bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for Behavioral Autorepression in Covid-19 Epidemiological Dynamics
Authors: Lewis Daniel D. , Pablo Michael , Chen Xinyue , Simpson Michael L. , Weinberger Leor
Published: June 2024

It has long been hypothesized that behavioral reactions to epidemic severity autoregulate infection dynamics, for example when susceptible individuals self-sequester based on perceived levels of circulating disease. However, evidence for such ‘behavioral autorepression’ has remained elusive, and its presence could significantly affect epidemic forecasting and interventions. Here, we analyzed early COVID-19 dynamics at 708 locations over three epidemiological scales (96 countries, 50 US states, and 562 US counties). Signatures of behavioral autorepression were identified through: (i) a counterintuitive mobility-death correlation, (ii) fluctuation-magnitude analysis, and (iii) dynamics of SARS-CoV-2 infection waves. These data enabled calculation of the average behavioral-autorepression strength (i.e., negative feedback ‘gain’) across different populations. Surprisingly, incorporating behavioral autorepression into conventional models was required to accurately forecast COVID-19 mortality. Models also predicted that the strength of behavioral autorepression has the potential to alter the efficacy of non-pharmaceutical interventions. Overall, these results provide evidence for the long-hypothesized existence of behavioral autorepression, which could improve epidemic forecasting and enable more effective application of non-pharmaceutical interventions during future epidemics.

Significance

Challenges with epidemiological forecasting during the COVID-19 pandemic suggested gaps in underlying model architecture. One long-held hypothesis, typically omitted from conventional models due to lack of empirical evidence, is that human behaviors lead to intrinsic negative autoregulation of epidemics (termed ‘behavioral autorepression’). This omission substantially alters model forecasts. Here, we provide independent lines of evidence for behavioral autorepression during the COVID-19 pandemic, demonstrate that it is sufficient to explain counterintuitive data on ‘shutdowns’, and provides a mechanistic explanation of why early shutdowns were more effective than delayed, high-intensity shutdowns. We empirically measure autorepression strength, and show that incorporating autorepression dramatically improves epidemiological forecasting. The autorepression phenomenon suggests that tailoring interventions to specific populations may be warranted.
Sex differences in donor T cell targeting of host splenocyte subpopulations in acute and chronic murine graft-vs.-host disease: implications for lupus-like autoimmunity
Authors: Soloviova Kateryna , Via Charles S.
Published: June 2024

This study sought to compare in vivo sex differences in either a Th1-dominant CTL response or a Tfh-mediated lupus-like antibody response using the parent-into F1 murine model of acute or chronic GVHD respectively. In acute GVHD we observed no significant sex differences in the hierarchy of donor CD8 CTL elimination of splenocyte subsets. B cells were the most sensitive to elimination in both sexes; however, the male response was significantly stronger. Sex differences in chronic GVHD were more widespread; females exhibited significantly greater numbers of total splenocytes and host CD4 Tfh cells, B cells and CD8 T cells consistent with reports of greater female autoantibody production in this model. The more potent male CTL response in acute GVHD conflicts with reports of greater female CTL responses following infections or vaccines and may reflect the absence of exogenous innate immune stimuli in this model.
Hematopoietic stem cell division is governed by distinct RUNX1 binding partners
Authors: Robertson Anne L. , Yue Lu , Choudhuri Avik , Kubaczka Caroline , Wattrus Samuel J. , Mandelbaum Joseph , Avagyan Serine , Yang Song , Freeman Rebecca J. , Chan Victoria , Blair Megan C. , Daley George Q. , Zon Leonard I.
Published: June 2024

A defined number of hematopoietic stem cell (HSC) clones are born during development and expand to form the pool of adult stem cells. An intricate balance between self-renewal and differentiation of these HSCs supports hematopoiesis for life. HSC fate is determined by complex transcription factor networks that drive cell-type specific gene programs. The transcription factor RUNX1 is required for definitive hematopoiesis, and mutations in Runx1 have been shown to reduce clonal diversity. The RUNX1 cofactor, CBFý, stabilizes RUNX1 binding to DNA, and disruption of their interaction alters downstream gene expression. Chemical screening for modulators of Runx1 and HSC expansion in zebrafish led us to identify a new mechanism for the RUNX1 inhibitor, Ro5-3335. We found that Ro5-3335 increased HSC divisions in zebrafish, and animals transplanted with Ro5-3335 treated cells had enhanced chimerism compared to untreated cells. Using human CD34+ cells, we show that Ro5-3335 remodels the RUNX1 transcription complex by binding to ELF1, independent of CBFý. This allows specific expression of cell cycle and hematopoietic genes that enhance HSC self-renewal and prevent differentiation. Furthermore, we provide the first evidence to show that it is possible to pharmacologically increase the number of stem cell clonesin vivo, revealing a previously unknown mechanism for enhancing clonal diversity. Our studies have revealed a mechanism by which binding partners of RUNX1 determine cell fate, with ELF transcription factors guiding cell division. This information could lead to treatments that enhance clonal diversity for blood diseases.
A first-in-Plasmodiumstudy on tRNA intron splicing endonuclease ‘PfTSEN1’ and its substrate expression in clinical stage malaria
Authors: Maurya Mukesh Kumar , Behl Ankita , Kahlon Amandeep Kaur , Leon Fernando De , Middha Palak , Nirban Reena , Joshi Prerna , Singhal Jhalak , Kumari Geeta , Munjal Akshay , Shoaib Rumaisha , Jha Neha , Pandey Jagriti , Dutta Tanmay , Arenz Christoph , Ranganathan Anand , Singh Shailja
Published: June 2024

Mature tRNAs play critical role in several cellular processes including protein translation, post-translational-modifications and programmed-cell-death. Maturation of pre-tRNAs require removal of 5’-leaders, 3’-trailers, splicing of introns and addition of conserved 3’-terminal CCA sequence. The tRNA splicing mechanism, an essential step in tRNA maturation govern by a tRNA splicing endonuclease. While the existence of functional tRNA splicing endonuclease(s) inPlasmodium falciparumhas not been identified, its significance in other eukaryotes suggests a potential role in tRNA splicing event. Our study identified total tRNAs inPlasmodiumand characterize aPftRNA splicing endonuclease (annotated asPfTSEN1) recognised recently as a component of ribonucleoprotein (RNP) complex, and synthesized a naphthoquinone derivative as a novel anti-malarial compound (‘TSENi’) targeting the functional activity of this protein. Enzyme activity assays elucidated thatPfTSEN1 catalyses splicing ofin vitrotranscribed pre-tRNAleu, the expression of which was confirmed during the clinical stages of malaria parasite by RT-PCR. Interestingly, TSENibinds to and inhibits enzymatic activity ofPfTSEN1, and showed potent anti-malarial activity against chloroquine-sensitive 3D7 and resistant strains Dd2 ofP. falciparum. Overall, our study deliver key knowledge towards the functional role ofPftRNA splicing endonuclease, and its inhibitor TSENias potent anti-malarial.
Structural Basis for Polθ-Helicase DNA Binding and Microhomology-Mediated End-Joining
Authors: Ito Fumiaki , Li Ziyuan , Minakhin Leonid , Khant Htet A. , Pomerantz Richard T. , Chen Xiaojiang S.
Published: June 2024

DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous recombination (HR) and non-homologous end joining (NHEJ). In HR-deficient cells, DNA polymerase theta (Polθ) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ). Thus, Polθ is synthetically lethal with BRCA1/2 and other HR factors, underscoring its potential as a therapeutic target in HR-deficient cancers. However, the molecular mechanisms governing Polθ-mediated MMEJ remain poorly understood. Here we present a series of cryo-electron microscopy structures of the Polθ helicase domain (Polθ-hel) in complex with DNA containing 3′-overhang. The structures reveal the sequential conformations adopted by Polθ-hel during the critical phases of DNA binding, microhomology searching, and microhomology annealing. The stepwise conformational changes within the Polθ-hel subdomains and its functional dimeric state are pivotal for aligning the 3′-overhangs, facilitating the microhomology search and subsequent annealing necessary for DSB repair via MMEJ. Our findings illustrate the essential molecular switches within Polθ-hel that orchestrate the MMEJ process in DSB repair, laying the groundwork for the development of targeted therapies against the Polθ-hel.
A VLP vaccine platform comprising the core protein of hepatitis B virus with N-terminal antigen capture
Authors: Fatema Kaniz , Snowden Joseph S. , Watson Alexander , Sherry Lee , Ranson Neil A. , Stonehouse Nicola J. , Rowlands David J.
Published: June 2024

Nanoparticle presentation systems offer the potential to develop new vaccines rapidly in response to emerging diseases, a public health need that has become increasingly evident in the wake of the COVID-19 pandemic. Previously, we reported a nanoparticle scaffold system termed VelcroVax. This was constructed by insertion of a high affinity SUMO binding protein (Affimer), able to recognise a SUMO peptide tag, into the major immunodominant region of VLPs assembled from a tandem (fused dimer) form of hepatitis B virus (HBV) core protein (HBc). Here we describe a modified form of VelcroVax, comprising monomeric HBc with the Affimer inserted at the N-terminus (termed N-VelcroVax). In contrast to the tandem form of VelcroVax, N-VelcroVax VLPs were expressed well inE. coli.The VLPs effectively bound SUMO-tagged Junín virus glycoprotein, gp1 as assessed by structural and serological analyses. Cryo-EM characterisation of N-VelcroVax complexed with a SUMO-Junín gp1 showed continuous density attributable to the fused Affimer, in addition to evidence of target antigen capture. Collectively, these data suggest that N-VelcroVax has potential as a versatile next generation vaccine scaffold.
Neural basis of cognitive control signals in anterior cingulate cortex during delay discounting
Authors: Seamans Jeremy K. , White Shelby , Morningstar Mitchell , Emberly Eldon , Linsenbardt David , Ma Baofeng , Czachowski Cristine L. , Lapish Christopher C.
Published: June 2024

Cognitive control involves allocating cognitive effort according to internal needs and task demands and the Anterior Cingulate Cortex (ACC) is hypothesized to play a central role in this process. We investigated the neural basis of cognitive control in the ACC of rats performing an adjusting-amount delay discounting task. Decision-making in this this task can be guided by using either a lever-value tracking strategy, requiring a ‘resource-based’ form of cognitive effort or a lever-biased strategy requiring a ‘resistance-based’ form of cognitive effort. We found that ACC ensembles always tightly tracked lever value on each trial, indicative of a resource-based control signal. These signals were prevalent in the neural recordings and were influenced by the delay. A shorter delay was associated with devaluing of the immediate option and a longer delay was associated with overvaluing of the immediate option. In addition, ACC theta (6-12Hz) oscillations were observed at the choice point of rats exhibiting a resistance-based strategy. These data provide candidates of neural activity patterns in the ACC that underlie the use of ‘resource-based’ and ‘resistance-based’ cognitive effort. Furthermore, these data illustrate how strategies can be engaged under different conditions in individual subjects.
Mechanisms of gene regulation by SRCAP and H2A.Z
Authors: Tollenaere Armelle , Ugur Enes , Dalla-Longa Susanna , Deluz Cédric , Assenheimer Devin , Gebhardt J Christof M , Leonhardt Heinrich , Suter David M
Published: June 2024

Discriminating regulatory functions of chromatin composition from those of chromatin-modifying complexes is a central problem in gene regulation. This question remains unexplored in the context of histone variants and their dedicated chromatin remodelers. Here we dissect the distinct and cell cycle-dependent functions of Snf2 Related CREBBP Activator Protein (SRCAP) and H2A.Z in gene regulation of pluripotent stem cells. We uncover dynamic changes of H2A.Z occupancy and continuous requirement of SRCAP over the cell cycle. We discover that SRCAP exhibits essential H2A.Z-independent functions in inhibiting DNA binding of dozens of pioneer transcription factors at enhancers by steric hindrance. In contrast, H2A.Z acts mainly as a transcriptional repressor gatekeeping the expression of lineage-specific genes. Our study establishes the catalytic-independent role of a chromatin remodeler in broadly regulating transcription factor binding, and demonstrates how a chromatin remodeler-histone variant pair orchestrates transcription to maintain self-renewal and plasticity of pluripotent stem cells.
Bursts boost nonlinear encoding in electroreceptor afferents
Authors: Barayeu Alexandra , Schlungbaum Maria , Lindner Benjamin , Grewe Jan , Benda Jan
Published: June 2024

Nonlinear mechanisms are at the heart of neuronal information processing, for example to fire an action potential, the membrane voltage must exceed a threshold nonlinearity. Even though, linear encoding schemes are commonly used and often successfully describe large parts of sensory encoding nonlinear mechanisms such as thresholds and saturations are well known to be crucial to encode behaviorally relevant features in the stimulus space not captured by linear methods. Here we analyze the role of bursts in p-type electroreceptor afferents (P-units) in the weakly electric fishApteronotus leptorhynchus. It is long known that subpopulations of these cells fire bursts of action potentials while others do not. Previous research suggests, that the non-bursting cells are better at encoding the stimulus time-course while bursting neurons are better suited to encode special features in the stimulus. We here show, based on the analysis of experimental data and modeling, that bursts affect the linear as well as the nonlinear encoding. Theoretical work predicts that in simple leaky-integrate-and-fire model neurons, two periodic stimuli interact nonlinearly when the sum of the two frequencies matches the neuron’s baseline firing rate as quantified by the second-order susceptibility. Indeed, such nonlinear responses have been found in non-bursting P-units when stimulated by two beats simultaneously but only in those cells, that exhibit very low levels of intrinsic noise. In this study, we found that bursts strongly enhance these nonlinear responses which may play a critical role in the detection of weak intruder signals in the presence of a strong female signal, i.e. an electrosensory cocktail party.
Enhancing oncolytic virotherapy by exosome-mediated microRNA reprograming of the tumour microenvironment
Authors: Jennings Victoria A. , Rumbold-Hall Reah , Migneco Gemma , Barr Tyler , Reilly Katarina , Ingram Nicola , Hilare Isabelle St , Heaton Samuel , Alzamel Noura , Jackson David , Ralph Christy , McNeish Iain , Bell John C. , Melcher Alan A. , Ilkow Carolina , Cook Graham , Errington-Mais Fiona
Published: June 2024

Background

There has been limited success of cancer immunotherapies in the treatment of ovarian cancer (OvCa) to date, largely due to the immunosuppressive tumour microenvironment (TME). Tumour-associated macrophages (TAMs) are a major component of both the primary tumour and malignant ascites, promoting tumour growth, angiogenesis, metastasis, chemotherapy resistance and immunosuppression. Differential microRNA (miRNA) profiles have been implicated in the plasticity of TAMs. Therefore, delivering miRNA to TAMs to promote an anti-tumour phenotype is a novel approach to reverse their pro-tumour activity and enhance the efficacy of cancer immunotherapies. Oncolytic viruses (OVs) preferentially replicate in tumour cells making them ideal vehicles to deliver miRNA mimetics to the TME. Importantly, miRNA expressed by OVs get packaged within tumour-derived extracellular vesicles (TDEVs), and release of TDEV is augmented by OV infection, thus enhancing the dissemination of miRNA throughout the TME.

Method

Small RNAseq was used to identify differentially expressed miRNA during TAM generation and following LPS/IFNγ stimulation to induce an anti-tumour phenotype. Two differentially expressed miRNA identified, miR-155 and miR-19a, were cloned into oncolytic rhabdovirus (ORV), and anti-tumour efficacy was investigated using bothin vitroandin vivomodels of OvCa.

Results

This study demonstrates that ORV infection enhances TDEV production in OvCa cell lines bothin vitroandin vivoand that TDEV are preferentially taken up by myeloid cells, including TAMs. Small RNAseq identified 23 miRNAs that were significantly upregulated in anti-tumour TAMs, including miR-155-5p. While 101 miRNAs were downregulated during pro-tumour TAM differentiation, including miR-19a-3p. Culturing TDEV expressing miR-155 or miR-19a with TAMs reversed their immunosuppressive activity, as measured by T cell proliferation. While ORV-miR-155 enhanced the generation of anti-tumour T cells, only ORV-miR19a significantly improved survival of mice bearing ovarian tumours.

Conclusion

This study demonstrates (i) that arming ORVs with immunomodulatory miRNA is an effective approach to deliver miRNA to myeloid cells within the TME and (ii) that miRNA have the capacity to reverse the tumour promoting properties of TAMs and improve the efficacy of cancer immunotherapies, such as OV.
PLA2G15 is a Lysosomal BMP Hydrolase and its Targeting Ameliorates Lysosomal Disease
Authors: Nyame Kwamina , Xiong Jian , Alsohybe Hisham N. , de Jong Arthur PH , Peña Isabelle V. , de Miguel Ricardo , Brummelkamp Thijn R. , Hartmann Guido , Nijman Sebastian M.B. , Raaben Matthijs , Simcox Judith A. , Blomen Vincent A. , Abu-Remaileh Monther
Published: June 2024

Lysosomes catabolize lipids and other biological molecules, a function essential for cellular and organismal homeostasis. Key to lipid catabolism in the lysosome is bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles and a stimulator of lipid-degrading enzymes. BMP levels are altered in a broad spectrum of human conditions, including neurodegenerative diseases. While a lysosomal BMP synthase was recently discovered, the enzymes that mediate BMP turnover has remained elusive. Here we show that the lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that BMP’s resistance to hydrolysis in the lysosome is conferred by the combination of its uniquesn2, sn2’esterification position and stereochemistry, as neither feature alone is sufficient to provide this resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes under acidic conditions. Furthermore, PLA2G15 catalytic activity against synthesized BMP stereoisomers with primary esters was comparable to its canonical substrates challenging the long-held thought that BMP’s unique stereochemistry is sufficient to confer resistance to acid phospholipases. Conversely, BMP with secondary esters andS,Sstereoconfiguration is intrinsically stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate multiple BMP species, a phenotype reversible by supplementing wildtype PLA2G15 but not its catalytically dead mutant. In addition, targeting PLA2G15 to increase BMP reverses the cholesterol phenotype in Niemann Pick Disease Type C (NPC1) patient fibroblasts and significantly ameliorates disease pathologies in NPC1-deficient mice leading to extended lifespan. Our findings establish the rules that govern the stability of BMP in the lysosome and identify PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases.
Determinants of raffinose family oligosaccharide use inBacteroidesspecies
Authors: Basu Anubhav , Adams Amanda N.D. , Degnan Patrick H. , Vanderpool Carin K.
Published: June 2024

Bacteroidesspecies are successful colonizers of the human gut and can utilize a wide variety of complex polysaccharides and oligosaccharides that are indigestible by the host. To do this, they use enzymes encoded in Polysaccharide Utilization Loci (PULs). While recent work has uncovered the PULs required for use of some polysaccharides, howBacteroidesutilize smaller oligosaccharides is less well studied. Raffinose family oligosaccharides (RFOs) are abundant in plants, especially legumes, and consist of variable units of galactose linked by ⍺-1,6 bonds to a sucrose (glucose ⍺-1-β-2 fructose) moiety. Previous work showed that an α-galactosidase, BT1871, is required for RFO utilization inBacteroides thetaiotaomicron. Here, we identify two different types of mutations that increaseBT1871mRNA levels and improveB. thetaiotaomicrongrowth on RFOs. First, a novel spontaneous duplication ofBT1872andBT1871places these genes under control of a ribosomal promoter, driving highBT1871transcription. Second, nonsense mutations in a gene encoding the PUL24 anti-sigma factor likewise increaseBT1871transcription. We then show that hydrolases from PUL22 work together with BT1871 to break down the sucrose moiety of RFOs and determine that the master regulator of carbohydrate utilization (BT4338) plays a role in RFO utilization inB. thetaiotaomicron. Examining the genomes of otherBacteroidesspecies, we found homologs of BT1871 in subset and show that representative strains of species containing a BT1871 homolog grew better on melibiose than species that lack a BT1871 homolog. Altogether, our findings shed light on how an important gut commensal utilizes an abundant dietary oligosaccharide.

Importance

The gut microbiome is important in health and disease. The diverse and densely populated environment of the gut makes competition for resources fierce. Hence, it is important to study the strategies employed by microbes for resource usage. Raffinose family oligosaccharides are abundant in plants and are a major source of nutrition for the gut microbiota since they remain undigested by the host. Here, we study how the model gut commensal,Bacteroides thetaiotaomicronutilizes raffinose family oligosaccharides. This work highlights how an important member of the microbiota uses an abundant dietary resource.
Synergy between Group 2 capsules and lipopolysaccharide underpins serum resistance in Extra-intestinal Pathogenic Escherichia coli
Authors: McGarry Naoise , Smith Stephen , Roe Domhnall
Published: June 2024

Escherichia coli (E. coli) is a major cause of urinary tract infections, bacteraemia, and sepsis. CFT073 is a prototypic, urosepsis isolate of sequence type (ST) 73. This laboratory, among others, has shown that strain CFT073 is resistant to serum, with capsule and other extracellular polysaccharides imparting resistance. The interplay of such polysaccharides remains under-explored. This study has shown that CFT073 mutants deficient in lipopolysaccharide (LPS) O-antigen and capsule display exquisite serum sensitivity. Additionally, O-antigen and LPS outer core mutants displayed significantly reduced surface K2 capsule, coupled with increased unbound K2 capsule being detected in the supernatant. The R1 core and O6 antigen are involved in the tethering of K2 capsule to the CFT073 cell surface, highlighting the importance of the R1 core in serum resistance. The dependence of capsule on LPS was shown to be post-transcriptional and related to changes in cell surface charge. Furthermore, immunofluorescence microscopy suggested that the surface pattern of capsule is altered in such LPS core mutants, which display a punctate capsule expression. Finally, targeting LPS biosynthesis using sub-inhibitory concentrations of a WaaG inhibitor resulted in increased serum sensitivity, antibiotic sensitivity, and reduced capsule in CFT073. Interestingly, the dependency of capsule on LPS has been observed previously in several Klebsiella pneumoniae isolates and a neonatal meningitic E. coli strain, indicating that the synergy between these polysaccharides is not just strain, serotype or species-specific but may be conserved across several pathogenic Gram-negative species. Therefore, using WaaG inhibitor derivatives or phage-derived depolymerases to target LPS is a promising avenue for co-administration with antibiotics to reduce morbidity and mortality by reducing or eliminating surface capsule.
The combination of three CD4-induced antibodies targeting highly conserved Env regions with a small CD4-mimetic achieves potent ADCC activity
Authors: Marchitto Lorie , Richard Jonathan , Prévost Jérémie , Tauzin Alexandra , Yang Derek , Chiu Ta-Jung , Chen Hung-Ching , Díaz-Salinas Marco A. , Nayrac Manon , Benlarbi Mehdi , Beaudoin-Bussières Guillaume , Anand Sai Priya , Dionne Katrina , Bélanger Étienne , Chatterjee Debashree , Medjahed Halima , Bourassa Catherine , Tolbert William D. , Hahn Beatrice H. , Munro James B. , Pazgier Marzena , Smith Amos B. , Finzi Andrés
Published: June 2024

The majority of naturally-elicited antibodies against the HIV-1 envelope glycoproteins (Env) are non-neutralizing (nnAbs), because they are unable to recognize the Env timer in its native “closed” conformation. Nevertheless, it has been shown that nnAbs have the potential to eliminate HIV-1-infected cells by Antibody-Dependent Cellular Cytotoxicity (ADCC) provided that Env is present on the cell surface in its “open” conformation. This is because most nnAbs recognize epitopes that become accessible only after Env interaction with CD4 and the exposure of epitopes that are normally occluded in the closed trimer. HIV-1 limits this vulnerability by downregulating CD4 from the surface of infected cells, thus preventing a premature encounter of Env with CD4. Small CD4-mimetics (CD4mc) sensitize HIV-1-infected cells to ADCC by opening the Env glycoprotein and exposing CD4-induced (CD4i) epitopes. There are two families of CD4i nnAbs, termed anti-cluster A and anti-CoRBS Abs, which are known to mediate ADCC in the presence of CD4mc. Here, we performed Fab competition experiments and found that anti-gp41 cluster I antibodies comprise a major fraction of the plasma ADCC activity in people living with HIV (PLWH). Moreover, addition of gp41 cluster I antibodies to cluster A and CoRBS antibodies greatly enhanced ADCC mediated cell killing in the presence of a potent indoline CD4mc, CJF-III-288. This cocktail outperformed broadly-neutralizing antibodies and even showed activity against HIV-1 infected monocyte-derived macrophages. Thus, combining CD4i antibodies with different specificities achieves maximal ADCC activity, which may be of utility in HIV cure strategies.

IMPORTANCE

The elimination of HIV-1-infected cells remains an important medical goal. While current antiretroviral therapy decreases viral loads below detection levels, it does not eliminate latently infected cells which form the viral reservoir. Here, we developed a cocktail of non-neutralizing antibodies targeting highly conserved Env regions and combined it with a potent indoline CD4mc. This combination exhibited very potent ADCC activity against HIV-1-infected primary CD4+ T cells as well as monocyte-derived macrophages, suggesting its potential utility in decreasing the size of the viral reservoir.
Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses
Authors: Oriol Lucie , Chao Melody , Kollman Grace J. , Dowlat Dina S. , Singhal Sarthak M. , Steinkellner Thomas , Hnasko Thomas S.
Published: June 2024

The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction.

Significance statement

GABA neurons in VTA are key regulators of VTA dopamine neurons and considered central to the mechanisms by which opioids and other drugs of abuse can induce addiction. Conventionally, these VTA GABA neurons are considered interneurons, but GABA projection neurons are also abundant in VTA, and it is unclear if these represent separate populations. We found that several markers enriched in non-dopamine neurons of VTA, including Mu-opioid receptor, are also expressed in projection neurons, and thus are not selective interneuron markers. Moreover, we found that VTA GABA and glutamate projection neurons collateralize within VTA where they make local synapses. These data challenge the notion of a VTA interneuron that synapses only within VTA and suggest that inhibitory projection neurons can serve functions previously attributed to VTA interneurons.
Understanding organism-habitat relationships and critically evaluating reference areas is key to marine protected area assessment
Authors: Jainese Conner , Carlson Peter M. , Seeto Katelin , McNeill Lyndsey , Sivertson Kelly , Caselle Jennifer E.
Published: June 2024

Marine Protected Areas (MPAs) have been implemented globally as a conservation tool to improve the health and function of marine ecosystems. Research has focused on assessing MPA effectiveness, however certain habitats and communities are often avoided because they are difficult or expensive to monitor. Mesophotic (30-100m) rocky reef fish communities are a valuable commercial and recreational resource that is highly targeted but often overlooked in monitoring due to depth restricted sampling. We used two MPAs in California’s statewide protection network, along with parried reference sites, to test how protection status along with environmental conditions influenced the abundance and biomass of three highly targeted species with varying life histories and habitat preferences. Depth and habitat were strong predictors for all groups; ocean whitefish (Caulolatilus princeps), California sheephead (Semicossyphus pulcher), and targeted rockfish (Sebastes spp). The pattern of these effects however, differed between the species groups and the influence of protection was mixed. This work highlights how species with high habitat affinities benefit differently from protection, as a function of depth and habitat representation within the MPA/reference pair. To accurately evaluate MPAs, and the network as a whole, researchers must recognize organism-habitat relationships and incorporate them when assessing conservation efforts.
Eyes on the past: Gaze stability differs between temporal expectation and temporal attention
Authors: Duyar Aysun , Carrasco Marisa
Published: June 2024

Temporal expectation and temporal attention distinctly improve performance and gaze stability, and interact at the behavioral and neural levels. Foreperiod—the interval between the preparatory signal and stimulus onset—facilitates temporal expectation. Preceding foreperiod—the foreperiod in the previous trial—modulates expectation at behavioral and oculomotor levels. Here, we investigated whether preceding foreperiod guides temporal attention. Regardless of the preceding foreperiod, temporal attention improved performance, particularly at early moments,and consistently accelerated gaze stability onset and offset by shifting microsaccade timing. However, only with preceding expected foreperiods, attention inhibited microsaccade rates. Moreover, preceding late foreperiods weakened expectation effects on microsaccade rates, but such a weakening was overridden by attention. Altogether, these findings reveal that the oculomotor system’s flexibility does not translate to performance, and suggest that although selection history can be utilized as one of the sources of expectation in subsequent trials, it does not necessarily determine, strengthen, or guide attentional deployment.
Mosquito population dynamics is shaped by the interaction among larval density, season, and land use
Authors: Solano Nicole , Herring Emily C. , Hintz Carl W. , Newberry Philip M. , Schatz Annakate M. , Walker Joseph W. , Osenberg Craig W. , Murdock Courtney C.
Published: June 2024

ABSTRACT (English)

Understanding how variation in key abiotic and biotic factors interact at spatial scales relevant for mosquito fitness and population dynamics is crucial for predicting current and future mosquito distributions and abundances, and the transmission potential for human pathogens. However, studies investigating the effects of environmental variation on mosquito traits have investigated environmental factors in isolation or in laboratory experiments that examine constant environmental conditions that often do not occur in the field. To address these limitations, we conducted a semi-field experiment in Athens, Georgia using the invasive Asian tiger mosquito (Aedes albopictus). We selected nine sites that spanned natural variation in impervious surface and vegetation cover to explore effects of the microclimate (temperature and humidity) on mosquitoes. On these sites, we manipulated conspecific larval density at each site. We repeated the experiment in the summer and fall. We then evaluated the effects of land cover, larval density, and time of season, as well as interactive effects, on the mean proportion of females emerging, juvenile development time, size upon emergence, and predicted per capita population growth (i.e., fitness). We found significant effects of larval density, land cover, and season on all response variables. Of most note, we saw strong interactive effects of season and intra-specific density on each response variable, including a non-intuitive decrease in development time with increasing intra-specific competition in the fall. Our study demonstrates that ignoring the interaction between variation in biotic and abiotic variables could reduce the accuracy and precision of models used to predict mosquito population and pathogen transmission dynamics, especially those inferring dynamics at finer-spatial scales across which transmission and control occur.
Evaluating regional heritability mapping methods for identifying QTLs in a wild population of Soay sheep
Authors: James Caelinn , Pemberton Josephine M. , Navarro Pau , Knott Sara
Published: June 2024

Regional heritability mapping (RHM) is a method that estimates the heritability of genomic segments that may contain both common and rare variants affecting a complex trait. We compared three RHM methods: SNP-RHM, which uses genomic relationship matrices (GRMs) based on SNP genotypes; Hap-RHM, which uses GRMs based on haplotypes; and SNHap-RHM, which uses both SNP-based and haplotype-based GRMs jointly. We applied these methods to data from a wild population of sheep, analysed eleven polygenic morphometric traits and compared the results with previous genome wide association analyses (GWAS). We found that whilst the inclusion of the regional matrix did not explain significant variation for all regions that were associated with trait variation using GWAS, it did for several regions that were not previously associated with trait variation.
Constitutively active receptor ADGRA3 signaling induces adipose thermogenesis
Authors: Zhao Zewei , Hu Longyun , Song Bigui , Jiang Tao , Wu Qian , Lin Jiejing , Li Xiaoxiao , Cai Yi , Li Jin , Qian Bingxiu , Liu Siqi , Lang Jilu , Yang Zhonghan
Published: June 2024

The induction of adipose thermogenesis plays a critical role in maintaining body temperature and improving metabolic homeostasis to combat obesity. β3-adrenoceptor (β3-AR) is widely recognized as a canonical β-adrenergic G protein-coupled receptor (GPCR) that plays a crucial role in mediating adipose thermogenesis in mice. Nonetheless, the limited expression of β3-AR in human adipocytes restricts its clinical application. The objective of this study was to identify a GPCR that is highly expressed in human adipocytes and to explore its potential involvement in adipose thermogenesis. Our research findings have demonstrated that the adhesion G protein-coupled receptor A3 (ADGRA3), an orphan GPCR, plays a significant role in adipose thermogenesis through its constitutively active effects. ADGRA3 exhibited high expression levels in human adipocytes and mouse brown fat. Furthermore, the knockdown ofAdgra3resulted in an exacerbated obese phenotype and a reduction in the expression of thermogenic markers. Conversely,Adgra3overexpression activated the adipose thermogenic program and improved metabolic homeostasis without an exogenous ligand supplementation. We found that ADGRA3 facilitates the biogenesis of beige adipocytes through the Gs-PKA-CREB axis. Moreover, hesperetin was identified as a potential agonist of ADGRA3, capable of inducing adipocyte browning and ameliorating insulin resistance. In conclusion, our study demonstrated that the overexpression of constitutively active ADGRA3 or the activation of ADGRA3 by hesperetin can induce adipocyte browning by Gs-PKA-CREB axis. These findings indicate that the utilization of hesperetin and the selectively overexpression of ADGRA3 in adipose tissue could serve as promising therapeutic strategies in the fight against obesity.
Systematic identification of secondary bile acid production genes in global microbiome
Authors: Yang Yuwei , Gao Wenxing , Zhu Ruixin , Tao Liwen , Chen Wanning , Zhu Xinyue , Shen Mengping , Xu Tingjun , Zhao Tingting , Zhang Xiaobai , Zhu Lixin , Jiao Na
Published: June 2024

Microbial metabolism of bile acids (BAs) is crucial for maintaining homeostasis in vertebrate hosts and environments. Although certain organisms involved in BA metabolism have been identified, a global, comprehensive elucidation of the microbes, metabolic enzymes, and BA remains incomplete. To bridge this gap, we employed hidden Markov models to systematically search in a large-scale and high-quality search library comprising 28,813 RefSeq multi-kingdom microbial complete genomes, which enabled us to construct a secondary bile acid (SBA)-production gene catalog. This catalog greatly expanded the distribution of SBA-production genes across 11 phyla, encompassing bacteria, archaea and fungi, and extended to 14 habitats spanning hosts and environmental contexts. Furthermore, we highlighted the associations between SBAs and gastrointestinal and hepatic disorders, including inflammatory bowel disease, colorectal cancer and nonalcoholic fatty liver disease, further elucidating disease-specific alterations in SBA-production genes. Additionally, we proposed the pig as a particularly suitable animal model for investigating SBA production in humans, given its closely aligned SBA-production gene composition. This gene catalog provides a comprehensive and reliable foundation on microbial BA metabolism for future studies, offering new insights into the microbial contributions to health and disease.
Chromosome-level reference genome assembly for the mountain hare (Lepus timidus)
Authors: Fekete Zsófia , Absolon Dominic E. , Michell Craig , Wood Jonathan M. D. , Goffart Steffi , Pohjoismäki Jaakko L. O.
Published: June 2024

We present here a high-quality genome assembly of a male mountain hare (Lepus timidusLinnaeus), from Ilomantsi, Eastern Finland, utilizing an isolated fibroblast cell line as the source for high quality DNA and RNA. Following the previously published brown hare reference genome assembly, the mountain hare is the second Finnish pilot species for the European Reference Genome Atlas (ERGA) initiative, a collaborative effort to generate reference genomes for European biodiversity.

The genome was assembled using 21× PacBio HiFi sequencing data and scaffolded using the Hi-C chromosome structure capture approach. After manual curation, the primary assembly length was 2,695,305,354 bp with N50 125,755,317 bp. The largest scaffold was 181 Mbp and the scaffold N50 127 Mbp, contributing to a primary assembly consisting of 85 scaffolds and an alternate assembly with 109 scaffolds. The scaffolds include 23 autosomes, numbered according to their size, as well as X and Y chromosomes, matching the known karyotype. Telomeric regions were present on at least one end of 19 of the chromosomes. The genome has a high degree of completeness based on the BUSCO score (mammalia_odb10 database), Complete: 95.1 % [Single copy: 92.3 %, Duplicated: 2.7 %], Fragmented 0.8 %, and Missing 4.1 %. The mitochondrial genome of the cell line was sequenced and assembled separately. The assembly meets the Earth BioGenome Project criteria for a reference-standard genome assembly.

Compared to the previous pseudo-reference genome assembly ofL. timidusssp.hibernicusBell, assembled using the rabbit genome, this new reference genome represents the nominate subspecies and the species-specific chromosomal conformation. The published genome assembly will provide a solid foundation for future genomic research on Lagomorpha, including the insights into the genomic basis of adaptations to snowy and cold environments. Furthermore, it opens opportunities for experimental analysis of mountain hare gene functions.
From X-ray crystallographic structure to intrinsic thermodynamics of protein–ligand binding using carbonic anhydrase isozymes as a model system
Authors: Paketurytė-Latvė Vaida , Smirnov Alexey , Manakova Elena , Baranauskiene Lina , Petrauskas Vytautas , Zubrienė Asta , Matulienė Jurgita , Dudutienė Virginija , Čapkauskaitė Edita , Zakšauskas Audrius , Leitans Janis , Gražulis Saulius , Tars Kaspars , Matulis Daumantas
Published: June 2024

Carbonic anhydrase (CA) was among the first proteins whose X-ray crystal structure was solved to atomic resolution. CA proteins have essentially the same fold and similar active centers that differ in only several amino acids. Primary sulfonamides are well defined, strong and specific binders of CA. However, minor variations in chemical structure can significantly alter their binding properties. Over 1000 sulfonamides have been designed, synthesized and evaluated to understand the correlations between the structure and thermodynamics of their binding to the human CA isozyme family. Compound binding was determined by several binding assays: fluorescence-based thermal shift assay, stopped-flow enzyme activity inhibition assay, isothermal titration calorimetry and competition assay for enzyme expressed on cancer cell surfaces. All assays have advantages and limitations but are necessary for deeper characterization of these protein–ligand interactions. Here, the concept and importance of intrinsic binding thermodynamics is emphasized and the role of structure–thermodynamics correlations for the novel inhibitors of CA IX is discussed – an isozyme that is overexpressed in solid hypoxic tumors, and thus these inhibitors may serve as anticancer drugs. The abundant structural and thermodynamic data are assembled into the Protein–Ligand Binding Database to understand general protein–ligand recognition principles that could be used in drug discovery.
Nudge research in agricultural economics: two-decade retrospective of empirical evidence
Authors: Čop Tajana , Njavro Mario
Published: June 2024

Purpose

Understanding farmer and consumer behavior is essential to the successful implementation of behavior change interventions. The purpose of this study is to summarize existing research, provide a comprehensive overview of nudge interventions, and identify important trends in behavioral agricultural economics. Research on nudge interventions can help policymakers encourage farmers and consumers to change their behavior in desired direction like switching to organic agriculture or eco-labeled products and promote innovation in sustainable agriculture.

Design/methodology/approach

The paper contains a bibliometric analysis of nudge research in general and agricultural economics as well as a literature review of the 53 empirical studies on nudge interventions between 2003 and 2023.

Findings

The frequency of nudge research in all research fields and in agricultural economics has increased over the years. This study summarizes nudge interventions that can be used by farmers and consumers on a variety of agricultural economic issues. Information, social norms, and social comparison as nudge interventions are most prominent in the publications, while green nudges have not been researched to a greater extent.

Originality/value

This study provides a comprehensive overview of nudge research in agricultural economics with potential for theoretical and policy implications. It highlights potential nudge interventions among farmers and consumers that can be applied in practices.
The era of artificial intelligence: what implications for the board of directors?
Authors: Agnese Paolo , Arduino Francesca Romana , Di Prisco Domenico
Published: June 2024

Purpose

Artificial intelligence (AI) is a cutting-edge new reality already having an unprecedented impact on society, the economy and businesses. Its future developments and long-term influence are still largely unknown. This article aims to examine AI’s potential benefits and challenges to corporate governance mechanisms, focusing on the board of directors.

Design/methodology/approach

The paper theoretically explores the influence of artificial intelligence on the board of directors’ capabilities, roles and functions.

Findings

Concerning rethinking board functioning in the era of artificial intelligence, the paper analyzes how artificial intelligence can impact the board of directors. It proposes some recommendations on how directors can more effectively integrate artificial intelligence into the boardroom, including establishing an internal artificial intelligence committee composed of experts with technical knowledge dedicated to managing artificial intelligence-related potential threats and opportunities.

Practical implications

Companies are invited to have some technical knowledge and expertise on artificial intelligence on the boards, fostering directors to upskill themselves in the new artificial intelligence technologies and establishing an ad-hoc internal committee. Policymakers are expected to keep pace with the growing proliferation of artificial intelligence solutions, defining a sharp regulatory framework.

Originality/value

The study advances knowledge in the corporate governance literature by shedding light on the effects of artificial intelligence on boards of directors and suggesting a set of best practices for its effective implementation.