here we examined whether C storage in triacylglycerides (TAGs) and polyhydroxybutyrate (PHB) contribute significantly to microbial biomass growth, under contrasting conditions of C availability and complementary nutrient supply. Together these compounds accounted for 19.1 ± 1.7% to 46.4 ± 8.0% of extractable soil microbial biomass, and revealed up to 279 ± 72% more biomass growth than observed by a DNA-based method alone. Even under C limitation, storage represented an additional 16 – 96% incorporation of added C into microbial biomass. These findings encourage greater recognition of storage synthesis and degradation as key pathways of biomass change and as mechanisms underlying resistance and resilience of microbial communities.
Does science drive species naming, or can species naming drive science? A perspective from plant-feeding arthropods
Authors: Mlynarek Julia J. , Cull Chloe , Parachnowitsch Amy L. , Vickruck Jess L. , Heard Stephen B.
Published: July 2022

How do researchers choose their study species? Some choices are based on ecological or economic importance, some on ease of study, some on tradition – but could the name of a species influence researcher decisions? We asked whether phytophagous arthropod species named after their host plants were more likely to be assayed for host-associated genetic differentiation (or ‘HAD’; the evolution of cryptic, genetically isolated host specialists within an apparently more generalist lineage). We chose 30 arthropod species (from a Google Scholar search) for which a HAD hypothesis has been tested. We traced the etymologies of species names in the 30 corresponding genera, and asked whether HAD tests were more frequent among species whose etymologies were based on host-plant names (e.g., Eurosta solidaginis) vs. those with other etymologies (e.g., Eurosta cribata). Species with host-derived etymologies were more likely to feature in studies of HAD than those with other etymologies. We speculate that the etymology of a scientific name can draw a researcher’s attention to aspects of life-history and thus influence the direction of our scientific gaze.
Gauge-and-compass migration: inherited magnetic headings and signposts can adapt to changing geomagnetic landscapes
Authors: McLaren James D. , Schmaljohann Heiko , Blasius Bernd
Published: July 2022

Background

For many migratory species, inexperienced (naïve) individuals reach remote nonbreeding areas independently using one or more inherited compass headings and, potentially, magnetic signposts to gauge where to switch between compass headings. Inherited magnetic-based migratory orientation programs have not yet been assessed as a population-level process, particularly where strong geomagnetic spatial gradients or long-term shifts could create mismatches with inherited magnetic headings. In particular, it remains unstudied whether and how, under natural selection, inherited headings and signposts could potentially adapt to long-term geomagnetic shifts.

Methods

To address these unknowns, we modelled bird migration using an evolutionary algorithm incorporating global geomagnetic data (1900-2023). Modelled population mixing incorporated both natal dispersal and trans-generational inheritance of magnetic headings and signposts, the latter including intrinsic (stochastic) variability. Using the model, we assessed robustness of signposted and non-signposted trans-hemispheric songbird migration across a rapidly magnetically-shifting Nearctic breeding region (mean 34° declination shift) via Europe to Africa.

Results

Model-evolved magnetic-signposted migration was (i) overall successful throughout the 124-year period, with 60-90% mean successful arrival across a broad range in plausible compass precision, (ii) through reduced trans-Atlantic flight distances, up to twice as successful compared with non-signposted migration, but (iii) to avoid evolving unsustainable open-ocean flights, intrinsic variability in inheritance of magnetic headings was required (model-evolved σ ≈ 2.6° standard error in inherited headings).

Conclusions

Our study supports the potential long-term viability of inherited magnetic migratory headings and signposts, and illustrates more generally how inherited migratory programs can both mediate and constrain evolution of routes, in response to global environmental change.
Factors Affecting Maternal and Neonatal Mortality in Northern Nigeria: A Multiple Linear Regression Analysis
Authors: Orjingene Obinna , Teryila Ogojah , Baffoe Peter , Ojo Olumuyiwa
Published: July 2022

Nigeria has a maternal mortality rate (MMR) of 512 deaths per 100,000 live births, an estimate which indicates that maternal deaths are responsible for about a third of all deaths among women of reproductive age. The regional distribution of neonatal deaths in Nigeria showed that the North East region had the highest neonatal deaths. This study provides insight into identified factors and their influence on maternal and neonatal mortalities. Targeted policy implementation will emerge from the analysis of these factors with the aim of reducing the mortalities which will invariably contribute to the reduction of the global maternal and newborn mortality index

Multiple linear regression analyses using secondary time series data from the district health information system (DHIS2) for the period 2012-2021. Multivariable logistic regression analyses were also used to examine a series of predictor variables to determine those that best predict the outcome variables. Statistical significance for all regressions performed was determined at p□<□0.05.

Regression results showed a negative relationship between antenatal care and neonatal mortality implying that an increase in the number of women attending ANC will lead to a reduction in neonatal mortality by about 43%. The regression result showed a positive relationship between low birth weight and neonatal mortality implying that an increase in the number of live births with low birth weight will lead to an increase in neonatal mortality by 94%. Regression analysis on factors affecting maternal mortality showed that 4th antenatal care visits and above, health facility delivery, postnatal care within 3 days for mothers, and skilled birth attendance all have a negative relationship with maternal mortality. The regression results are all statistically significant (p<0.05).

The study revealed significant relationships between some factors (antenatal care, low birth weight, skilled birth attendants, health facility delivery, post-natal care for both mother and newborn) affecting maternal and neonatal mortality.
MENTAL STATUS OVERVIEW IN THE ELDERLY DURING THE COVID-19 PANDEMIC: A PHYLOSOPHICAL PERSPECTIVE
Authors: Andriani  , Lio Fransisca , Saleh Ariyanti , Fiqri Andi Muhammad
Published: July 2022

Background

During the Covid-19 pandemic, there was a change in the mental status of the elderly, namely anxiety disorders and depression. It is important to know the mental status of the elderly and the role of effective communication because elderly people are easily infected with Covid-19. Therefore, it is necessary to carry out early detection in basic health services.

Objective

To know the description of the mental status of the elderly during the Covid-19 pandemic.

Method

Non-experimental quantitative design through a descriptive survey approach. The sample size is 202 people using quota sampling technique. Collecting data through home visits and implementing Covid-19 health protocols. The instruments used were the Geriatric Depression Scale 15 (Cronbach’s alpha 0.75) and the Geriatric Anxiety Scale (Cronbach’s alpha 0.93).

Results

There were 50.0% did not experience depression and 44.6% had mild depression. Although small, there is a small proportion of respondents experiencing moderate depression as much as 4.5% and 1.0% experiencing severe depression. There are 77.2% experiencing mild anxiety. A total of 21.8% experienced moderate anxiety. Although a small proportion, there are respondents experiencing severe anxiety as much as 1%.

Conclusion

During the Covid-19 pandemic, most of the elderly experienced a change in mental status.

Suggestion

Health workers are expected to carry out early detection of changes in mental status in the elderly.
Synchronous high-amplitude co-fluctuations of functional brain networks during movie-watching
Authors: Tanner Jacob C. , Faskowitz Joshua , Byrge Lisa , Kennedy Daniel P. , Sporns Olaf , Betzel Richard F.
Published: July 2022

Recent studies have shown that functional connectivity can be decomposed into its exact framewise contributions, revealing short-lived, infrequent, and high-amplitude time points referred to as “events.” Events contribute disproportionately to the time-averaged connectivity pattern, improve identifiability and brain-behavior associations, and differences in their expression have been linked to endogenous hormonal fluctuations and autism. Here, we explore the characteristics of events while subjects watch movies. Using two independently-acquired imaging datasets in which participants passively watched movies, we find that events synchronize across individuals and based on the level of synchronization, can be categorized into three distinct classes: those that synchronize at the boundaries between movies, those that synchronize during movies, and those that do not synchronize at all. We find that boundary events, compared to the other categories, exhibit greater amplitude, distinct co-fluctuation patterns, and temporal propagation. We show that underlying boundary events is a specific mode of co-fluctuation involving the activation of control and salience systems alongside the deactivation of visual systems. Events that synchronize during the movie, on the other hand, display a pattern of co-fluctuation that is time-locked to the movie stimulus. Finally, we found that subjects’ time-varying brain networks are most similar to one another during these synchronous events.
Effects of packetization on communication dynamics in brain networks
Authors: Fukushima Makoto , Leibnitz Kenji
Published: July 2022

Computational studies in network neuroscience build models of communication dynamics in the con-nectome that help us understand the structure-function relationships of the brain. In these models, the dynamics of cortical signal transmission in brain networks are approximated with simple propagation strategies such as random walks and shortest path routing. Furthermore, the signal transmission dynamics in brain networks are associated with the switching architectures of engineered communication systems (e.g., message switching and packet switching). However, it has been unclear how propagation strategies and switching architectures are related in models of brain network communication. Here, we investigate the effects of the difference between packet switching and message switching (i.e., whether signals are packetized or not) on the transmission efficiency of the propagation strategies when simulating signal propagation in a macaque brain network. The results show that packetization decreases the efficiency of the random walk strategy and does not change the efficiency of the shortest path strategy, but increases the efficiency of more plausible strategies for brain networks that balance between communication speed and information cost. This finding suggests an advantage of packet-switched communication in the connectome and provides new insights into modeling the communication dynamics in brain networks.
Early detection of mandible osteoradionecrosis risk in a high comorbidity Veteran population
Authors: Wilde David Chamberlayne , Kansara Sagar , Sapienza Lucas Gomez , Banner Logan , Morlen Rickey , Hernandez David , Huang Andrew Tsao , Mai Weiyuan , Fuller Clifton David , Lai Stephen , Sandulache Vlad Constantin
Published: July 2022

Objective

Osteoradionecrosis (ORN) of the mandible is a devastating complication of external beam radiation therapy (EBRT) for head and neck squamous cell carcinoma (HNSCC). We sought to ascertain ORN risk in a Veteran HNSCC population treatment with definitive or adjuvant EBRT and followed prospectively.

Study design

Retrospective analysis of prospective cohort.

Setting

Tertiary care Veterans Health Administration (VHA) medical center.

Methods

Patients with HNSCC who initiated treatment at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) are prospectively tracked for quality of care purposes through the end of the cancer surveillance period (5 years post treatment completion). We retrospectively analyzed this patient cohort and extracted clinical and pathologic data for 164 patients with SCC of the oral cavity, oropharynx, larynx and hypopharynx who received definitive or adjuvant EBRT (2016-2020).

Results

Most patients were dentate and 80% underwent dental extractions prior to EBRT of which 16 (16%) had complications. The rate of ORN was 3.7% for oral cavity SCC patients and 8.1% for oropharyngeal SCC patients. Median time to ORN development was 156 days and the earliest case was detected at 127 days post EBRT completion. All ORN patients were dentate and underwent extraction prior to EBRT start.

Conclusion

ORN development can occur early following EBRT in a Veteran population with significant comorbid conditions but overall rates are in line with the general population. Prospective tracking of HNSCC patients throughout the post-treatment surveillance period is critical to early detection of this devastating EBRT complication.
Network of hotspot interactions cluster tau amyloid folds
Authors: Mullapudi Vishruth , Vaquer-Alicea Jaime , Bommareddy Vaibhav , Vega Anthony R. , Ryder Bryan D. , White Charles L. , Diamond Marc. I. , Joachimiak Lukasz A.
Published: July 2022

Cryogenic electron microscopy has revealed unprecedented molecular insight into the conformation of β-sheet-rich protein amyloids linked to neurodegenerative diseases. It remains unknown how a protein can adopt a diversity of folds and form multiple distinct fibrillar structures. Here we develop an in silico alanine scan method to estimate the relative energetic contribution of each amino acid in an amyloid assembly. We apply our method to twenty-seven ex vivo and in vitro fibril structural polymorphs of the microtubule-associated protein tau. We uncover networks of energetically important interactions involving amyloid-forming motifs that stabilize the different fibril folds. We test our predictions in cellular and in vitro aggregation assays. Using a machine learning approach, we classify the structures based on residue energetics to identify distinguishing and unifying features. Our energetic profiling suggests that minimal sequence elements that control the stability of tau fibrils, allowing future design of protein sequences that fold into unique structures.
SiRCle (Signature Regulatory Clustering) model integration reveals mechanisms of phenotype regulation in renal cancer
Authors: Mora Ariane , Schmidt Christina , Balderson Brad , Frezza Christian , Bodén Mikael
Published: July 2022

Clear cell renal cell carcinoma (ccRCC) tumours develop and progress via complex remodelling of the kidney epigenome, transcriptome, proteome, and metabolome. Given the subsequent tumour and inter-patient heterogeneity, drug-based treatments report limited success, calling for multi-omics studies to extract regulatory relationships, and ultimately, to develop targeted therapies. However, current methods are unable to extract nonlinear multi-omics perturbations.

Here, we present SiRCle (Signature Regulatory Clustering), a novel method to integrate DNA methylation, RNA-seq and proteomics data. Applying SiRCle to a case study of ccRCC, we disentangle the layer (DNA methylation, transcription and/or translation) where dys-regulation first occurs and find the primary biological processes altered. Next, we detect regulatory differences between patient subsets by using a variational autoencoder to integrate omics’ data followed by statistical comparisons on the integrated space. In ccRCC patients, SiRCle allows to identify metabolic enzymes and cell-type-specific markers associated with survival along with the likely molecular driver behind the gene’s perturbations.
ATP synthase interactome analysis identifies Mco10 – a new modulator of permeability transition pore in yeast
Authors: Panja Chiranjit , Wiesyk Aneta , Niedźwiecka Katarzyna , Baranowska Emilia , Kucharczyk Roza
Published: July 2022

In S. cerevisiae, the uncharacterized protein Mco10 (Mitochondrial class one protein of 10 kDa) was previously found to be associated with mitochondrial ATP synthase and referred to as a new ‘subunit l’. However, recent cryo-EM structures of S. cerevisiae ATP synthase could not ascertain Mco10 as a structural subunit of the enzyme, either monomers or dimers, making questionable its role as a structural subunit. The N-terminal part of Mco10 is very similar to Atp19 (subunit k) of ATP synthase. The subunit k/Atp19, along with the subunits g/Atp20 and e/Atp21 plays a major role in stabilization of the ATP synthase dimers. In our effort to confidently define the small protein interactome of ATP synthase we similarly found Mco10 associated with ATP synthase of S. cerevisiae. We herein investigated the impact of Mco10 on ATP synthase functioning. Biochemical analysis revealed in spite of similarity in sequence and evolutionary lineage, that Mco10 and Atp19 differ significantly in function. This is the first work to show Mco10 is an auxiliary ATP synthase subunit that only functions in permeability transition.
The Crimean population of the lesser grey shrike (Lanius minor) has low behavioural flexibility in its response to approaching humans
Authors: Mikula Peter , Kwieciński Zbigniew , Kaługa Ireneusz , Tryjanowski Piotr
Published: July 2022

The ongoing growth of the human population will increase the rate of wildlife−human interactions. High levels of animal tolerance and flexible responses towards human presence seem to be among the key mechanisms behind successful wildlife−human coexistence, but this behaviour remains unexplored for most populations and species of animals. Here, we investigate the escape behaviour (measured as flight initiation distance) of the Crimean population of a charismatic and declining bird species, the lesser grey shrike (Lanius minor). We examined its relationship with starting distance of the approaching human, directness of that approach (direct or tangential), habitat type (rural or suburban), and height of the perch used by shrikes. We found that the starting distance was significantly associated with escape responses of shrikes to approaching humans. In contrast, we found no significant association between escape responses and directness of approach, habitat type, or height of perch. Our results indicate that the lesser grey shrike may exhibit low flexibility in their escape responses towards humans which may have implications for their conservation management. Our results also indicate that the widely used 30 metres threshold for minimum starting distance may be insufficient for rural populations, even of small passerines.
WiChR, a highly potassium selective channelrhodopsin for low-light two-photon neuronal inhibition
Authors: Vierock Johannes , Peter Enrico , Grimm Christiane , Rozenberg Andrey , Castro Scalise Alejandro G. , Augustin Sandra , Tanese Dimitrii , Forget Benoît C. , Emiliani Valentina , Béjà Oded , Hegemann Peter
Published: July 2022

The electric excitability of muscle, heart and brain tissue relies on the precise interplay of Na+- and K+-selective ion channels. The involved ion fluxes are controlled in optogenetic studies using light-gated channelrhodopsins (ChRs). While non-selective cation-conducting ChRs are well-established for excitation, K+-selective ChRs (KCRs) for efficient inhibition have only recently come into reach. Here, we report the molecular analysis of recently discovered KCRs from the stramenopile Hyphochytrium catenoides and identify a novel type of hydrophobic K+-selectivity filter. Next, we demonstrate that the KCR signature motif is conserved in related stramenopile ChRs. Among them, WiChR from Wobblia lunata features an unmatched 80-fold preference for K+ over Na+, stable photocurrents under continuous illumination and a prolonged open state lifetime. Well expressed in neurons, WiChR allows two-photon inhibition at low irradiance and reduced tissue heating,_recommending WiChR as the long-awaited efficient and versatile optogenetic inhibitor.
Missing values are informative in label-free shotgun proteomics data: estimating the detection probability curve
Authors: Li Mengbo , Smyth Gordon K.
Published: July 2022

Mass spectrometry proteomics is a powerful tool in biomedical research but its usefulness is limited by the frequent occurrence of missing values in peptides that cannot be reliably quantified for particular samples. Many analysis strategies have been proposed for missing values where the discussion often focuses on distinguishing whether values are missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR). We argue here that missing values should always be viewed as MNAR in label-free proteomics because physical missing value mechanisms cannot be identified for individual points and because the probability of detection is related to underlying intensity. We show that the probability of detection can be accurately modeled by a logit linear curve. The curve asymptotes close to 100%, limiting the potential role of missing values unrelated to intensity. The curve is also incompatible with simple censoring mechanisms. We propose a statistical method for estimating the detection probability curve as a function of the underlying intensity, whether observed or not. The model quantifies the bias of missing intensities as compared to those that are observed. The model demonstrates that missing values are informative and suggests possible approaches to imputation and differential expression.
Vertebrates but not ants protect rainforest trees from herbivorous insects along an elevational gradient in Papua New Guinea
Authors: Sam Katerina , Jorge Leonardo Re , Koane Bonny , Amick Pita , Sivault Elise
Published: July 2022

Aim

The theory on trophic interactions between plants, insect herbivores, and their predators predicts that predators increase plant biomass by feeding on herbivores. However, it remains unclear whether different types of predators regulate herbivores to the same degree, and how the trophic interactions affect lower trophic levels along elevational gradients where predator communities differ significantly. Therefore, we aimed to investigate the impact of vertebrate predators and ants (individually and in combination) on arthropod communities and leaf herbivory along a complete tropical forest gradient.

Location

Papua New Guinea

Taxon

Multi-taxon

Methods

We excluded predators from 560 saplings in two six-month long predator exclusion experiments spanning wet and dry seasons. Saplings were spread across 8 study sites which were evenly spaced at 500 m elevational increments from 200 to 3700m a.s.l..

Results

On average the density of arthropods increased significantly by 37% and 33% respectively when vertebrate predators, and both ants and vertebrates predators, were removed. Both season and elevation mediated this effect significantly. At lower trophic levels, both the exclusion of both vertebrates alone, and exclusion of vertebrates plus ants, led to a significant increase in leaf damage by 50% and 36% respectively. In contrast, the exclusion of ants alone had no significant effect on arthropod density or leaf damage, which increased by 12% and 9% respectively.

Main conclusions

Our results indicate that the relative contribution of birds and bats changes at different elevational sites, while the overall effect of vertebrate predators remains consistent along the whole elevational gradient. This contrasts with ant driven trophic cascades which brought about increased herbivory only at the most productive sites of the elevational gradient, where ant abundance is highest. We conclude that disappearance of insectivorous vertebrate predators can lead to substantial negative consequences for plants.
Selection for greater dispersal in early life leads to faster age-dependent decline in locomotor activity and shorter lifespan
Authors: Ruchitha B G , Kumar Nishant , Sura Chand , Tung Sudipta
Published: July 2022

Locomotor activity is one of the major traits that is affected by age. Greater locomotor activity is also known to evolve in the course of dispersal evolution. However, the impact of dispersal evolution on the functional senescence of locomotor activity is largely unknown. We addressed this knowledge gap using large outbred populations ofDrosophila melanogasterselected for increased dispersal. We tracked locomotor activity of these flies at regular intervals until a late age. Longevity of these flies was also recorded. We found that locomotor activity declines with age in general. However interestingly, activity level of dispersal selected populations never drops below the ancestry-matched-controls, despite the rate of age-dependent decline in activity of the dispersal selected populations being greater than their respective controls. Dispersal selected population was also found to have shorter lifespan as compared to its control, a potential cost of elevated level of activity throughout their life. These results are crucial in the context of invasion biology as contemporary climate change, habitat degradation, and destruction provide congenial conditions for dispersal evolution. Such controlled and tractable studies investigating the ageing pattern of important functional traits are important in the field of biogerontology as well.
Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness Versus Lineage Output inDnmt3a-Mutant Clonal Hematopoiesis
Authors: SanMiguel Jennifer M. , Eudy Elizabeth , Loberg Matthew A. , Young Kira A. , Mistry Jayna J. , Schwartz Logan S. , Stearns Tim , Challen Grant A. , Trowbridge Jennifer J.
Published: July 2022

Clonal hematopoiesis resulting from enhanced fitness of mutant hematopoietic stem cells (HSCs) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of a clonal hematopoiesis-associated mutation,DNMT3AR882/+(Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs as well as stimulated mutant B lymphoid cell production. Genetic loss of TNFα receptor TNFR1 impaired mutant HSC fitness without altering lineage output, while loss of TNFR2 reduced lymphoid cell production and favored myeloid cell production from mutant HSCs without altering overall fitness. These results support a model where clone size and mature blood lineage production can be independently controlled to harness potential beneficial aspects of clonal hematopoiesis.

Statement of Significance

Through identification and dissection of TNFα signaling as a key driver of murineDnmt3a-mutant hematopoiesis, we report the discovery that clone size and production of specific mature blood cell types can be independently regulated.
Oligodendrocyte-mediated Myelin Plasticity and its role in Neural Synchronization
Authors: Pajevic Sinisa , Plenz Dietmar , Basser Peter J. , Fields R. Douglas
Published: July 2022

Temporal synchrony of signals arriving from different neurons or brain regions is essential for proper neural processing. Nevertheless, it is not well understood how such synchrony is achieved and maintained in a complex network of time-delayed neural interactions. Myelin plasticity has been suggested as an efficient mechanism for controlling timing in brain communications through adaptive changes of axonal conduction velocity and consequently conduction time delays, or latencies; however, local rules and feedback mechanisms that oligodendrocytes (OL) use to achieve synchronization are not known. We propose a mathematical model of oligodendrocyte-mediated myelin plasticity (OMP) in which OL play an active role in providing such feedback. This is achieved without using arrival times at the synapse or modulatory signaling from astrocytes; instead, it relies on the presence of global and transient OL responses to local action potentials in the axons they myelinate. While inspired by OL morphology, we provide the theoretical underpinnings that motivated the model and explore its performance for a wide range of its parameters. Our results indicate that when the characteristic time of OL’s spike responses is between 10 and 40 ms and the firing rates in individual axons are relatively low (⪅ 10 Hz), the OMP model efficiently synchronizes correlated and time-locked signals while latencies in axons carrying independent signals are unaffected. This suggests a novel form of selective synchronization in the CNS in which oligodendrocytes play an active role by modulating the conduction delays of correlated spike trains as they traverse to their targets.

Significance Statement

Synchronization of signals arriving from different neurons or brain regions is of great importance for proper brain function. In vertebrates, myelination provides an efficient way to achieve this by adjusting the conduction velocity and consequently the conduction delays. It is increasingly evident that myelination is an adaptive process and involved in learning; however, the local rules and the feedback that guide oligodendrocytes towards achieving desired delays are not known. Here we propose a simple and biologically plausible model of myelin plasticity in which oligodendrocytes play an active role in providing the needed feedback. We use theoretical arguments, mathematical modeling and computer simulations to show its robust synchronization capabilities which enable efficient communication between the brain regions.
Iron-catalyzed antagonism between NO and H2O2 / HOCl causes mutual exclusivity of HOCl- and NO/peroxynitrite-mediated apoptosis-inducing signaling
Authors: Bauer Georg
Published: July 2022

Membrane-associated NADPH oxidase of malignant cells drives intercellular apoptosis-inducing HOCl- and NO/peroxynitrite signaling. Cells from late stages of oncogenesis, i. e. bona fide tumor cells, interfere with these signaling pathways through expression of membrane-associated catalase. Transformed cells and tumor cells with inhibited catalase show mutual exclusivity of apoptosis-inducing NO/peroxynitrite and HOCl signaling. H2O2 is the substrate for HOCl synthesis by DUOX-coded peroxidase. However, at high concentrations of H2O2, HOCl signaling is abrogated through the reaction between excess H2O2 and HOCl. Experimental increase in the NO concentration through addition of NO donors, induction of NO synthase (NOS), addition or the NOS substrate arginine, or inhibition of NO dioxygenase(NOD) leads to the inhibition of HOCl signaling, but also to abrogation of H2O2-mediated interference with HOCl signaling. Vice versa, an increase in extracellular H2O2 through increasing the cell density, gamma irradiation or addition of glucose oxidase inhibits NO/peroxynitrite signaling. These mutual reactions between NO and H2O2/HOCl are catalyzed by an iron-mediated reaction cycle, which allows consumption of NO by H2O2/HOCl and vice versa. These reactions explain the preferences of tumor cell lines for NO/peroxynitrite or HOCl signaling after inhibition of their protective catalase, as well as the differential expression of these pathways dependent on the degree of catalase inhibition. The understanding of these reactions allows to rationally modulate quality and strength of ROS/RNS-dependent apoptosis-inducing signaling pathways of malignant cells. The knowledge about these reactions should allow to optimize strategies for tumor therapy that are based on reactivation of intercellular ROS/RNS-dependent apoptosis-inducing signaling of tumor cells.

Graphical abstract

Highlights

•

NADPH oxidase and peroxidase drive apoptosis-inducing HOCl signaling

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NADPH oxidase and NO synthase drive apoptosis-inducing NO/peroxynitrite signaling

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H2O2 establishes and interferes with HOCl signaling, dependent on its concentration

•

NO inhibits HOCl signaling and abrogates H2O2-dependent inhibition of HOCl signaling

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H2O2 interferes with NO/peroxnitrite signaling

•

Mutual interactions of NO and H2O2 are catalysed by an iron-mediated reaction cycle
Directed growth and fusion of membrane-wall microdomains requires CASP-mediated inhibition and displacement of secretory foci
Authors: Barbosa ICR , De Bellis D , Flückiger I , Bellani E , Grangé-Guerment M , Hématy K , Geldner N
Published: July 2022

Casparian strips (CS), the main extracellular diffusion barrier in plant roots, are precisely localized cell wall lignin-impregnations, contrasting animal tight-junctions. The CS membrane domain (CSD) proteins 1-5 (CASP1-5) define and accumulate at the CS associated membrane domains displaying matrix adhesion and protein exclusion. A full CASP knock-out (caspQ) now reveals that CASPs are not needed for localization of lignification or lignin-polymerizing enzymes, since correctly aligned spots still form in the mutant. Ultra-structurally, however, these spots appear as highly disorganized secretory foci, with neither exclusion zone nor membrane attachment and excessive cell wall growth. Biotin proximity labelling identifies RabA-GTPases as potential CASP-interactors. We confirm their localisation and function at the CSD, similar to exocyst subunits, known Rab effectors. Our work reveals that CASPs enforce displacement of initial secretory foci through exclusion of vesicle tethering factors, thereby ensuring rapid fusion of microdomains and effective sealing of the cell wall space.
Repurposing azithromycin in combination with last-line fosfomycin, colistin and tigecycline against Multi-Drug ResistantKlebsiella pneumoniae
Authors: Gómara-Lomero Marta , López-Calleja Ana Isabel , Rezusta Antonio , Aínsa José A. , Ramón-García Santiago
Published: July 2022

Background

New therapeutical strategies are urgently needed against multidrug-resistant (MDR) Enterobacterales. Azithromycin is a widely prescribed antibiotic with additional immunomodulatory properties, but traditionally underused for the treatment of enterobacterial infections. We previously identified azithromycin as a potent enhancer of colistin, fosfomycin and tigecycline againstKlebsiella pneumoniaeATCC 13883.

Objectives

The aim of this work was to evaluate the antibacterialin vitroactivity of azithromycin-based combinations with last-line antibiotics against an expanded panel of MDR/XDRK. pneumoniaeisolates.

Methods

Time-kill assays of azithromycin alone and in pair-wise combinations with fosfomycin, colistin and tigecycline were performed against a collection of 12 MDR/XDRK. pneumoniaeisolates. Synergistic and bactericidal activities of azithromycin-based combinations were analyzed after 8, 24 and 48 hours of treatment, and compared with antimicrobial combinations frequently used in the clinic for the treatment of MDR Enterobacterales.

Results

Synergistic interactions were detected in 100% (12/12) for azithromycin/fosfomycin, 58.3% (7/12) for azithromycin/colistin and 75% (9/12) for azithromycin/tigecycline of the strains, showing potent killing activities. Clinical combinations currently used in the clinic showed synergy in 41.6% (5/12) for meropenem/ertapenem, 33.33% (4/12) for meropenem/colistin, 75% (9/12) for fosfomycin/colistin and 66.6% (8/12) for fosfomycin/tigecycline of the strains, with lower bactericidal efficacy.

Conclusions

Novel azithromycin-based combinations with last-line MDR/XDRK. pneumoniaeantibiotics were identified showingin vitrocapacity to eradicate MDR/XDRK. pneumoniae. Our results provide anin vitrobasis supporting azithromycin used in combinatorial treatment for MDR-related infections.
Reciprocal Best Structure Hits: Using AlphaFold models to discover distant homologues
Authors: Monzon Vivian , Paysan-Lafosse Typhaine , Wood Valerie , Bateman Alex
Published: July 2022

1

The conventional methods to detect homologous protein pairs use the comparison of protein sequences. But the sequences of two homologous proteins may diverge significantly and consequently may be undetectable by standard approaches. The release of the AlphaFold 2.0 software enables the prediction of highly accurate protein structures and opens many opportunities to advance our understanding of protein functions, including the detection of homologous protein structure pairs. In this proof-of-concept work, we search for the closest homologous protein pairs using the structure models of five model organisms from the AlphaFold database. We compare the results with homologous protein pairs detected by their sequence similarity and show that the structural matching approach finds a similar set of results. Additionally, we detect potential novel homologues solely with the structural matching approach, which can help to understand the function of uncharacterised proteins and make previously overlooked connections between well-characterised proteins. We also observe limitations of our implementation of the structure based approach, particularly when handling highly disordered proteins or short protein structures. Our work shows that high accuracy protein structure models can be used to discover homologous protein pairs, and we expose areas for improvement of this structural matching approach.
Gyne production is regulated by the brood in a social bee (Bombus impatiens)
Authors: Santos Priscila K. F. , Murray Cameron S. , Amsalem Etya
Published: July 2022

Sexual production in social insects marks the peak of colony development, yet the mechanisms regulating it remain unclear. We investigated the role of brood in colony development and sexual production inBombus impatiens. While larvae are known to reduce worker egg-laying and enhance the queen’s reproductive inhibition, these effects were previously tested only in small groups. We manipulated brood size in full-size, young colonies by doubling or removing brood and monitored development. Colonies with doubled brood produced significantly more gynes, independent of colony size, while reduced-brood colonies showed a slight, non-significant increase in male production. Worker reproduction was delayed in double-brood colonies, with no change in aggression. These findings suggest brood strongly influences colony development, possibly acting as an extended phenotype of the queen or shaping worker behaviour. Understanding brood dynamics may be key to unravelling female caste determination in social insects.
Structural basis of the mycobacterial stress-response RNA polymerase auto-inhibition via oligomerization
Authors: Morichaud Zakia , Trapani Stefano , Vishwakarma Rishi , Chaloin Laurent , Lionne Corinne , Lai-Kee-Him Joséphine , Bron Patrick , Brodolin Konstantin
Published: July 2022

Self-assembly of macromolecules into higher-order symmetric structures is fundamental for the regulation of biological processes. Higher-order symmetric structure self-assembly by the gene expression machinery, such as bacterial DNA-dependent RNA polymerase (RNAP), has never been reported before. Here, we show that the stress-response σB factor from the human pathogen, Mycobacterium tuberculosis, induces the RNAP holoenzyme oligomerization into a supramolecular complex composed of eight RNAP units. Cryo-electron microscopy revealed a pseudo-symmetric structure of the RNAP octamer in which RNAP protomers are captured in an auto-inhibited state and display an open-clamp conformation. The structure shows that σB is sequestered by the RNAP flap and clamp domains. The transcriptional activator RbpA prevented octamer formation by promoting the initiation-competent RNAP conformation. Our results revealed that nonconserved region of σ is an allosteric controller of transcription initiation and demonstrated how basal transcription factors can regulate gene expression by modulating the RNAP holoenzyme assembly and hibernation.
Graft of cardiac progenitors in a pig model of right ventricular failure triggers myocardial epimorphosis, regeneration and protection of function
Authors: Lambert V , Deleris A , Tibourtine F , Fouilloux V , Martin A , Bridge P , Aries E , Benoist D , Pucéat M
Published: July 2022

The failure of diseased adult heart to regenerate is a major burden to our societies. Besides patients with ischemia and left ventricular dysfunction, progress in pediatric surgery to repair cardiac malformations has led to a growing population of now adult congenital heart diseases patients with right ventricular failure. In the absence of any efficient pharmacological therapy for these patients, cell therapy has turned out to be the only option to regenerate the RV myocardium.

In this study, we demonstrate that the adult pig with RV failure, a model of repaired tetralogy of Fallot, has the ability of regenerative epimorphosis.

Human embryonic stem cell-derived cardiac Nkx2.5+ progenitor cells were seeded in a collagen based patch to cover the whole pig failing RV. We report that these cells migrate within the myocardium while reversing the interstitial fibrosis. They then engraft and fully differentiate into fetal-like human myocytes within the myocardium. The graft triggers activation of macrophages and the reprogramming of surrounding pig myocytes into Oct4+/Nanog-blastemal-like cells. The reprogrammed myocytes re-differentiate and proliferate around human myocytes. Altogether, our findings reveal that mammalian hearts have the ability to undergo epimorphosis, the major process of endogenous regeneration that leads to a recovery of their contractile function.
Synthesis, chiral crystal structure, and magnetic properties of Ba3Ga2O5Cl2
Authors: Rine Jeremy , Yang Yongqi , Shu Zhixue , Zhao Jianda , Xie Weiwei , Kong Tai
Published: July 2022

A new compound, Ba3Ga2O5Cl2, isostructural with Ba3Fe2O5Cl2, was synthesized by solid-state reaction in air. Through single-crystal and powder X-ray diffraction analysis, the crystal structure was determined to be cubic with chiral space group I213 and unit-cell parameter a = 9.928 (1) Å. The Ga3+ ions in Ba3Ga2O5Cl2 are coordinated by O atoms and form GaO4 tetrahedra. Ten neighboring GaO4 tetrahedra are further bridged through corner sharing and rotation along the body diagonal, producing the chiral structure. Magnetization measurements indicate temperature-independent diamagnetic behavior, which is qualitatively consistent with core diamagnetism from all the constituent elements.