bluuebunny/crossref_metadata_2025 huggingface dataset:
Summary of best evidence for interventions for nurse burnout
Authors: Wang Liping , Li Guixiang , Liu Jiayi , Diao Yanjun , Zhuo Yu
Published: June 2024

Objective

To search, evaluate and summarize the best evidence on nurse burnout intervention at home and abroad, and provide evidence-based basis for clinical nursing staff.

Methods

The literature on nurse burnout intervention was searched in Chinese and English guideline websites and databases, including guidelines, evidence summaries, systematic reviews, clinical decision-making, expert consensus, and randomized controlled studies. The search period was from database establishment to December 31, 2023.

Results

16 articles were included, including 1 guideline, 1 consensus, 1 evidence summary, 1 randomized controlled study, and 12 systematic reviews. After comprehensive analysis and induction, we extracted five aspects, including effective communication, self-care, resource support, education and training, and social environment, with a total of 15 best evidence.

Conclusion

The best evidence for evidence-based intervention for nurse burnout is scientific and practical, and can provide a certain reference for clinical practice in reducing nurse burnout.
Preclinical evaluation of tissue-selective gene therapies for congenital generalised lipodystrophy
Authors: Tiwari Mansi , Roumane Ahlima , Sommer Nadine , Han Weiping , Delibegović Mirela , Rochford Justin J. , Mcilroy George D.
Published: June 2024

Lipodystrophy is a rare disorder which can be life-threatening. Here individuals fail to develop or maintain appropriate adipose tissue stores. This typically causes severe metabolic complications, including hepatic steatosis and lipoatrophic diabetes. There is no cure for lipodystrophy, and treatment options remain very limited. Here we evaluate whether tissue-selective adeno-associated virus (AAV) vectors can provide a targeted form of gene therapy for lipodystrophy, using a preclinical lipodystrophic mouse model ofBscl2deficiency. We designed AAV vectors containing the mini/aP2 or thyroxine-binding globulin promoter to selectively target adipose or liver respectively. The AAV-aP2 vectors also contained the liver-specific microRNA-122 target sequence, restricting hepatic transgene expression. Systemic delivery of AAV-aP2 vectors overexpressing humanBSCL2restored adipose tissue development and metabolic health in lipodystrophic mice without detectable expression in the liver. High doses (1×1012GCs) of liver-selective vectors led to off target expression and adipose tissue development, whilst low doses (1×1010GCs) expressed selectively and robustly in the liver but did not improve metabolic health. This reveals that adipose tissue-selective, but not liver directed, AAV-mediated gene therapy is sufficient to substantially recover metabolic health in generalised lipodystrophy. This provides an exciting potential new avenue for an effective, targeted, and thereby safer therapeutic intervention.
Inclusion of Hsp70 co-chaperone and RNA binding activities facilitate optimal function of spliceosomal disassembly factor Cwf23 in intron-richSchizosaccharomyces pombe
Authors: Yadav Kirpa , Raut Sandeep , Roy Meghna G , Gopika S , Desai Minita , Balashankar R. , Kumar Mishra Shravan , Sahi Chandan
Published: June 2024

Cwc23 is an essential J-domain protein that collaborates with the disassembly factor Ntr1 to facilitate spliceosomal disassembly. Although Cwc23 orthologs have been identified in spliceosomal extracts of many eukaryotes, their functionality in intron-rich eukaryotes remains largely unexplored. Here, we investigate the functionality of Cwf23, an ortholog of Cwc23 inSchizosaccharomyces pombe. Our study reveals that while the interaction between Cwf23 andSpNtr1 is conserved, it is not essential inS. pombe. Additionally, the RNA recognition motif (RRM) in Cwf23 is crucial for its function, as mutations in the RRM affect both growth and pre-mRNA splicing. Unlike its budding yeast counterpart, the J-domain of Cwf23 is indispensable, as J-domain mutants cannot support cell viability. These findings suggest a new paradigm in which the presence of a functional RRM and the essential nature of the J-domain underscore the increased requirements for an RNA-binding Hsp70 co-chaperone machinery in spliceosomal remodelling in “intron-rich” eukaryotes.
Long-term in vitro exposure ofTreponema pallidumto sub-bactericidal doxycycline did not induce resistance: Implications for doxy-PEP and syphilis
Authors: Tantalo Lauren C. , Luetkemeyer Ann , P. Lieberman Nicole A. , Nunley B. Ethan , Avendaño Carlos , Greninger Alexander L. , Celum Connie , Giacani Lorenzo
Published: June 2024

Doxycycline post-exposure prophylaxis (doxy-PEP) could significantly reduce syphilis incidence. However, the increase in intermittent doxycycline usage might select resistantTreponema pallidum(T. pallidum) strains. To assess whether resistance to doxycycline could be induced in this pathogen, we exposed the SS14 strain in vitro both intermittently and continuously to a sub-bactericidal doxycycline concentration that still exerts antibiotic pressure. During and after each exposure experiment, we assessed the doxycycline minimal inhibitory concentration in test and control treponemes and performed whole genome sequencing, concluding that no resistance developed. This work suggests that doxycycline-resistantT. pallidumis not an immediate threat for doxy-PEP implementation.
Highly synchronized inhibition from Purkinje cells entrains cerebellar output in zebrafish
Authors: Agarwal Vandana , Narayanan Sriram , Sengupta Mohini , Varma Aalok , Sarkar Sudeepta , Chinta Suma , Thirumalai Vatsala
Published: June 2024

Cerebellar function, known to be important for motor learning and motor coordination, is mediated by efferent neurons that project to diverse motor areas. To understand cerebellar function, it is imperative to study how these efferent neurons integrate inputs from the principal neurons of the cerebellar cortex, the inhibitory Purkinje neurons (PNs). In zebrafish, PNs are bistable and we show here that bistability influences spike synchrony among PNs. Bistability also alters spike correlation with motor bouts. We asked how PN population synchrony influences Eurydendroid cells (ECs), which are postsynaptic targets of PNs and are the cerebellar efferent cells in zebrafish. Using optogenetics, we artificially modulated population synchrony of PNs over millisecond time scales and showed that under conditions of high synchrony, EC firing is briefly suppressed and entrained by PN spiking. However, the magnitude of such modulation is relatively small and indicates a strong combined influence of other synaptic inputs on EC spiking.

Key Points

Cerebellar Purkinje neurons (PN) in larval zebrafish alter simple spike correlations with each other based on cellular state.

They also alter simple spike correlations with motor bouts as a function of state.

We altered PN population synchrony in a graded manner using optogenetics.

PN targets are cerebellar efferent neurons, which in teleosts are called eurydendroid cells.

When PN population is firing with high synchrony, eurydendroid cells are entrained better than when the PN input is asynchronous.

This can explain how PNs use bistability to modulate their influence on cerebellar output and ultimately, motor behavior.
The ventral hippocampal-nucleus accumbens shell circuit drives approach decisions under social novelty and learned cue approach-avoidance conflict
Authors: Patterson Dylan P , Khan Nisma , Sassaninejad Kian , Stewart Norman R , Collins Emily , Yeates Dylan , Lee Andy CH , Ito Rutsuko
Published: June 2024

Successful resolution of approach-avoidance conflict (AAC) is fundamentally important for survival, and its dysregulation is a hallmark of many neuropsychiatric disorders, and yet the underlying neural circuit mechanisms are not well elucidated. Converging human and animal research has implicated the anterior/ventral hippocampus (vHPC) as a key node in arbitrating AAC in a region-specific manner. In this study, we sought to target the vHPC CA1 projection pathway to the nucleus accumbens (NAc) to delineate its contribution to AAC decision-making, particularly in the arbitration of learned reward- and punishment signals, as well as innate signals. To this end, we used pathway-specific chemogenetics in male and female Long Evans rats to inhibit the NAc shell projecting vHPC CA1 neurons while rats underwent a test in which cues of positive and negative valence were presented concurrently to elicit AAC. Further behavioral assays of social preference and memory, reward and punishment cue processing, anxiety, and novelty processing were administered to further interrogate the conditions under which the vCA1-NAc shell pathway is recruited. Chemogenetic inhibition of the vCA1-NAc shell circuit resulted in animals exhibiting increased decision-making time and avoidance bias specifically in the face of motivational conflict, as the same behavioral phenotype was absent in separate conditioned cue preference and avoidance tests. vCA1-NAc shell inhibition also led to a reduction in seeking social interaction with a novel rat but did not alter anxiety-like behaviors. The vCA1-NAc shell circuit is therefore critically engaged in biasing decisions to approach in the face of social novelty and approach-avoidance conflict. Dysregulation of this circuit could lead to the precipitation of addictive behaviours in substance abuse, or potentiation of avoidance in situations of approach-avoidance conflict.
Providing context: Extracting non-linear and dynamic temporal motifs from brain activity
Authors: Geenjaar Eloy , Kim Donghyun , Calhoun Vince
Published: June 2024

Approaches studying the dynamics of resting-state functional magnetic resonance imaging (rs-fMRI) activity often focus on time-resolved functional connectivity (tr-FC). While many approaches have been proposed, these typically focus on linear approaches like computing the linear correlation at a timestep or within a window. In this work, we propose to use a generative non-linear deep learning model, a disentangled variational autoencoder (DSVAE), that factorizes out window-specific (context) information from timestep-specific (local) information. This has the advantage of allowing our model to capture differences at multiple temporal scales. For the timestep-specific scale, which has higher temporal precision, we find significant differences between schizophrenia patients and control subjects in their temporal step distance through our model's latent space. We also find that window-specific embeddings, or as we refer to them, context embeddings, more accurately separate windows from schizophrenia patients and control subjects than the standard tr-FC approach. Moreover, we find that for individuals with schizophrenia, our model's context embedding space is significantly correlated with both age and symptom severity. Interestingly, patients appear to spend more time in three clusters, one closer to controls which shows increased visual-sensorimotor, cerebellar-subcortical, and reduced cerebellar-sensorimotor functional network connectivity (FNC), an intermediate station showing increased subcortical-sensorimotor FNC, and one that shows decreased visual-sensorimotor, decreased subcortical-sensorimotor, and increased visual-subcortical domains. We verify that our model captures features that are complementary to - but not the same as - standard tr-FC features. Our model can thus help broaden the neuroimaging toolset in analyzing fMRI dynamics and shows potential as an approach for finding psychiatric links that are more sensitive to individual and group characteristics.
Levels of DNA accessibility in human sperm vary across individuals with differing reproductive parameters
Authors: Gill Mark E. , Fischer Manuel , De Geyter Christian , Peters Antoine H.F.M.
Published: June 2024

Mammalian sperm DNA is packaged in a much denser form than in somatic cells, protecting the DNA from damage and reducing the size of the nucleus to improve passage towards the oocyte. While defective sperm DNA packaging correlates with reduced fertilization rates and impaired pre-implantation embryonic development, these defects are not currently examined in standard semen analysis. Here, we adapted NicE-view, an assay that directly labels accessible DNA, for use in human sperm and applied this method including extensive image quantification to examine spermatozoa from individuals with normal conventional semen parameters but variable reproductive outcomes. We found that two sub-populations of cells differing greatly in their DNA accessibility exist within both total and motile sperm. The frequencies of these two sub-populations vary between individuals, and selection of motile sperm by swim-up generally enriches for sperm with high DNA accessibility. Individuals with high frequencies of sperm with high DNA accessibility possess decreased sperm concentrations and increased DNA nicking levels and a subset of these individuals have a history of post-fertilization embryogenic failure. NicE-view shows much clearer separation of staining levels than alternative DNA labeling approaches, and represents a valuable tool for the assessment of human sperm.
Declining Genetic Polymorphisms of the C-terminus Merozoite Surface Protein-1 Amidst IncreasedPlasmodium knowlesiTransmission in Thailand
Authors: Tapaopong Parsakorn , Chainarin Sittinont , Mala Abdulrohman , Rannarong Arnuwat , Kangkasikorn Nikom , Kusolsuk Teera , Roobsoong Wanlapa , Cui Liwang , Nguitragool Wang , Sattabongkot Jetsumon , Bantuchai Sirasate
Published: June 2024

Recent reports from Thailand reveal a substantial surge inPlasmodium knowlesicases over the past decade, with a more than eightfold increase in incidence by 2023 compared to 2018. This study investigates temporal changes in genetic polymorphism associated with the escalating transmission ofP. knowlesimalaria in Thailand over the past two decades. Twenty-fiveP. knowlesisamples collected in 2018–2023 were sequenced for the 42-kDa region ofpkmsp1and compared with 24 samples collected in 2000–2009, focusing on nucleotide diversity, natural selection, recombination rate, and population differentiation. Seven unique haplotypes were identified in recent samples, compared to 15 in earlier samples. Nucleotide and haplotype diversities were lower in recent samples (π = 0.016, Hd = 0.817) than in earlier samples (π = 0.018, Hd = 0.942). Significantly higher synonymous substitution rates were observed in both sample sets (dS– dN= 2.77 and 2.43, p < 0.05), indicating purifying selection and reduced genetic diversity over time. Additionally, 8 out of 17 mutation points were located on B-cell epitopes, suggesting an adaptive response by the parasites to evade immune recognition. Population differentiation analysis using the fixation index (Fst) revealed high genetic differentiation between parasite populations in central and southern Thailand or Malaysia. Conversely, the relatively lower Fstvalue between southern Thailand and Malaysia suggests a closer genetic relationship, possibly reflecting historical gene flow. In conclusion, our findings highlight a decline in genetic diversity and evidence of purifying selection associated with the recently increased incidence ofP. knowlesimalaria in Thailand. The minor genetic differentiation betweenP. knowlesipopulations from southern Thailand and Malaysia suggests a shared recent ancestry of these parasites and underscores the need for coordinated efforts between the two countries for the elimination ofP. knowlesi.
Phosphoglucomutase A mediated regulation of carbon flux is essential for antibiotic and disease persistence inMycobacterium tuberculosis
Authors: Sharma Taruna , Tyagi Shaifali , Pal Rahul , Kundu Jayendrajyoti , Gupta Sonu Kumar , Barik Vishawjeet , Nain Vaibhav Kumar , Pandey Manitosh , Dwivedi Prabhanjan , Panda Bhishma Narayan , Kumar Yashwant , Nanda Ranjan Kumar , Chatterjee Samrat , Pandey Amit Kumar
Published: June 2024

The long-term survival of Mtb mandates judicious utilization of the available resources inside the host. Uninterrupted access to host-derived nutrients holds the key to the success of Mtb. Phosphoglucomutase enzyme besides synthesizing glycogen, which serves as a nutrient reservoir, also helps modulate the carbon flux in different pathogens. Studies on the role of glycogen metabolism in disease progression, reactivation, and drug susceptibility in tuberculosis are severely lacking. To investigate this, we generated an Mtb strain (ΔpgmA) devoid of the gene that encodes for the enzyme phosphoglucomutase A (pgmA). The absence ofpgmAimpedes the ability of the pathogen to survive under nutrient-limiting and reactivation conditions. In the current study, we demonstrate that the absence of cell membrane-associated glycolipids in ΔpgmAcompromised the cell wall integrity and increased the susceptibility of ΔpgmAto various stresses. Interestingly, in comparison to the wild type, low cAMP levels in ΔpgmAimparted an enhanced growth phenotype on cholesterol. Differential gene expression and carbon flux analysis suggest that stored carbon in the form of glycogen is essential for the survival of Mtb under nutrient-limiting conditions. Finally, we demonstrate that thepgmAgene of Mtb is essential for the growth of Mtb inside the host. Overall, this study unveils the significance ofpgmA-mediated regulation of membrane glycolipids and its implication on antibiotic and disease persistence in tuberculosis. Additionally, information derived from this study will help design anti-TB strategies that are novel, short, and more efficient.
A flexible, high-throughput system for studying mRNA translation kineticsin vitroandin cellulowith HiBit technology
Authors: Ascanelli C. , Lawrence E. , Batho C. A. P. , Wilson C. H.
Published: June 2024

HiBit is an engineered luciferase’s 11 amino acid component that can be introduced as a tag at either terminus of a protein of interest. When the LgBit component and a substrate are present, HiBit and LgBit dimerise forming a functional luciferase. The HiBit technology has been extensively used for high-throughput protein turnover studies in cells. Here, we have adapted the use of the HiBit technology to quantify mRNA translation temporallyin vitroin the rabbit reticulocyte system andin celluloin HEK293 cells constitutively expressing LgBit. The assay system can detect differences in Cap, 5’UTR, modified nucleotide composition, coding sequence optimisation and poly(A) length. Importantly, using these assays we established the optimal mRNA composition varied depending on the encoded protein of interest, highlighting the importance of screening methods tailored to the protein of interest, and not reliant on reporter proteins. Our findings demonstrated that HiBit can be easily and readily adapted to monitor mRNA translation and offers a novel and highly favourable method for the development of mRNA-based therapeutics.

Graphical abstract
Metagenomic global survey and in-depth genomic analyses ofRuminococcus gnavusreveal differences across host lifestyle and health status
Authors: Nooij S. , Plomp N. , Sanders I.M.J.G. , Schout L. , van der Meulen A.E. , Terveer E.M. , Norman J.M. , Karcher N. , Larralde M.F. , Vossen R.H.A.M. , Kloet S.L. , Faber K.N. , Harmsen H.J.M. , Zeller G.F. , Kuijper E.J. , Smits W.K. , Ducarmon Q.R.
Published: June 2024

Ruminococcus gnavusis a highly prevalent gut bacterium (present in >90% of healthy individuals), of which increased abundance is associated with chronic inflammatory diseases, most notably Crohn’s disease. Nevertheless, its global distribution has not been investigated and little is known about intraspecies genomic variation. Through a large-scale survey of 12,791 gut metagenomes, we recapitulated known associations with metabolic diseases and inflammatory bowel disease. We uncover a higher prevalence and abundance ofR. gnavusin Westernized populations and observe relative abundances of up to 83% in newborns and infants. Next, we built a collection of existing and newly culturedR. gnavusisolates (N = 45) from both healthy individuals and Crohn’s disease patients and subjected these to PacBio circular consensus sequencing to greatly expand the number of completeR. gnavusgenomes. Analysis of these genomes as well as publicly available high quality draft genomes (total > 300 genomes) revealed multiple clades which separated Crohn’s-derived isolates from healthy-derived isolates. Functional analyses of genes predicted to constituteR. gnavusvirulence factors could not explain this separation. Bacterial GWAS revealed that Crohn’s-derived isolates were enriched in genes related to mobile elements and putative mucin foraging. Together, we present one of the largest complete genome collections of any commensal gut microbe and provide novel biological insights into the global distribution and genomic variation ofR. gnavus.
Free Amino Acids Accelerate the Time-Dependent Inactivation of Rat Liver Nucleotide Pyrophosphatase / Phosphodiesterase Enpp3 elicited by EDTA
Authors: Romero Ana , Cumplido-Laso Guadalupe , Fernández Ascensión , Moreno Javier , Canales José , Ferreira Rui , López-Gómez Juan , Ribeiro João Meireles , Costas María Jesús , Cameselle José Carlos
Published: June 2024

Nucleotide-pyrophosphatases/phosphodiesterases (NPP/PDE) are membrane or secreted Zn2+-metallohydrolases of nucleoside-5’-monophosphate derivatives. They hydrolyze, for instance, ATP and 4-nitrophenyl-dTMP, and belong to the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family that contains seven members (ENPP1-ENPP7). Earlier we had shown that an NPP/PDE activity solubilized and partially purified from rat liver membranes is inactivated by EDTA in a time-dependent fashion, an effect enhanced by glycine and blocked by the 4-nitrophenyl-dTMP. Here, we extended this observation to other free amino acids. Activity assays started after different incubation lengths with EDTA provided first-order, apparent inactivation constants (ki(ap)). With the exception of cysteine (a strong inhibitor) and histidine (itself evoking a time-dependent inactivation), free amino acids themselves did not affect activity but increased ki(ap). The results are compatible with a conformational change of NPP/PDE evoked by interaction with free amino acids. The enzyme preparation was analyzed to identify what ENPP family members were present. First, the hydrolytic activity on 2’,3’-cGAMP was assayed because until very recently ENPP1 was the only mammalian enzyme known to display it. 2’,3’-cGAMP hydrolase activity was clearly detected, but mass spectrometry data obtained by LC-MS/MS gave evidence that only rat Enpp3, Enpp4 and Enpp5 were present with low abundance. This finding coincided in time with a recent publication claiming that mouse Enpp3 hydrolyzes 2’,3’-cGAMP, and that Enpp1 and Enpp3 account for all the 2’,3’-cGAMP hydrolase activity in mice. So, our results are confirmatory of Enpp3 activity towards 2’,3’-cGAMP. Finally, the effect of amino acids could be relevant to NPP/PDE actions dependent on protein-protein interactions, like the known insulin-related effects of ENPP1 and possibly ENPP3.
Highly Multiplexed Spatial Transcriptomics in Bacteria
Authors: Sarfatis Ari , Wang Yuanyou , Twumasi-Ankrah Nana , Moffitt Jeffrey R.
Published: June 2024

Single-cell decisions made in complex environments underlie many bacterial phenomena. Image-based transcriptomics approaches offer an avenue to study such behaviors, yet these approaches have been hindered by the massive density of bacterial mRNA. To overcome this challenge, we combine 1000-fold volumetric expansion with multiplexed error robust fluorescencein situhybridization (MERFISH) to create bacterial-MERFISH. This method enables high-throughput, spatially resolved profiling of thousands of operons within individual bacteria. Using bacterial-MERFISH, we dissect the response ofE. colito carbon starvation, systematically map subcellular RNA organization, and chart the adaptation of a gut commensalB. thetaiotaomicronto micron-scale niches in the mammalian colon. We envision bacterial-MERFISH will be broadly applicable to the study of bacterial single-cell heterogeneity in diverse, spatially structured, and native environments.
Energy Aware Technology Mapping of Genetic Logic Circuits
Authors: Kubaczka Erik , Gehri Maximilian , Marlhens Jérémie J. M. , Schwarz Tobias , Molderings Maik , Engelmann Nicolai , Garcia Hernan G. , Hochberger Christian , Koeppl Heinz
Published: June 2024

Energy and its dissipation are fundamental to all living systems, including cells. Insufficient abundance of energy carriers -as caused by the additional burden of artificial genetic circuits-shifts a cell’s priority to survival, also impairing the functionality of the genetic circuit. Moreover, recent works have shown the importance of energy expenditure in information transmission. Despite living organisms being non-equilibrium systems, non-equilibrium models capable of accounting for energy dissipation and non-equilibrium response curves are not yet employed in genetic design automation (GDA) software. To this end, we introduce Energy Aware Technology Mapping, the automated design of genetic logic circuits with respect to energy efficiency and functionality. The basis for this is an energy aware non-equilibrium steady state (NESS) model of gene expression, capturing characteristics like energy dissipation -which we link to the entropy production rate- and transcriptional bursting, relevant to eukaryotes as well as prokaryotes. Our evaluation shows that a genetic logic circuit’s functional performance and energy efficiency are disjoint optimization goals. For our benchmark, energy efficiency improves by 37.2% on average when comparing to functionally optimized variants. We discover a linear increase in energy expenditure and overall protein expression with the circuit size, where Energy Aware Technology Mapping allows for designing genetic logic circuits with the energy efficiency of circuits that are one to two gates smaller. Structural variants improve this further, while results show the Pareto dominance among structures of a single Boolean function. By incorporating energy demand into the design, Energy Aware Technology Mapping enables energy efficiency by design. This extends current GDA tools and complements approaches coping with burdenin vivo.

TOC Graphic
Structural Insights into the Roles of PARP4 and NAD+in the Human Vault Cage
Authors: Lodwick Jane E. , Shen Rong , Erramilli Satchal , Xie Yuan , Roganowicz Karolina , Kossiakoff Anthony A. , Zhao Minglei
Published: June 2024

Vault is a massive ribonucleoprotein complex found across Eukaryota. The major vault protein (MVP) oligomerizes into an ovular cage, which contains several minor vault components (MVCs) and is thought to transport transiently bound “cargo” molecules. Vertebrate vaults house a poly (ADP-ribose) polymerase (known as PARP4 in humans), which is the only MVC with known enzymatic activity. Despite being discovered decades ago, the molecular basis for PARP4’s interaction with MVP remains unclear. In this study, we determined the structure of the human vault cage in complex with PARP4 and its enzymatic substrate NAD+. The structures reveal atomic-level details of the protein-binding interface, as well as unexpected NAD+-binding pockets within the interior of the vault cage. In addition, proteomics data show that human vaults purified from wild-type and PARP4-depleted cells interact with distinct subsets of proteins. Our results thereby support a model in which PARP4’s specific incorporation into the vault cage helps to regulate vault’s selection of cargo and its subcellular localization. Further, PARP4’s proximity to MVP’s NAD+-binding sites could support its enzymatic function within the vault.
Contribution of telacebec to novel drug regimens in a murine tuberculosis model
Authors: Komm Oliver D. , Tyagi Sandeep , Garcia Andrew , Almeida Deepak , Chang Yong , Lee Si-Yang , Castillo Jennie Ruelas , Converse Paul J. , Black Todd , Fotouhi Nader , Nuermberger Eric L.
Published: June 2024

The clinical efficacy of combination drug regimens containing the first generation diarylquinoline (DARQ) bedaquiline in the treatment of multidrug-resistant tuberculosis has validated ATP synthesis as a vulnerable pathway inMycobacterium tuberculosis. New DARQs in clinical development may be even more effective than bedaquiline, including against emerging bedaquiline-resistant strains. Telacebec (T) is a novel cytochrome bc1:aa3oxidase inhibitor that also inhibits ATP synthesis. Based on its demonstrated efficacy as a monotherapy in mice and in a phase 2a clinical trial, we used an established BALB/c mouse model of tuberculosis (TB) to test the contribution of T to novel combination therapies against two strains ofM. tuberculosis(H37Rv and HN878) in an effort to find more effective regimens. Overall, T was more effective in regimens against the HN878 strain than against the H37Rv strain, a finding that supports the greater vulnerability of the former strain to T and to genetic depletion of QcrB. Against both strains, combinations of a DARQ, clofazimine (CFZ), and T were highly bactericidal. However, only against HN878 did T contribute synergistically, whereas an antagonistic effect was observed against H37Rv. These results demonstrate the therapeutic potential of T and highlight how differences in the susceptibility ofM. tuberculosisstrains could lead to different conclusions about a drug’s potential contribution to novel drug regimens.
A test of limited transpiration traits in sorghum to improve late-season water use, photosynthesis, growth, and grain yield in the high plains of Northern Colorado
Authors: Gleason Sean M. , Stewart Jared J. , Polutchko Stephanie K. , Allen Brendan S.
Published: June 2024

Limited transpiration (LT) traits aim to conserve early-season water to benefit late-season grain development. While theoretical and modeling efforts support LT efficacy, empirical tests directly measuring water loss from leaves and canopies are scarce. This study evaluates the performance of LT genotypes in achieving reduced early-season water use and improved late-season growth and yield in semi-arid Colorado. The research involved near-isogenic lines (NILs) derived from sorghum inbred lines, subjected to different irrigation treatments. Measurements included stomatal conductance, net CO2assimilation, and photosystem II (PSII) efficiency. Results indicate that LT genotypes did not consistently exhibit lower early-season water use or higher late-season growth compared to non-LT genotypes. Early-season water use waspositivelycorrelated with above-ground biomass, challenging the assumption that early-season water conservation can be leveraged for late-season benefits. We question the efficacy of LT traits, highlighting the physiological link between water use and carbon gain, and the potential opportunity costs of reduced early-season growth. We suggests that breeding strategies should focus on enhancing deep soil water access and maximizing carbon gain rather than merely reducing transpiration or shifting water use in arid and semi-arid environments.
SOX9 Expression in Colorectal Adenomas Improves Surveillance Colonoscopy Risk Stratification in a Bowel Screening Population
Authors: Al-Badran Sara Samir Foad , Bigley Christopher , Johnstone Mark , Ammar Aula , Winton Alexander , Hay Jennifer , Quinn Jean , Jawny Jakub , Andersen Ditte , Fisher Natalie , Dunne Philip D. , Maka Noori , Lynch Gerard , McSorley Stephen , Edwards Joanne
Published: June 2024

Objectives

Adenomas are known precursors to colorectal cancer (CRC). Current UK post-polypectomy surveillance guidelines use polyp size, numbers, and histology to stratify the risk of patients developing metachronous polyps or CRC. However, these risk guidelines suffer from poor predictive value, often leading to under/over surveillance.

Design

Adenomas removed from 1257 patients at bowel screening colonoscopy were retrospectively identified to investigate mutational profile and protein expression trends associated with the detection of metachronous polyps or CRC. The presence or absence of metachronous polyps or CRC was recorded 6 months to 6 years after index polypectomy.

Results

APCandKRASwere the most mutated genes in these patients (87% and 34% respectively), and both were significantly co-occurring with the 6th most mutated geneSOX9(17% co-occurring withAPC, p=0.047; 23% co-occurring withKRAS, p=0.012). High SOX9 cytoplasmic expression was significantly associated with the detection of metachronous polyps or CRC (HR 1.543, p=0.001) and improved high risk stratification when combined with BSG2020 guidelines versus guidelines alone (HR 2.626, p<0.0001). High cytoplasmic SOX9 alone and in combination with current guidelines was an independent predictor of metachronous polyps or CRC according to various regression models. This was validated in an independent test dataset, where high cytoplasmic expression was significantly associated with the detection of metachronous polyps or CRC (HR 1.654, p=0.012) and enhanced risk stratification when combined with BSG2020 guidelines versus guidelines alone (HR 2.473, p=0.0018).

Conclusion

High cytoplasmic SOX9 expression within adenomas is associated with shorter time to detection of metachronous polyps or CRC.
Population divergence manifested by genomic rearrangements in a keystone Arctic species with high gene flow
Authors: Hoff Siv N.K , Maurstad Marius F. , Le Moan Alan , Ravinet Mark , Pampoulie Christophe , Vieweg Ireen , Collard France , Moiseev Denis , Bradbury Ian R. , Tørresen Ole K. , Godiksen Jane Aanestad , Hop Haakon , Renaud Paul E. , Nahrgang Jasmine , Jakobsen Kjetill S. , Præbel Kim , Durant Joël M. , Jentoft Sissel
Published: June 2024

Genomic rearrangements have in recent years gained attention due to their evolutionary role in processes related to adaptation to local environmental conditions as well as diversification and speciation. In this study, we report on genomic rearrangements in the cold-water adapted polar cod (Boreogadus saida), a keystone Arctic fish species. By taking advantage of a new chromosome-level genome assembly in combination with whole-genome population sequencing data from specimens across the northern Barents Sea and adjacent regions, we identified a substantial number of larger chromosomal inversions (n=20) and characterized the previously identified chromosomal fusions (n=5). These genomic features — encompassing over 20% of the genome — exhibited genetic divergence, strong internal linkage disequilibrium, and signals of selection. Two of the identified inversions were associated with the two previously described hemoglobin clusters, while a third chromosomal region was found to differentiate between males and females. Moreover, clustering analyses on genotype frequencies of inversions revealed sub- structuring according to five geographic sub-groups suggesting sub-populations and/or the existence of cryptic ecotypes. These results provide novel insights into the impact of genomic rearrangements in population divergence and thus, potentially local adaptation, especially in species with high gene flow.
Molecular evolution of the meiotic recombination pathway in vertebrates
Authors: Szasz-Green Taylor , Shores Katherynne , Vanga Vineel , Zacharias Luke , Lawton Andrew K. , Dapper Amy L.
Published: June 2024

Meiotic recombination is an integral cellular process, required for the production of viable gametes, and the rate at which it occurs is a fundamental genomic parameter, modulating how the genome responds to selection. Our increasingly detailed understanding of its molecular underpinnings raises the prospect that we can gain insight into trait divergence by examining the molecular evolution of recombination genes from a pathway perspective, as in mammals, where protein-coding changes in the later stages of the recombination pathway are connected to divergence in intra-clade recombination rate. Here, we leveraged increasing availability of avian and teleost genomes to reconstruct the evolution of the recombination pathway across two additional vertebrate clades: birds, which have higher and more variable rates of recombination and similar divergence times to mammals; and teleost fish, which have much deeper divergence times. We found that the rates of molecular evolution of recombination genes are highly correlated between vertebrate clades, suggesting that they experience similar selective pressures. However, recombination genes in birds were significantly more likely to exhibit signatures of positive selection, unrestricted to later stages of the pathway. There is a significant correlation between genes linked to recombination rate variation in mammalian populations and those with signatures of positive selection across the avian phylogeny, suggesting a link between selection and recombination rate. In contrast, the teleost fish recombination pathway is more highly conserved with significantly less evidence of positive selection. This is surprising given the high variability of recombination rates in this clade.
Reference genome bias in light of species-specific chromosomal reorganization and translocations
Authors: Maurstad Marius F. , Hoff Siv Nam Khang , Cerca José , Ravinet Mark , Bradbury Ian , Jakobsen Kjetill S. , Præbel Kim , Jentoft Sissel
Published: June 2024

Whole-genome sequencing efforts has during the past decade unveiled the central role of genomic rearrangements—such as chromosomal inversions—in evolutionary processes, including local adaptation in a wide range of taxa. However, employment of reference genomes from distantly or even closely related species for mapping and the subsequent variant calling, can lead to errors and/or biases in the datasets generated for downstream analyses. Here, we capitalize on the recently generated chromosome-anchored genome assemblies for Arctic cod (Arctogadus glacialis), polar cod (Boreogadus saida), and Atlantic cod (Gadus morhua) to evaluate the extent and consequences of reference bias on population sequencing datasets (approx. 15-20x coverage) for both Arctic cod and polar cod. Our findings demonstrate that the choice of reference genome impacts population genetic statistics, including individual mapping depth, heterozygosity levels, and cross-species comparisons of nucleotide diversity (π) and genetic divergence (DXY). Further, it became evident that using a more distantly related reference genome can lead to inaccurate detection and characterization of chromosomal inversions, i.e., in terms of size (length) and location (position), due to inter-chromosomal reorganizations between species. Additionally, we observe that several of the detected species-specific inversions were split into multiple genomic regions when mapped towards a heterospecific reference. Inaccurate identification of chromosomal rearrangements as well as biased population genetic measures could potentially lead to erroneous interpretation of species-specific genomic diversity, impede the resolution of local adaptation, and thus, impact predictions of their genomic potential to respond to climatic and other environmental perturbations.
Beam physics studies for a high charge and high beam quality laser-plasma accelerator
Authors: Marini Samuel , Minenna Damien F. G. , Massimo Francesco , Batista Laury , Bencini Vittorio , Chancé Antoine , Chauvin Nicolas , Doebert Steffen , Farmer John , Gschwendtner Edda , Moulanier Ioaquin , Muggli Patric , Uriot Didier , Cros Brigitte , Nghiem Phu Anh Phi
Published: June 2024

Electron acceleration by laser-plasma techniques is approaching maturity and is getting ready for the construction of particle accelerators with dedicated applications. We present a general methodology showing how beam physics studies can be used to achieve a specific parameter set in a laser-plasma accelerator. Laser systems, plasma targets, and magnetic component properties are designed to optimize the electron beam so as to achieve the required performances. Beam physics in its full 6D phase space is studied from electron injection to beam delivery to the end user, through the plasma acceleration stage and transport line. As each beam parameter can only be modified by specific electric/magnetic field configurations, it is crucial to assign from the beginning specific roles to given accelerator sections in obtaining given beam parameters. These beam physics considerations were successfully applied to the design of a plasma-based electron injector for the AWAKE Run2 experiment. Electron beam parameters were calculated using a global simulation, achieving simultaneously unprecedented high charge (100 pC) and high quality (micrometric beam emittance and size).

Published by the American Physical Society
2024
Arbitrary relaxation rate under non-Hermitian matrix iterations
Authors: Bensa Jaš
Published: June 2024

We study the exponential relaxation of observables propagated with a non-Hermitian transfer matrix, an example being out-of-time-ordered correlations (OTOC) in brick-wall (BW) random quantum circuits. Until a time that scales as the system size, the exponential decay of observables is not usually determined by the second largest eigenvalue of the transfer matrix, as one can naively expect, but it is, in general, slower—this slower decay rate was dubbed “phantom eigenvalue.” Generally, this slower decay is given by the largest value in the pseudospectrum of the transfer matrix; however, we show that the decay rate can be an arbitrary value between the second largest eigenvalue and the largest value in the pseudospectrum. This arbitrary decay can be observed, for example, in the propagation of OTOC in periodic boundary conditions BW circuits. To explore this phenomenon, we study a matrix iteration made from a simple tridiagonal Toeplitz matrix. This setting can be used to propagate OTOC in random circuits with open boundary conditions and to describe a one-dimensional biased random walk with dissipation at the edges.

Published by the American Physical Society
2024
Intrinsic Limits of Charge Carrier Mobilities in Layered Halide Perovskites
Authors: Cucco Bruno , Leveillee Joshua , Ha Viet-Anh , Even Jacky , Kepenekian Mikaël , Giustino Feliciano , Volonakis George
Published: June 2024

Layered halide perovskites have emerged as potential alternatives to three-dimensional (3D) halide perovskites due to their improved stability and larger material phase space, allowing fine tuning of structural, electronic, and optical properties. However, their charge carrier mobilities are significantly smaller than those of 3D halide perovskites, which has a considerable impact on their application in optoelectronic devices. Here, we employ state-of-the-art approaches to unveil the electron-phonon mechanisms responsible for the diminished transport properties of layered halide perovskites. Starting from a prototypical AMX3 halide perovskite, we model the case of n=1 and n=2 layered structures and compare their electronic and transport properties to the 3D reference. The electronic and phononic properties are investigated within density functional theory (DFT) and density functional perturbation theory (DFPT), while transport properties are obtained via the Boltzmann transport equation. The vibrational modes contributing to charge carrier scattering are investigated and associated with polar-phonon scattering mechanisms arising from the long-range Fröhlich coupling and deformation-potential scattering processes. Our investigation reveals that the lower mobilities in layered systems primarily originate from the increased electronic density of states at the vicinity of the band edges, while the electron-phonon coupling strength remains similar. Such an increase is caused by the dimensionality reduction and the break in octahedra connectivity along the stacking direction. Our findings provide a fundamental understanding of the electron-phonon coupling mechanisms in layered perovskites and highlight the intrinsic limitations of the charge carrier transport in these materials.

Published by the American Physical Society
2024
Simple Mechanism for Optimal Light-Use Efficiency of Photosynthesis Inspired by Giant Clams
Authors: Holt Amanda L. , Rehm Lincoln F. , Sweeney Alison M.
Published: June 2024

In photosymbiotic giant clams, vertical columns of single-celled algae absorb sunlight that has first been forward scattered from a superficial layer of light-scattering cells called iridocytes. In principle, this arrangement could lead to a highly efficient system but it has been unclear how to calculate a productivity denominator to normalize the performance of the system. Inspired by the geometry observed in the clam, we have created an analytical model that calculates the idealized performance of a system with a geometry similar to the clam. In our model, photosynthesis-irradiance behavior obeys that of algal cells isolated from clams. Using a standard rate of eight photons of photosynthetically active radiation required to create one molecule of O2, we find that a fixed geometry of the “light-dilution” strategy employed by the clams can reach a quantum efficiency of 43% relative to the solar resource in intense tropical sunlight. In comparing the performance of the model to published photosynthesis-irradiance relations of living clams, we have observed that the living system easily exceeds the performance of the static model. Therefore, we have next considered a model in which the system geometry changes dynamically to optimize the quantum efficiency as a function of the solar irradiance. In this scenario, with changes in irradiance typical of a sunny tropical day, the performance of the model was consistent with that of large mature living clams and had a quantum efficiency of 67%. We also show that a similar dynamic modulation of the clam-tissue geometry could plausibly occur in the living animals. We have considered the possibility that efficiency gains in the living system could also occur via further optimization of per-cell absorbance of multiply scattered light within the highly absorbing system. However, a numerical model of radiative transfer within clam tissue that captures realistic multiple scattering has not located efficiency gains relative to the simpler single-pass analytical model. Therefore, we infer that additional resource efficiency over the dynamic, large-clam-like model would require nontrivial organization among cells at small length scales. We also observe that boreal spruce forests coupled to atmospheric haze may realize the same scale-invariant scattering-and-absorbance strategy as the clams but at a different, larger, length scale. Given these results, our model may demonstrate the maximum realizable light-use efficiency of a large photosynthetic system relative to the solar resource. The general principles here also readily generalize to any photosynthetic cell type or organic photoconversion material and solar-irradiance regime. They could therefore provide inspiration both for engineering novel efficient photoconversion processes and materials and inform optimal land-use estimates for efficient industrial biomass production.

Published by the American Physical Society
2024