bluuebunny/crossref_metadata_2025 huggingface dataset:
N-terminal region of Drosophila melanogaster Argonaute2 forms amyloid-like aggregates
Authors: Narita Haruka , Shima Tomohiro , Iizuka Ryo , Uemura Sotaro
Published: August 2022

Argonaute proteins play a central role in RNA silencing by forming protein-small RNA complexes responsible for the silencing process. While most Argonaute proteins have a short N-terminal region, Argonaute2 in Drosophila melanogaster (DmAgo2) harbors a long and unique N-terminal region. Previous in vitro biochemical studies have shown that the loss of this region does not impair the RNA silencing activity of the complex. However, an N-terminal mutant of Drosophila melanogaster has demonstrated abnormal RNA silencing activity. To explore the causes of this discrepancy between in vitro and in vivo studies, we investigated the biophysical properties of the region. Because the N-terminal region is highly rich in glutamine and glycine residues, which is a well-known property for prion-like domains (PrLD), the possibility of the N-terminal region functioning as a PrLD was tested. Our biochemical assays demonstrated that the N-terminal region can form aggregates that are not dissociated even in the presence of SDS. Also, the aggregates enhanced the fluorescence intensity of thioflavin-T, an amyloid detection reagent. The kinetics of the aggregation followed that of typical amyloid formation exhibiting the self-propagating activity. Further, we directly visualized the aggregation process of the N-terminal region under fluorescence microscopy and found that the aggregations took fractal or fibril shapes. Together, the results indicate that the N-terminal region is a PrLD. Many other PrLDs have been reported to modulate the function of proteins through their aggregation. Therefore, our results raise the possibility that aggregation of the N-terminal region regulates the RNA silencing activity of DmAgo2.
The evolution and spread of sulfur-cycling enzymes reflect the redox state of the early Earth
Authors: Mateos Katherine , Chappell Garrett , Klos Aya , Le Bryan , Boden Joanne , Stüeken Eva , Anderson Rika
Published: August 2022

The biogeochemical sulfur cycle plays a central role in fueling microbial metabolisms, regulating the Earth’s redox state, and impacting climate. However, geochemical reconstructions of the ancient sulfur cycle are confounded by ambiguous isotopic signals. Here, we use phylogenetic reconciliation to ascertain the timing of ancient sulfur cycling gene events across the tree of life. Our results suggest that metabolisms using sulfide oxidation emerged in the Archean, but those involving thiosulfate emerged only after the Great Oxidation Event. Our data reveal that observed geochemical signatures resulted not from the expansion of a single type of organism, but were instead associated with genomic innovation across the biosphere. Moreover, our results provide the first indication of organic sulfur cycling from the mid-Proterozoic onwards, with implications for climate regulation and atmospheric biosignatures. Overall, our results provide insights into how the biological sulfur cycle evolved in tandem with the redox state of the early Earth.

Teaser:Phylogenomics analyses reveal that the evolution of microbial sulfur metabolisms co-evolved with the redox state of the early Earth.
Synonymous codon substitutions regulate transcription and translation of an upstream gene
Authors: Rodriguez Anabel , Wright Gabriel S. , Lundgren Taylor J. , Moss McKenze J. , Li Jun , Milenkovic Tijana , Huber Paul W. , Champion Matthew M. , Emrich Scott J. , Clark Patricia L.
Published: August 2022

Synonymous codons were originally viewed as interchangeable with no phenotypic consequences. However, over the years a substantial body of evidence has demonstrated that some synonymous substitutions can perturb a variety of gene expression and protein homeostasis mechanisms, including translational efficiency, translational fidelity and co-translational folding of the encoded protein. To date, synonymous codon-derived perturbations have largely focused on effects within a single gene. Here we show that synonymous codon substitutions made far within an E. coli plasmid-encoded protein coding sequence frequently led to significant upregulation of a neighboring, upstream gene. Notably, in four out of nine synonymously recoded sequences, significant upregulation of the upstream gene arose due to cryptic transcription of the anti-sense strand. Surprisingly, cryptic transcription of the upstream gene readily bypassed its native transcriptional repression mechanism. Even more surprisingly, translation of this upstream gene correlates closely with the subset of its mRNA transcribed from the cryptic internal promoter, rather than its total mRNA level. These results suggest that synonymous codons in bacteria may be under selection to both preserve the amino acid sequence of the encoded gene while also avoiding internal sequence elements that significantly perturb transcriptional and translational regulation of neighboring genes.
A host E3 ubiquitin ligase regulatesSalmonellavirulence by targeting an SPI-2 effector involved in SIF biogenesis
Authors: Meng Kun , Yang Jin , Xue Juan , Lv Jun , Zhu Ping , Shi Liuliu , Li Shan
Published: August 2022

SalmonellaTyphimurium creates an intracellular niche for its replication by utilizing a large cohort of effectors, including several that function to interfere with host ubiquitin signaling. Although the mechanism of action of many such effectors has been elucidated, how the interplay between the host ubiquitin network and bacterial virulence factors dictates the outcome of infection largely remains undefined. Here we found that the SPI-2 effector SseK3 inhibits SNARE pairing to promote the formation ofSalmonella-induced filament by Arg-GlcNAcylation of SNARE proteins, including SNAP25, VAMP8, and Syntaxin. Further study reveals that host cells counteract the activity of SseK3 by inducing the expression of the ubiquitin E3 ligase TRIM32, which catalyzes K48-linked ubiquitination on SseK3 and targets its membrane-associated portion for degradation. Hence, TRIM32 antagonizes SNAP25 Arg-GlcNAcylation induced by SseK3 to restrict SIF biogenesis andSalmonellareplication. Our study reveals a mechanism by which host cells inhibit bacterial replication by eliminating specific virulence factor.
Molecular characterization of the type VI secretion system effector Tlde1a reveals a structurally altered LD-transpeptidase fold
Authors: Cobo Neil Lorente , Sibinelli-Sousa Stephanie , Biboy Jacob , Vollmer Waldemar , Bayer-Santos Ethel , Prehna Gerd
Published: August 2022

The type VI secretion system (T6SS) is a molecular machine that Gram-negative bacteria have adapted for multiple functions, including interbacterial competition. Bacteria use the T6SS to deliver protein effectors into adjacent cells to kill rivals and establish niche dominance. Central to T6SS mediated bacterial competition is an arms race to acquire diverse effectors to attack and neutralize target cells. The peptidoglycan has a central role in bacterial cell physiology, and effectors that biochemically modify peptidoglycan structure effectively induce cell death. One such T6SS effector is Tlde1a fromSalmonellaTyphimurium. Tlde1a functions as an LD-carboxypeptidase to cleave tetrapeptide stems and as an LD-transpeptidase to exchange the terminal D-alanine of a tetrapeptide stem with a noncanonical D-amino acid. To understand how Tlde1a exhibits toxicity at the molecular level, we determined the X-ray crystal structure of Tlde1a alone and in complex with D-amino acids. Our structural data revealed that Tlde1a possesses a unique LD-transpeptidase fold consisting of a dual pocket active site with a capping subdomain. This includes an exchange pocket to bind a D-amino acid for exchange and a catalytic pocket to position the D-alanine of a tetrapeptide stem for cleavage. Toxicity assays inEscherichia coliandin vitropeptidoglycan biochemical assays with Tlde1a variants, correlate Tlde1a molecular features directly to its biochemical functions. We observe that the LD-carboxypeptidase and LD-transpeptidase activities of Tlde1a are both structural and functionally linked. Overall, our data highlights how an LD-transpeptidase fold has been structurally altered to create a toxic effector in the T6SS arms race.
Bernstein polynomial approximation of fixation probability in finite population evolutionary games
Authors: Park Jiyeon , Newton Paul K.
Published: August 2022

We use the Bernstein polynomials of degree d as the basis for constructing a uniform approximation to the rate of evolution (related to the fixation probability) of a species in a two-component finite-population frequency-dependent evolutionary game setting. The approximation is valid over the full range 0 ≤ w ≤ 1, where w is the selection pressure parameter, and converges uniformly to the exact solution as d → ∞. We compare it to a widely used non-uniform approximation formula in the weak-selection limit (w ∼ 0) as well as numerically computed values of the exact solution. Because of a boundary layer that occurs in the weak-selection limit, the Bernstein polynomial method is more efficient at approximating the rate of evolution in the strong selection region (w ∼ 1) (requiring the use of fewer modes to obtain the same level of accuracy) than in the weak selection regime.
Genetic disruption of isocitrate dehydrogenase arrests the full development of sexual stage parasites in Plasmodium falciparum
Authors: Yang Ming , Ke Hangjun , Morrisey Joanne M. , Mather Michael W. , Vaidya Akhil B.
Published: August 2022

The malaria parasites encode all eight mitochondrial enzymes that can constitute the classical tricarboxylic acid (TCA) cycle. We previously reported that genetic ablation of six out of eight TCA enzymes had no significant impact on the parasite survival and growth in asexual blood stage; aconitase knockout (ΔACO) parasites were, however, arrested as late-stage gametocytes. Herein, we describe a defective gametocyte development phenotype resulting from the knockout of another TCA enzyme, isocitrate dehydrogenase (IDH). Similar to the ΔACO gametocytes, ΔIDH gametocytes stall at stage III/IV and cannot form mature gametocytes or undergo exflagellation. Both ACO and IDH KO gametocytes exhibit fragmented mitochondrial morphology. Knockout of IDH also exerts a fitness cost, leading to a decrease in growth rate in erythrocytic stages. We examined two possible causes for the phenotype in the ΔIDH gametocytes: 1. Accumulation of reactive oxygen species (ROS) within the parasite mitochondrion due to diminished production of mitochondrial NADPH during the 10-14 days of gametocyte development; or 2. Cytotoxicity of built-up citrate upstream of IDH. We found that antioxidant agents such as N-acetylcysteine and MitoQ did not rescue the phenotype of ΔACO or ΔIDH gametocytes. Large amounts of citrate in the medium also had no significant effect on the gametocyte development or gamete formation of wildtype parasites. Our results demonstrate the importance of IDH in gametocytogenesis, providing evidence that IDH as well as aconitase could be further explored as targets for gametocidal agents and malaria transmission blockers.
A key regulator with a MIF-like domain orchestrates cellular differentiation and virulence in the fungal pathogen Magnaporthe oryzae
Authors: Galli Matteo , Jacob Stefan , Zheng Ying , Ghezellou Parviz , Gand Martin , Albuquerque Wendell , Imani Jafargholi , Allasia Valérie , Coustau Christine , Keller Harald , Spengler Bernhard , Thines Eckhard , Kogel Karl-Heinz
Published: August 2022

MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) is a pleiotropic protein with chemotactic, pro-inflammatory, and growth-promoting activities first discovered in mammals. In parasites, MIF homologs are involved in immune evasion and pathogenesis. Here, we present the first comprehensive analysis of a MIF protein from the devastating plant pathogen Magnaporthe oryzae (Mo). The fungal genome encodes a single MIF protein (MoMIF1) that, unlike the human homolog, harbors multiple low-complexity regions (LCRs) and is unique to Ascomycota. Following infection, MoMIF1 is expressed in the biotrophic phase of the fungus, and is strongly down-regulated during subsequent necrotrophic growth in leaves and roots. We show that MoMIF1 is secreted during plant infection, affects the production of the mycotoxin tenuazonic acid and inhibits plant cell death. Our results show that MoMIF1 is a novel key regulator of fungal virulence that maintains the balance between biotrophy and necrotrophy during the different phases of fungal infection.
Now What Sequence? Pre-trained Ensembles for Bayesian Optimization of Protein Sequences
Authors: Yang Ziyue , Milas Katarina A. , White Andrew D.
Published: August 2022

Pre-trained models have been transformative in natural language, computer vision, and now protein sequences by enabling accuracy with few training examples. We show how to use pre-trained sequence models in Bayesian optimization to design new protein sequences with minimal labels (i.e., few experiments). Pre-trained models give good predictive accuracy at low data and Bayesian optimization guides the choice of which sequences to test. Pre-trained sequence models also remove the common requirement of having a list of possible experiments. Any sequence can be considered. We show significantly fewer labeled sequences are required for three sequence design tasks, including creating novel peptide inhibitors with AlphaFold. These de novo peptide inhibitors require only sequence information, no known protein-protein structures, and we can predict highly-efficient binders with less than 10 AlphaFold calculations.
Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol
Authors: Sneddon Elizabeth A. , Fennell Kaila A. , Bhati Sachi , Setters Joshua E. , Schuh Kristen M. , DeMedio Jenelle N. , Arnold Brandon J. , Monroe Sean C. , Quinn Jennifer J. , Radke Anna K.
Published: August 2022

Background

One characteristic of alcohol use disorder (AUD) is compulsive drinking, or drinking despite negative consequences. When quinine is used to model such aversion-resistant drinking, female rodents typically are more resistant to punishment than males. Using an operant response task where C57BL/6J responded for ethanol (EtOH) mixed with quinine, we previously demonstrated that female mice tolerate higher concentrations of quinine in EtOH than males. Here, we aimed to determine if this female vulnerability to aversion-resistant drinking behavior is similarly observed when footshock punishment is used.

Methods

Male and female C57BL/6J mice were trained to respond for 10% EtOH in an operant task on a fixed ratio 3 schedule. After consistent responding, mice were tested in a punishment session using either a 0.25 mA or 0.35 mA footshock. To assess footshock sensitivity, a subset of mice underwent a flinch, jump, vocalize test in which behavioral responses to increasing amplitudes of footshock (0.05 – 0.95 mA) were assessed. In a separate cohort of mice, males and females were trained to respond for 2.5% sucrose and responses were punished using a 0.25 mA footshock.

Results

Males and females continued to respond for 10% EtOH when paired with a 0.25 mA footshock. Females alone continued to respond for EtOH when a 0.35 mA footshock was delivered. Both males and females reduced responding for 2.5% sucrose when punished with a 0.25 mA footshock. Finally, footshock sensitivity in the flinch, jump, vocalize test did not differ by sex.

Conclusions

Females continue to respond for 10% EtOH despite a 0.35 mA footshock and this behavior is not due to differences in footshock sensitivity between males and females. These results suggest that female C57BL/6J mice are generally more resistant to punishment in an operant self-administration paradigm. These results add to the literature characterizing aversion-resistant alcohol drinking behaviors in females.
Drosophila Tropomodulin is required for multiple actin-dependent processes in myofiber assembly and maintenance
Authors: Zapater i Morales Carolina , Carman Peter J. , Soffar David B. , Windner Stefanie E. , Dominguez Roberto , Baylies Mary K.
Published: August 2022

Proper muscle contraction requires the assembly and maintenance of sarcomeres and myofibrils. While the protein components of myofibrils are generally known, less is known about the mechanisms by which they individually function and together synergize for myofibril assembly and maintenance. For example, it is unclear how the disruption of actin filament (F-actin) regulatory proteins leads to the muscle weakness observed in myopathies. Here, we show that knockdown of Drosophila Tropomodulin (Tmod) results in several myopathy-related phenotypes, including reduction of muscle cell (myofiber) size, increased sarcomere length, disorganization and misorientation of myofibrils, ectopic F-actin accumulation, loss of tension-mediating proteins at the myotendinous junction, and misshaped and internalized nuclei. Our findings support and extend the tension-driven self-organization myofibrillogenesis model. We show that, like its mammalian counterpart, Drosophila Tmod caps F-actin pointed-ends, and this activity is critical for cellular processes in different locations within the myofiber that directly and indirectly contribute to the maintenance of muscle function. Our findings provide significant insights to the role of Tmod in muscle development, maintenance, and disease.

SUMMARY STATEMENT

Drosophila Tropomodulin knockdown in larval myofibers results in myopathy-related phenotypes. Our findings support that Tmod acts in actin-related processes at different subcellular locales, all critical for muscle integrity and function.
Psychometric and subcortical neurometric measures of temporal discrimination in rhesus macaques
Authors: Mackey Chase A. , Hauser Samantha , Schoenhaut Adriana M. , Temghare Namrata , Ramachandran Ramnarayan
Published: August 2022

Temporal envelope fluctuations are abundant in nature and are critical for perception of complex sounds. While psychophysical sinusoidal amplitude modulation (SAM) processing studies have characterized the perception of SAM, and neurophysiological studies report a subcortical transformation from temporal to rate-based code, no studies have characterized this transformation in unanesthetized animals or in nonhuman primates. To address this, we recorded single-unit responses and compared derived neurometric measures in the cochlear nucleus (CN) and inferior colliculus (IC) to psychometric measures of modulation frequency (MF) discrimination in macaques. IC and CN neurons often exhibited tuned responses to SAM in their rate and spike-timing. Neurometric thresholds spanned a large range (2-200 Hz Δ MF). The lowest 40% of IC thresholds were less than or equal to psychometric thresholds, regardless of which code was used, while CN thresholds were greater than psychometric thresholds. Discrimination at 10-20 Hz could be explained by indiscriminately pooling 30 units in either structure, while discrimination at higher MFs was best explained by more selective pooling. This suggests that pooled brainstem activity was sufficient for AM discrimination. Psychometric and neurometric thresholds decreased as a function of stimulus duration, but IC and CN thresholds were greater and more variable than behavior at durations less than 500 ms. This slower subcortical temporal integration compared to behavior was consistent with a drift diffusion model which reproduced individual differences in performance and can constrain future neurophysiological studies of temporal integration. These measures provide an account of AM perception at the neurophysiological, computational, and behavioral levels.

Significance statement

Listening in everyday environments tasks the brain with extracting information from sound envelopes. This process involves both sensory encoding and decision-making. Different neural codes for envelope representation have been well characterized in the auditory midbrain and cortex, but studies of the brainstem have usually been conducted in anesthetized rodents or cats. Moreover, these candidate neural codes have been studied in isolation from the decision-making process. In this study, we found that population activity in the primate subcortical auditory system contains sufficient information for discriminating sound envelope and applied a biologically plausible model of decision-making to sound envelope discrimination performance from rhesus macaques, a species with great phylogenetic and perceptual similarity to humans.
Multi-areal neural dynamics encode human decision making
Authors: Overton Jacqueline A. , Moxon Karen , Stickle Matthew P. , Peters Logan M. , Lin Jack J. , Chang Edward F. , Knight Robert T. , Hsu Ming , Saez Ignacio
Published: August 2022

Value-based decision-making involves multiple cortical and subcortical brain areas, but the distributed nature of neurophysiological activity underlying economic choices in the human brain remains largely unexplored. Here, we use intracranial recordings from neurosurgical patients to show that risky choices are reflected in high frequency activity distributed across multiple prefrontal and subcortical brain regions, whereas reward-related computations are less widely represented and more modular. State space modeling reveals sub-second neural dynamics underlying choices during deliberation and allows high-accuracy trial-by-trial decoding of subjects’ choices robustly across patients despite differences in anatomical coverage. These results shed light into the neural basis of choice across brain areas and open the door to new intracranial approaches for brain state decoding.
Estimating the genetic parameters of yield-related traits under different nitrogen conditions in maize
Authors: Delen Semra Palali , Xu Gen , Velazquez-Perfecto Jenifer , Yang Jinliang
Published: August 2022

Understanding the genetic basis responding to nitrogen (N) fertilization in crop production is a long-standing research topic in plant breeding and genetics. Albeit years of continuous efforts, the genetic architecture parameters, such as heritability, polygenicity, and mode of selection, underlying the N responses in maize remain largely unclear. In this study, aboutn= 230 maize inbred lines were phenotyped under high N (HN) and low N (LN) conditions for two consecutive years to obtain six yield-related traits. Heritability analyses suggested that traits highly responsive to N treatments were less heritable. Using publicly available SNP genotypes, the genome-wide association study (GWAS) was conducted to identifyn= 231 andn= 139 trait-associated loci (TALs) under HN and LN conditions, respectively, andn= 162 TALs for N-responsive (NR) traits. Furthermore, genome-wide complex trait Bayesian (GCTB) analysis, a method complementary to GWAS, was performed to estimate genetic parameters, including genetic polygenicity and the mode of selection (S). GCTB results suggested that the NR value of a yield component trait was highly polygenic and that four NR traits exhibited negative correlations between SNP effects and their minor allele frequencies (or theSvalue < 0) — a pattern consistent with negative selection to purge deleterious alleles. This study reveals the complex genetic architecture underlying N responses for yield-related traits and provides insights into the future direction for N resilient maize development.
Intracytoplasmic membranes develop inGeobacter sulfurreducensunder thermodynamically limiting conditions
Authors: Howley Ethan , Mangus Anna , Williams Dewight , Torres César I.
Published: August 2022

Geobacter sulfurreducensis an electroactive bacterium capable of reducing metal oxides in the environment and electrodes in engineered systems1,2.Geobacter sp. are the keystone organisms in electrogenic biofilms, as their respiration consumes fermentation products produced by other organisms and reduces a terminal electron acceptor e.g. iron oxide or an electrode. To respire extracellular electron acceptors with a wide range of redox potentials,G. sulfurreducenshas a complex network of respiratory proteins, many of which are membrane-bound3–5. We have identified intracytoplasmic membrane (ICM) structures inG. sulfurreducens. This ICM is an invagination of the inner membrane that has folded and organized by an unknown mechanism, often but not always located near the tip of a cell. Using confocal microscopy, we can identify that at least half of the cells contain an ICM when grown on low potential anode surfaces, whereas cells grown at higher potential anode surfaces or using fumarate as electron acceptor had significantly lower ICM frequency. 3D models developed from cryo-electron tomograms show the ICM to be a continuous extension of the inner membrane in contact with the cytoplasmic and periplasmic space. The differential abundance of ICM in cells grown under different thermodynamic conditions supports the hypothesis that it is an adaptation to limited energy availability, as an increase in membrane-bound respiratory proteins could increase electron flux. Thus, the ICM provides extra inner-membrane surface to increase the abundance of these proteins.G. sulfurreducensis the first Thermodesulfobacterium or metal-oxide reducer found to produce ICMs.
Rates but not acoustic features of ultrasonic vocalizations are related to non-vocal behaviors in mouse pups
Authors: Pranic Nicole M. , Kornbrek Caroline , Yang Chen , Cleland Thomas A. , Tschida Katherine A.
Published: August 2022

Mouse pups produce ultrasonic vocalizations (USVs) in response to isolation from the nest (i.e., isolation USVs). Rates and acoustic features of isolation USVs change dramatically over the first two weeks of life, and there is also substantial variability in the rates and acoustic features of isolation USVs at a given postnatal age. The factors that contribute to within-age variability in isolation USVs remain largely unknown. Here, we explore the extent to which non-vocal behaviors of mouse pups relate to the within-age variability in rates and acoustic features of their USVs. We recorded non-vocal behaviors of isolated C57BL/6J mouse pups at four postnatal ages (postnatal days 5, 10, 15, and 20), measured rates of isolation USV production, and applied a combination of hand-picked acoustic feature measurements and an unsupervised machine learning-based vocal analysis method to examine USV acoustic features. When we considered different categories of non-vocal behavior, our analyses revealed that mice in all postnatal age groups produce higher rates of isolation USVs during active non-vocal behaviors than when lying still. Moreover, rates of isolation USVs are correlated with the intensity (i.e., magnitude) of non-vocal body and limb movements within a given trial. In contrast, USVs produced during different categories of non-vocal behaviors and during different intensities of non-vocal movement do not differ substantially in their acoustic features. Our findings suggest that levels of behavioral arousal contribute to within-age variability in rates, but not acoustic features, of mouse isolation USVs.
Compost Teas: market survey and microbial analysis
Authors: Legein Marie , Van Beeck Wannes , Muyshondt Babette , Wuyts Karen , Samson Roeland , Lebeer Sarah
Published: August 2022

Compost teas (CTs) are fermented watery compost extracts that can be made with a wide variety of organic ingredients. These extracts are applied on plants to promote plant growth and increase protection against pathogens. Several studies have shown that the live micro-organisms present in these teas play an important role in plant protection. Still, our knowledge on the identity and functionality of bacterial communities in CTs remains limited. Moreover, CTs are a heterogeneous group, as various combinations of ingredients, fermentation parameters and application guidelines are possible and little is known on the current practices in commercially available products. Consequently, also the microbial communities in these commercially available CTs are unknown. Here, we surveyed 68 CTs on ingredients, claims and guidelines regarding preparation and application. This revealed that most products were sold in dried form which needed to be rehydrated by the customers. Moreover, kelp, humic acid, sugar and molasses, were common ingredients. Additionally, we investigated the bacterial communities of eight products, covering different ingredients and preparations, using sequencing and culture-based techniques. Bacterial communities were remarkably similar at genus level, with Pseudomonas, Massilia, Comamonas, Chryseobacterium, Brevundimonas and Acinetobacter as most prevalent genera. The genus Pseudomonas was more abundant in CTs that were prepared without aeration. Moreover, differences between liquid and dry products revealed the importance of formulation to secure the viability of the desired microbes. This study has given insight in common practices in CTs on the market, their microbial composition, and highlighted several discrepancies with current literature.

Importance

Compost teas are fermented watery compost extracts which are used in professional and amateur horticulture to promote plant growth and suppress plant diseases. Beneficial microbes present in these extracts are suggested to play an important role in the mode of action. However, little is known on the identity and functionality of the bacteria in compost teas. Moreover, compost teas are a heterogeneous group of products that can be made with numerous combinations of ingredient and fermentation parameters and little is known on current practices in products available on the market. Therefore, we surveyed these practices in 68 commercial products and for a subset of these, we explored their bacterial communities using both culture dependent and independent techniques. This study has unveiled the common practices on the market, their microbial communities, and highlighted several discrepancies between commercial practices and scientific research.
Simulated colonic fluid replicates the in vivo growth capabilities of Citrobacter rodentium cpxRA mutants and uncovers additive effects of Cpx regulated genes on fitness
Authors: Gilliland Ashley , Gavino Christina , Gruenheid Samantha , Raivio Tracy
Published: August 2022

Citrobacter rodentium is an attaching and effacing (A/E) pathogen used to model enteropathogenic and enterohemorrhagic Escherichia coli infections in mice. During colonization, C. rodentium must adapt to stresses in the gastrointestinal tract such as antimicrobial peptides, pH changes, and bile salts. The Cpx envelope stress response (ESR) is a two-component system used by some bacteria to remediate stress by modulating gene expression and is necessary for C. rodentium pathogenesis in mice. Here, we utilized simulated colonic fluid (SCF) to mimic the gastrointestinal environment which we show strongly induces the Cpx ESR and highlights a fitness defect specific to the ΔcpxRA mutant. While investigating genes in the Cpx regulon that may contribute to C. rodentium pathogenesis, we found that the absence of the Cpx ESR resulted in higher expression of the LEE master regulator, ler, and the genes yebE, ygiB, bssR, and htpX relied on CpxRA for proper expression. We then determined that CpxRA and select gene mutants were essential for proper growth in SCF when in the presence of extraneous stressors and in competition. Although none of the Cpx-regulated gene mutants exhibited marked virulence phenotypes in vivo, the ΔcpxRA mutant had reduced colonization and attenuated virulence, as previously determined, which replicated the in vitro growth phenotypes specific to SCF. Overall, these results indicate that the ΔcpxRA virulence defect is not due to any single Cpx regulon gene examined. Instead, attenuation may be the result of defective growth in the colonic environment resulting from the collective impact of multiple Cpx-regulated genes.
Genetically-proxied impaired GIPR signalling and risk of 6 cancers
Authors: Rogers Miranda , Gill Dipender , Ahlqvist Emma , Robinson Tim , Mariosa Daniela , Johansson Mattias , Penha Ricardo Cortez Cardoso , Dossus Laure , Gunter Marc J , Moreno Victor , Davey Smith George , Martin Richard M , Yarmolinsky James
Published: August 2022

Background

Preclinical and human genetics studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling worsens glycaemic control. The relationship between GIPR signalling and risk of cancers influenced by impaired glucose homeostasis is unclear.

Methods

We examined the association of a missense variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signalling and lower circulating GIP concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis. Summary genetic association data on breast, colorectal, endometrial, lung, pancreatic, and renal cancer risk were obtained from GWAS consortia (235,698 cases, 333,932 controls). Replication analyses were performed in the FinnGen consortium (8,401 breast cancer cases, 99,321 controls). Colocalisation was performed to examine robustness of findings to genetic confounding. Finally, we examined the association of E354Q with potential downstream molecular mediators of GIPR signalling to identify possible mechanisms underpinning an effect on cancer risk.

Results

Each copy of E354Q was associated with a higher risk of overall breast cancer (OR:1.05,95%CI:1.03-1.06,P=4.23×10−9) and luminal A-like breast cancer (OR:1.05,95%CI:1.03-1.06,P=6.02×10−7). In replication analysis, E354Q was likewise associated with breast cancer risk (OR:1.06,95%CI:1.02-1.08,P=1.09×10−3) and in colocalisation there was a >99.9% posterior probability of circulating GIP concentrations sharing a causal variant with overall and luminal A-like breast cancer in GIPR. E354Q was not associated with risk of the 5 other cancers examined. In mechanistic analysis, this variant was associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations.

Conclusion

Our comprehensive drug target-Mendelian randomization analysis across 6 cancers suggests an adverse effect of the GIPR E354Q variant on overall and luminal A-like breast cancer risk. These findings provide genetic evidence to support further evaluation of the therapeutic potential of GIPR signalling in breast cancer prevention.
The tryptophan catabolite or kynurenine pathway in a major depressive episode with melancholia, psychotic features and suicidal behaviors; a systematic review and meta-analysis
Authors: Almulla Abbas F. , Thipakorn Yanin , Vasupanrajit Asara , Tunvirachaisakul Chavit , Oxenkrug Gregory , Al-Hakeim Hussein K. , Maes Michael
Published: August 2022

Background

Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory and oxidative pathways which may stimulate indoleamine 2,3- dioxygenase (IDO), the first and rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway resulting in increased tryptophan degradation and elevated tryptophan catabolites (TRYCTAs).

Objective

The purpose of the current study is to systematically review and meta-analyze levels of TRP, its competing amino-acids (CAAs) and TRYCATs in patients with severe affective disorders.

Methods

PubMed, Google Scholar and SciFinder were searched in the present study and we recruited 35 studies to examine 4,647 participants including 2,332 unipolar (MDD) and bipolar (BD) depressed patients and 2,315 healthy controls.

Results

Severe patients showed significant lower (p<0.0001) TRP (standardized mean difference, SMD=-0.517, 95% confidence interval, CI: -0.735; -0.299) and TRP/CAA (SMD= -0.617, CI: -0.957; -0.277) levels with moderate effect sizes, while no significant difference in CAAs were found. Kynurenine (KYN) levels were unaltered in severe MDD/BD phenotypes, while the KYN/TRP ratio showed a significant increase only in patients with psychotic features (SMD= 0.224, CI: 0.012; 0.436). Quinolinic acid (QA) was significantly increased (SMD= 0.358, CI: 0.015; 0.701) and kynurenic acid (KA) significantly decreased (SMD= -0.260, CI: -0.487; -0.034) in severe MDD/BD.

Conclusion

Patients with affective disorders with melancholic and psychotic features and suicidal behaviors show normal IDO enzyme activity but a lowered availability of plasma/serum TRP to the brain, which is probably due to other processes such as low albumin levels.
Humans account for cognitive costs when finding shortcuts: An information-theoretic analysis of navigation
Authors: Lancia Gian Luca , Eluchans Mattia , D’Alessandro Marco , Spiers Hugo J. , Pezzulo Giovanni
Published: August 2022

When faced with navigating back somewhere we have been before we might either retrace our steps or seek a shorter path. Both choices have costs. Here, we ask whether it is possible to characterize formally the choice of navigational plans as abounded rationalprocess that trades off the quality of the plan (e.g., its length) and the cognitive cost required to find and implement it. We analyze the navigation strategies of two groups of people that are firstly trained to follow a “default policy” taking a route in a virtual maze and then asked to navigate to various known goal destinations, either in the way they want (“Go To Goal”) or by taking novel shortcuts (“Take Shortcut”). We address these wayfinding problems using InfoRL: an information-theoretic approach that formalizes the cognitive cost of devising a navigational plan, as the informational cost to deviate from a well-learned route (the “default policy”). In InfoRL, optimality refers to finding the best trade-off between route length and the amount of control information required to find it. We report five main findings. First, the navigational strategies automatically identified by InfoRL correspond closely to different routes (optimal or suboptimal) in the virtual reality map, which were annotated by hand in previous research. Second, people deliberate more in places where the value of investing cognitive resources (i.e., relevant goal information) is greater. Third, compared to the group of people who receive the “Go To Goal” instruction, those who receive the “Take Shortcut” instruction find shorter but less optimal solutions, reflecting the intrinsic difficulty of finding optimal shortcuts. Fourth, those who receive the “Go To Goal” instruction modulate flexibly their cognitive resources, depending on the benefits of finding the shortcut. Finally, we found a surprising amount of variability in the choice of navigational strategies and resource investment across participants. Taken together, these results illustrate the benefits of using InfoRL to address navigational planning problems from a bounded rational perspective.
Phased grapevine genome sequence of anRpv12carrier for biotechnological exploration of resistance toPlasmopara viticola
Authors: Frommer Bianca , Müllner Sophia , Holtgräwe Daniela , Viehöver Prisca , Hüttel Bruno , Töpfer Reinhard , Weisshaar Bernd , Zyprian Eva
Published: August 2022

The downy mildew disease caused by the oomycetePlasmopara viticolais a serious threat for grapevine and can cause enormous yield losses in viticulture. The quantitative trait locusRpv12,mediating resistance againstP. viticola, was originally found in AsianVitis amurensis. This locus and its genes were analyzed here in detail. A haplotype-separated genome sequence of the diploidRpv12-carrier Gf.99-03 was created and annotated. The defense response againstP. viticolawas investigated in an infection time-course RNA-Seq experiment, revealing approximately 600 up-regulatedVitisgenes during host-pathogen interaction. TheRpv12regions of the resistance conferring and the sensitivity encoding Gf.99-03 haplotypes were structurally and functionally compared to each other. Two different clusters of resistance-related genes were identified within theRpv12locus. One cluster carries a set of four differentially expressed genes with threeACCELERATED CELL DEATH 6-like genes. The other cluster carries a set of six resistance gene analogues related to qualitative pathogen resistance. TheRpv12locus and its candidate genes forP. viticolaresistance provide a precious genetic resource forP. viticolaresistance breeding. Newly developed co-segregating simple sequence repeat markers in close proximity to theR-genes enable its improved applicability in marker-assisted grapevine breeding.
Functional Ultrasound Imaging of the Human Spinal Cord
Authors: Agyeman K. A. , Lee D.J. , Russin J. , Kreydin E.I. , Choi W. , Abedi A. , Edgerton V.R. , Liu C. , Christopoulos V.N.
Published: August 2022

The integration of functional responses in the human spinal cord into the nervous system is not well understood. Herein we demonstrate the first in-human functional ultrasound imaging (fUSI) of spinal cord response to epidural electrical stimulation. fUSI is a minimally invasive neuroimaging technique that can record blood flow at a level of spatial and temporal precision not previously achieved in the human spinal cord. By leveraging fUSI and epidural electrical spinal cord stimulation in patients who underwent surgery, we recorded and characterized for the first-time hemodynamic responses of the human spinal cord to an electrical neuromodulatory intervention commonly used for treating pain, and increasingly used for sensory-motor and autonomic functions. We found that the hemodynamic response to epidural stimulation reflects a spatiotemporal modulation of the spinal cord circuitry not previously recognized. The impact of this analytical capability is significant for several reasons. It offers a mechanism to assess blood flow changes with a new level of precision which can be obtained in real time under in vivo conditions. Additionally, we demonstrate that fUSI can successfully decode the spinal cord state in a single trial, which is of fundamental importance for developing real-time closed-loop neuromodulation systems. Also, we show that spinal cord hemodynamic changes due to epidural electrical stimulation occur primarily at the level of small vessels. Overall, our work is a critical step towards developing a vital technique to study spinal cord function and understand the potential effects of clinical neuromodulation for spinal cord and other neurological disorders.

One Sentence Summary

The first in-human quantitative evaluation of spinal cord hemodynamics using functional ultrasound imaging (fUSI).
NF-κB-Inducing Kinase (NIK) Governs the Mitochondrial Respiratory Capacity, Differentiation, and Inflammatory Status of Innate Immune Cells
Authors: Keeney Justin N. , Winters Ashley , Sitcheran Raquel , West A. Phillip
Published: August 2022

NF-κB-Inducing Kinase (NIK), which is essential for the activation of the noncanonical NF-κB pathway, regulates diverse processes in immunity, development, and disease. While recent studies have elucidated important functions of NIK in adaptive immune cells and cancer cell metabolism, the role of NIK in metabolic-driven inflammatory responses in innate immune cells remains unclear. Here, we demonstrate that NIK-deficient bone marrow-derived macrophages exhibit defects in mitochondrial-dependent metabolism and oxidative phosphorylation (OXPHOS), which impairs the acquisition of a pro-repair, anti-inflammatory phenotype. Subsequently, NIK-deficient mice exhibit skewing of myeloid cells characterized by aberrant eosinophil, monocyte, and macrophage cell populations in the blood, bone marrow, and adipose tissue. Furthermore, NIK-deficient blood monocytes display hyperresponsiveness to bacterial lipopolysaccharide and elevated TNFα production ex vivo. These findings suggest that NIK governs metabolic rewiring, which is critical for balancing pro- and anti-inflammatory myeloid immune cell function. Overall, our work highlights a previously unrecognized role for NIK as a molecular rheostat that fine-tunes immunometabolism in innate immunity and suggests that metabolic dysfunction may be an important driver of inflammatory diseases caused by aberrant NIK expression or activity.

Key Points

NIK-deficient macrophages exhibit impaired mitochondrial oxidative phosphorylation

NIK-deficient mice have more inflammatory myeloid cells in blood and bone marrow

NIK-dependent metabolic rewiring shapes pro- and anti-inflammatory innate immunity
Balancing is a necessity not leisure: a study on work–life balance witnessing healthcare sector of Pakistan
Authors: Aman-Ullah Attia , Ibrahim Hadziroh , Aziz Azelin , Mehmood Waqas
Published: August 2022

Purpose

This study aimed to examine the direct impact of work–life balance on employee retention and turnover intentions among doctors in Pakistan. Further, it also aimed to test the mediating role of job satisfaction on these relationships.

Design/methodology/approach

This study's data were collected from 394 doctors working in public hospitals in Pakistan, using survey-based questionnaires and stratified random sampling technique. For data analysis, structural equation modelling was utilised to investigate the direct and indirect associations among the variables, while Statistical Software for the Social Sciences (SPSS) was used for data management.

Findings

Work–life balance was found to have a positive association with employee retention and a negative association with turnover intention. Results suggest that a fair work–life balance is a significant predictor of employee retention and turnover intention. Also, job satisfaction significantly mediated the relationship between work–life balance and employee retention and between work–life balance and turnover intention.

Research limitations/implications

This study's focus was limited to doctors working in public hospitals. Thus, future research can extend the scope to other segments such as nurses, paramedics and pharmacists from both public and private organisations.

Practical implications

Human resource (HR) executives can improve employee retention and turnover intentions through strategic implementation of work–life balance practices. Policymakers should stress upon hospitals to implement favourable working hours that are satisfactory to employees to reduce turnover intention.

Social implications

In the healthcare industry, suitable work–life balance strategies will help improve employees' lifestyle, which will positively impact their family and social relationships.

Originality/value

This study is expected to contribute to the existing healthcare literature in the context of Pakistan by explaining the process by which work–life balance affects employee retention and turnover intention. Specifically, job satisfaction is the mechanism that explains these relationships.