bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in cognitive function before and after myocardial infarction : findings from the China Health and Retirement Longitudinal Study
Authors: Zhu Sijia , Shang Jing , Dong Jianye , Chen Qingmei , Hua Jianian
Published: August 2023

Objectives

Incident stroke was associated with cognitive dysfunction after stroke and even before stroke. However, cognitive trends prior to myocardial infarction (MI) and the timeline of cognitive decline in a few years following incident MI remain unclear, especially among the Chinese population. We aimed to evaluate whether MI was associated with cognitive change both before and after MI in China.

Methods

This cohort study included 11287 participants without baseline heart problems or stroke from the China Health and Retirement Longitudinal Study. The exposure was self-reported MI. The outcomes were scores of cognitive function in five domains, which reflected abilities of episodic memory, visuospatial abilities, orientation, attention and calculation, and global cognition as a summary measure. Linear mixed models explored cognitive function before and after incident MI among the MI participants and the cognitive trends of participants free of MI.

Results

During the 7-year follow-up, 421 individuals (3.7% of 11287, mean [SD] age, 60.0 [9.0] years; 59.1% female) experienced MI events. The cognitive scores of participants of both the MI group and the control group without MI declined gradually due to aging. The annual decline rate of the MI group before incident MI was similar to that of the control group during the whole follow-up period. Incident MI was not associated with acute cognitive decline in all five cognitive domains. Moreover, MI did not accelerate the cognitive decline rate after MI compared with the pre-MI cognitive trends. The decline rate of cognitive function after MI was similar to the rate before MI.

Conclusions

Different from stroke, participants who had an MI did not show steeper cognitive decline before MI. MI was not associated with acute cognitive decline and accelerated long-term decline after MI. Future studies are needed to learn the mechanisms behind the different patterns of cognitive decline between MI and stroke.
Retrospective, observational analysis of the first one hundred consecutive cases of personalized bacteriophage therapy of difficult-to-treat infections facilitated by a Belgian consortium
Authors: Pirnay Jean-Paul , Djebara Sarah , Steurs Griet , Griselain Johann , Cochez Christel , De Soir Steven , Glonti Tea , Spiessens An , Berghe Emily Vanden , Green Sabrina , Wagemans Jeroen , Lood Cédric , Schrevens Eddie , Chanishvili Nina , Kutateladze Mzia , de Jode Mathieu , Ceyssens Pieter-Jan , Draye Jean-Pierre , Verbeken Gilbert , De Vos Daniel , Rose Thomas , Onsea Jolien , Van Nieuwenhuyse Brieuc ,   Bacteriophage Therapy Providers,   Bacteriophage Donors, Soentjens Patrick , Lavigne Rob , Merabishvili Maya
Published: August 2023

In contrast to the many reports of successful cases of personalized bacteriophage therapy, randomized controlled trials of non-personalized bacteriophage products did not bring the expected results. Here, we present the outcomes of a retrospective, observational analysis of the first 100 consecutive cases of personalized bacteriophage therapy of difficult-to-treat infections facilitated by a Belgian consortium. The most common indications were lower respiratory tract, skin & soft tissue, and bone infections, and involved combinations of 26 bacteriophages, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. Eradication was 70% less probable when no concomitant antibiotics were used (odds-ratio = 0.3; 95% confidence interval = 0.127–0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage-antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. (BT100 study,ClinicalTrials.govregistration:NCT05498363.)
Delays in accessing high-quality care for newborns in East Africa: An analysis of survey data in Malawi, Mozambique, and Tanzania
Authors: Niehaus Lori , Sheffel Ashley , Kalter Henry , Amouzou Agbessi , Koffi Alain , Munos Melinda K.
Published: August 2023

Background

Despite the existence of evidence-based interventions, substantial progress in reducing neonatal mortality is lagging, indicating that small and sick newborns (SSNs) are likely not receiving the care they require to survive and thrive. The “three delays model” provides a framework for understanding the challenges in accessing care for SSNs. However, the extent to which each of the delays impacts access to care for SSNs is not well-understood. To fill this evidence gap, we explored the impact of each of the three delays on access to care for SSNs in Malawi, Mozambique, and Tanzania.

Methods

Secondary analyses of data from three different surveys served as the foundation of this study. To understand the impact of delays in the decision to seek care (delay 1) and the ability to reach an appropriate point of care (delay 2), we investigated time trends in place of birth disaggregated by facility type and explored care-seeking behaviors for newborns who died. To understand the impact of delays accessing high-quality care after reaching a facility (delay 3), we measured facility readiness to manage care for SSNs and used this measure to adjust institutional delivery coverage for SSN care readiness.

Findings

Coverage of institutional deliveries was substantially lower after adjusting for facility readiness to manage SSN care, with decreases of 30 percentage points (pp) in Malawi, 14pp in Mozambique, and 24pp in Tanzania. While trends suggest more SSNs are born in facilities, substantial gaps remain in facilities’ capacities to provide lifesaving interventions. In addition, exploration of care-seeking pathways revealed that a substantial proportion of newborn deaths occurred outside of health facilities, indicating barriers in the decision to seek care or ability to reach an appropriate source of care may also prevent SSNs from receiving these interventions.

Conclusions

Investments are needed to overcome delays in accessing high quality care for the most vulnerable newborns – those who are born small or sick. As more mothers and newborns access health services in low- and middle-income countries, ensuring that life-saving interventions for SSNs are available at the locations where newborns are born and seek care after birth is critical.
Tau phosphorylated at serine 356 is associated with Alzheimer’s disease pathology and can be lowered in mouse and human brain tissue using the NUAK inhibitor WZ4003
Authors: Taylor Lewis W. , Simzer Elizabeth M. , Pimblett Claire , Lacey-Solymar Oscar T.T. , McGeachan Robert I. , Meftah Soraya , Rose Jamie L. , Spires-Jones Maxwell P. , Catterson James H. , Koch Henner , Liaquat Imran , Clarke Jonathan H. , Skidmore John , Booker Sam A. , Brennan Paul M. , Spires-Jones Tara L. , Durrant Claire S.
Published: August 2023

Tau hyperphosphorylation and aggregation is a common feature of many dementia-causing neurodegenerative diseases. Tau can be phosphorylated at up to 85 different sites, and there is increasing interest in whether tau phosphorylation at specific epitopes, by specific kinases, plays an important role in disease progression. The AMP-activated protein kinase (AMPK) related enzyme NUAK1 been identified as a potential mediator of tau pathology, whereby NUAK1-mediated phosphorylation of tau at Ser356 prevents the degradation of tau by the proteasome, further exacerbating tau hyperphosphorylation and accumulation. This study provides a detailed characterisation of the association of p-tau Ser356 with progression of Alzheimer’s disease pathology, identifying a Braak stage-dependent increase in p-tau Ser356 protein levels and an almost ubiquitous presence in neurofibrillary tangles. We also demonstrate, using sub-diffraction-limit resolution array tomography imaging, that p-tau Ser356 co-localises with synapses in AD post-mortem brain tissue, increasing evidence that this form of tau may play important roles in AD progression. To assess the potential impacts of pharmacological NUAK inhibition in anex vivosystem that retains multiple cell types and brain-relevant neuronal architecture, we treated postnatal mouse organotypic brain slice cultures from wildtype or APP/PS1 littermates with the commercially available NUAK1/2 inhibitor WZ4003. Whilst there were no genotype specific effects, we found that WZ4003 results in a culture-phase dependent loss of total tau and p-tau Ser356, which corresponds with a reduction in neuronal and synaptic proteins. By contrast, application of WZ4003 to live human brain slice cultures results in a specific lowering of p-tau Ser356, alongside increased neuronal tubulin protein. This work identifies differential responses of postnatal mouse organotypic brain slice cultures and adult human brain slice cultures to NUAK1 inhibition that will be important to consider in future work developing tau-targeting therapeutics for human disease.
Dopaminergic D2 receptor modulation of striatal cholinergic interneurons contributes to sequence learning
Authors: Chancey Jessica Hotard , Kellendonk Christoph , Javitch Jonathan A. , Lovinger David M.
Published: August 2023

Learning action sequences is necessary for normal daily activities. Medium spiny neurons (MSNs) in the dorsal striatum (dStr) encode action sequences through changes in firing at the start and/or stop of action sequences or sustained changes in firing throughout the sequence. Acetylcholine (ACh), released from cholinergic interneurons (ChIs), regulates striatal function by modulating MSN and interneuron excitability, dopamine and glutamate release, and synaptic plasticity. Cholinergic neurons in dStr pause their tonic firing during the performance of learned action sequences. Activation of dopamine type-2 receptors (D2Rs) on ChIs is one mechanism of ChI pausing. In this study we show that deleting D2Rs from ChIs by crossing D2-floxed with ChAT-Cre mice (D2Flox-ChATCre), which inhibits dopamine-mediated ChI pausing and leads to deficits in an operant action sequence task and lower breakpoints in a progressive ratio task. These data suggest that D2Flox-ChATCre mice have reduced motivation to work for sucrose reward, but show no generalized motor skill deficits. D2Flox-ChATCre mice perform similarly to controls in a simple reversal learning task, indicating normal behavioral flexibility, a cognitive function associated with ChIs.In vivoelectrophysiological recordings show that D2Flox-ChatCre mice have deficits in sequence encoding, with fewer dStr MSNs encoding entire action sequences compared to controls. Thus, ChI D2R deletion appears to impair a neural substrate of action chunking. Virally replacing D2Rs in dStr ChIs in adult mice improves action sequence learning, but not the lower breakpoints, further suggesting that D2Rs on ChIs in the dStr are critical for sequence learning, but not for driving the motivational aspects of the task.

Significance statement

The role of striatal projection neurons in encoding action sequences has been extensively studied, and cholinergic interneurons play a central role in striatal physiology, but we do not yet understand how cholinergic interneurons contribute to action sequencing. Using a combination of mouse genetics, behavior, andin vivoelectrophysiology this work shows that genetic deletion of D2 receptors from striatal cholinergic interneurons disrupts the learning, performance, and encoding of action sequences, without changing general locomotion or motor skill learning. Virally replacing D2 receptors specifically in dorsal striatal cholinergic interneurons is sufficient to rescue the sequence behavior. Our observations may be useful in understanding and treating movement disorders in which dopamine and acetylcholine are imbalanced.
Effort cost of reaching prompts vigor reduction in older adults
Authors: Summerside Erik M. , Courter Robert J. , Shadmehr Reza , Ahmed Alaa A.
Published: August 2023

As people age, they move slower. Is age-related reduction in vigor a reflection of a reduced valuation of reward by the brain, or a consequence of increased effort costs by the muscles? Here, we quantified cost of movements objectively via the metabolic energy that young and old participants consumed during reaching and found that in order reach at a given speed, older adults expended more energy than the young. We next quantified how reward modulated movements in the same populations and found that like the young, older adults responded to increased reward by initiating their movements earlier. Yet, their movements were less sensitive to increased reward, resulting in little or no modulation of reach speed. Lastly, we quantified the effect of increased effort on how reward modulated movements in young adults. Like the effects of aging, when faced with increased effort the young adults responded to reward primarily by reacting faster, with little change in movement speed. Therefore, reaching required greater energetic expenditure in the elderly, suggesting that the slower movements and reactions exhibited in aging are partly driven by an adaptive response to an elevation in the energetic landscape of effort. That is, moving slower appears to be a rational economic consequence of aging.

Significance statement

Healthy aging coincides with a reduction in speed, or vigor, of walking, reaching, and eye movements. Here we focused on disentangling two opposing sources of aging-related movement slowing: reduced reward sensitivity due to loss of dopaminergic tone, or increased energy expenditure movements related to mitochondrial or muscular inefficiencies. Through a series of three experiments and construction of a computational model, here we demonstrate that transient changes in reaction time and movement speed together offer a quantifiable metric to differentiate between reward- and effort-based alterations in movement vigor. Further, we suggest that objective increases in the metabolic cost of moving, not reductions in reward valuation, are driving much of the movement slowing occurring alongside healthy aging.
Mosquitoes escape looming threats by actively flying with the bow-wave induced by the attacker
Authors: Cribellier Antoine , Camilo Leonardo Honfi , Goyal Pulkit , Muijres Florian T.
Published: August 2023

To detect and escape from a looming threat, night-flying insects must rely on other senses than vision alone. Nocturnal mosquitoes have been described to escape looming objects in the dark, but how they achieve this is still unknown. Here, we show how night-active female malaria mosquitoes escape from a rapidly looming object that simulates the defensive action of a blood-host. By combining videography-based automatic tracking with numerical simulations of the attacker-induced airflow, we first show that night-flying mosquitoes use airflow-sensing to detect the danger and trigger their escape. Secondly, by combining these data with mechanistic movement modelling, we unravelled how mosquitoes control their escape manoeuvres: they actively steer away from the danger, and passively travel with the bow-wave produced by the attacker. Our results demonstrate that night-flying mosquitoes escaping from a looming object use the object-induced airflow both to detect the danger, and as fluid medium to move with for avoiding collision. This shows that the escape strategy of flying insects is more complex than previous visually-induces escape flight studies suggest. As mosquitoes are average-sized insects, a combined airflow-induced and visual-induced escape strategy is expected to be common amongst millions of flying insect species. Also, our research helps explain the high escape performance of mosquitoes from counterflow-based odour-baited mosquito traps. It can therefore provide new insights for the development of novel trapping techniques for integrative vector management.
Sedentary behavior may accelerate aging through impact on epigenome and transcriptome: lessons from muscle inactivation inDrosophilalarvae
Authors: Brener Avivit , Lorber Dana , Reuveny Adriana , Toledano Hila , Porat-Kuperstein Lilach , Lebenthal Yael , Weizman Eviatar , Olender Tsviya , Volk Talila
Published: August 2023

Aim

The biological mechanisms linking sedentary lifestyles and metabolic derangements are incompletely understood. Our animal model mimics sedentary behavior during early life, enabling us to explore the associated chromatin epigenetic and transcriptomic landscapes.

Methods

Drosophilalarvae carrying a temperature-sensitive mutation in theshibire1(shi) gene were used.shihomozygous mutant larvae undergo instant arrest of muscle contraction at a restrictive temperature (30°C), without affecting other systems. Bothshiand control (y,w) larvae were held at permissive temperature (18°C), and transferred to restrictive temperature (30°C) for six hours. Larvae were then dissected, fixed, and double-labeled with antibodies specific for epigenetic marks of chromatin activation (H3K9ac) and repression (H3K27me3), and their fluorescence signal was quantified. In addition, whole genome analysis of RNA-Pol II binding to DNA in muscle-specific inactive, or control larvae was performed using muscle-specific targeted DamID (TaDa) protocol.

Results

Inducing muscle inactivity inshilarvae at 300C yielded a significantly higher ratio between chromatin activation and repression, based upon H3K9ac/H3K27me3 signals (p=0.025), relative to all control groups for which this ratio was comparable (p=0.995). Furthermore, muscle inactivation led to altered Pol II binding to 121 out of 2010 genes (6%). The suppressed protein-coding genes included genes associated with longevity, DNA repair, muscle function, and ubiquitin-dependent proteostasis. In addition, a three-fold enrichment of genes coding for lncRNAs was noted in the muscle-inactive larvae.

Conclusion

Inducing muscle inactivation exerted a multi-level impact upon chromatin, triggering an altered epigenetic balance, as well as downregulation of the transcriptional activity of genes essential for muscle function, carbohydrate metabolism, longevity and others. Extrapolating these findings to humans holds promise for establishing a molecular link between sedentary behavior and metabolic diseases.
Integration of Multiple Spatial Omics Modalities Reveals Unique Insights into Molecular Heterogeneity of Prostate Cancer
Authors: Zhang Wanqiu , Spotbeen Xander , Vanuytven Sebastiaan , Kint Sam , Sarretto Tassiani , Socciarelli Fabio , Vandereyken Katy , Dehairs Jonas , Idkowiak Jakub , Wouters David , Alvira Larizgoitia Jose Ignacio , Partel Gabriele , Ly Alice , Laat Vincent de , Q Mantas Maria José , Gevaert Thomas , Devlies Wout , Mah Chui Yan , Butler Lisa M , Loda Massimo , Joniau Steven , Moor Bart De , Sifrim Alejandro , Ellis Shane R. , Voet Thierry , Claesen Marc , Verbeeck Nico , Swinnen Johannes V.
Published: August 2023

Recent advances in spatial omics methods are revolutionising biomedical research by enabling detailed molecular analyses of cells and their interactions in their native state. As most technologies capture only a specific type of molecules, there is an unmet need to enable integration of multiple spatial-omics datasets. This, however, presents several challenges as these analyses typically operate on separate tissue sections at disparate spatial resolutions. Here, we established a spatial multi-omics integration pipeline enabling co-registration and granularity matching, and applied it to integrate spatial transcriptomics, mass spectrometry-based lipidomics, single nucleus RNA-seq and histomorphological information from human prostate cancer patient samples. This approach revealed unique correlations between lipids and gene expression profiles that are linked to distinct cell populations and histopathological disease states and uncovered molecularly different subregions not discernible by morphology alone. By its ability to correlate datasets that span across the biomolecular and spatial scale, the application of this novel spatial multi-omics integration pipeline provides unprecedented insight into the intricate interplay between different classes of molecules in a tissue context. In addition, it has unique hypothesis-generating potential, and holds promise for applications in molecular pathology, biomarker and target discovery and other tissue-based research fields.
Inactivation oflmo0946(sif) induces the SOS response and MGEs mobilization and silences the general stress response and virulence program inListeria monocytogenes
Authors: Ładziak Magdalena , Prochwicz Emilia , Gut Karina , Gomza Patrycja , Jaworska Karolina , Ścibek Katarzyna , Młyńska-Witek Marta , Kadej-Zajączkowska Katarzyna , Lillebaek Eva M.S. , Kallipolitis Birgitte H. , Krawczyk-Balska Agata
Published: August 2023

Bacteria have evolved numerous regulatory pathways to survive in changing environments. The SOS response is an inducible DNA damage repair system that plays an indispensable role in bacterial adaptation and pathogenesis. Here we report a discovery of the previously uncharacterized protein Lmo0946 as an SOS response interfering factor (Sif) in the human pathogenListeria monocytogenes.Functional genetic studies demonstrated thatsifis indespensible for normal growth ofL. monocytogenesin stress-free as well as multi-stress conditions, andsifcontributes to susceptibility to β-lactam antibiotics, biofilm formation and virulence. Absence of Sif promoted the SOS response and elevated expression of mobilome genes accompanied by mobilization of the A118 prophage and ICELm-1 mobile genetic elements (MGEs). These changes were found to be associated with decreased expression of general stress response genes from the σB regulon as well as virulence genes, including the PrfA regulon. Together, this study uncovers an unexpected role of a previously uncharacterized factor, Sif, as an inhibitor of the SOS response inL. monocytogenes.

This study uncovers an unexpected role of a previously uncharacterized factor, Sif, as an inhibitor of the SOS response inL. monocytogenes.
Oral StreptococciS. anginosusandS. mitisinduce distinct morphological, inflammatory, and metabolic signatures in macrophages
Authors: Kumar Sangeetha Senthil , Gunda Venugopal , Reinartz Dakota M. , Pond Kelvin , Raj Paul Victor Santiago , Johnson Michael D. L. , Wilson Justin E.
Published: August 2023

Oral streptococci are the pioneer colonizer and structural architect of the complex oral biofilm. Disruption of this architectural framework causes oral dysbiosis associated with various clinical conditions, including dental caries, gingivitis, and oral cancer. Among the genusStreptococcus,S. anginosusis associated with esophageal, gastric, and pharyngeal cancer tissues, whileS. mitisis correlated with oral cancer. However, no study has investigated mechanistic links between theseStreptococcus speciesand cancer-related inflammatory responses. To explore the underlying involvement ofS. anginosus and S. mitisin inflammation-associated cancer development, we investigated the innate immune response elicited byS. anginosusversusS. mitisusing the RAW264.7 macrophage cell line. Compared to untreated orS. mitisinfected macrophages,S. anginosusinfected macrophages exhibited a robust proinflammatory response characterized by significantly increased levels of inflammatory cytokines and mediators, including TNF, IL-6, IL-1β, NOS2, and COX2, accompanied by enhanced NF-κB activation. Mitostress analysis revealed an increased extracellular acidification rate in macrophages infected withS. anginosuscompared toS. mitis.Further, macrophages infected withS. anginosusfor 6h displayed upregulated aconitate decarboxylase, which catalyzes itaconate production. In contrast, no significant alterations were observed in succinate dehydrogenase that converts succinate to fumarate. At 24h,S. anginosusinduced significant shifts in succinate and itaconate, emphasizing a unique macrophage metabolic profile, and an augmented inflammatory response in response toS. anginosus.This study underscores the capacity ofS. anginosusto elicit a robust proinflammatory response in macrophages and opens new avenues of secretory immune metabolites in response to oral streptococci.

Importance

The surge in head and neck cancer cases among individuals devoid of typical risk factors such as HPV infection, tobacco and alcohol use sparks an argumentative discussion around the emerging role of oral microbiota as a novel risk factor in oral squamous cell carcinoma (OSCC). While substantial research has dissected the gut microbiome’s influence on physiology, the oral microbiome, notably oral streptococci, a gatekeeper of systemic health, has been underappreciated in mucosal immunopathogenesis.S. anginosus,a viridans streptococci group, has been linked to abscess formation and an elevated presence in esophageal cancer and OSCC. The current study aims to probe the innate immune response toS. anginosuscompared to the early colonizerS. mitisas an initial ride towards understanding the impact of distinct oralStreptococcusspecies on the host immune response in the progression of OSCC.
Structural and functional analyses of viral H2 protein of the vaccinia virus entry fusion complex
Authors: Kao Chi-Fei , Liu Chang-Yi , Hsieh Chia-Lin , Carillo Kathleen Joyce D. , Tzou Der-Lii M. , Wang Hao-Ching , Chang Wen
Published: August 2023

Virus-mediated membrane fusion involves conformational changes of the viral fusion protein to fuse the opposing viral and host lipid bilayers. Unlike all other known viruses that contain a single fusion protein, poxviruses harbor a multimeric protein complex of 11 subunits, termed the entry fusion complex (EFC), to mediate fusion with host membranes. Yet, how the poxviral EFC mediates membrane fusion remains enigmatic. To establish the mechanism of EFC-triggered membrane fusion, we are deciphering the structure and function of individual EFC components. Here, we determined the crystal structure of the H2 ectodomain by X-ray diffraction, revealing a folded conformation comprising a central five-stranded β-sheet and three cladding α-helices. We reconstructed the full-length H2 byin silicoprediction, revealing that the N-terminal region (aa 51-90) of H2 protein may fold as a long helix connecting the ectodomain and transmembrane region. Using alanine-mutagenesis screening in a transient complementation system, coimmunoprecipitation, isothermal titration calorimetry and MV-triggered membrane fusion assays, we concluded that the surface of the ectodomain of H2 protein, including two loop regions,170LGYSG174and125RRGTGDAW132, constitutes a broad A28-binding region. Moreover, although not involved in A28 binding, the N-terminal helical region approximal to the transmembrane part, encompassing64RIK66,72W, and83ESDRGR88, is also crucial for viral EFC formation and MV infectivity.
Widespread regulation of the maternal transcriptome by Nanos in Drosophila
Authors: Marhabaie Mohammad , Wharton Tammy H. , Kim Sung Yun , Wharton Robin P.
Published: August 2023

The translational repressor Nanos (Nos) regulates a single target, maternalhunchback(hb)mRNA, to govern abdominal segmentation in the early Drosophila embryo. Nos is recruited specifically to sites in the 3’-UTR ofhbmRNA in collaboration with the sequence-specific RNA-binding protein Pumilio (Pum); on its own, Nos has no binding specificity. Nos is expressed at other stages of development, but very few mRNA targets that might mediate its action at these stages have been described. Nor has it been clear whether Nos is targeted to other mRNAs in concert with Pum or via other mechanisms. In this report, we identify mRNAs targeted by Nos via two approaches. In the first method, we identify mRNAs depleted upon expression of a chimera bearing Nos fused to the nonsense mediated decay (NMD) factor Upf1. We find that, in addition tohb, Upf1-Nos depletes ∼2600 mRNAs from the maternal transcriptome in early embryos. Virtually all of these appear to be targeted in a canonical,hb-like manner in concert with Pum. In a second, more conventional approach, we identify mRNAs that are stabilized during the maternal zygotic transition (MZT) in embryos fromnos-females. Most (86%) of the 1185 mRNAs regulated by Nos are also targeted by Upf1-Nos, validating use of the chimera. Approximately 60% of mRNAs targeted by Upf1-Nos are not stabilized in the absence of Nos. However, Upf1-Nos mRNA targets are hypo-adenylated and inefficiently translated at the ovary-embryo transition, whether or not they suffer Nos-dependent degradation in the embryo. We suggest that the late ovarian burst of Nos represses a large fraction of the maternal transcriptome, priming it for later degradation by other factors during the MZT in the embryo.
An autochthonous model of lung cancer in the Naked Mole-Rat (Heterocephalus glaber)
Authors: Shepard Alyssa , Troutman Scott , Hoxha Sany , Lester Daniel , Khaled Walid , Smith Ewan St. John , Park Thomas , Buffenstein Rochelle , Du Dongliang , Teng Mingxiang , Crish Christine , Tsai Kenneth Y. , Flores Elsa R. , Ventura Andrea , Kissil Joseph L.
Published: August 2023

Studies on cancer resistance in the naked mole-rat (NMR) have generally failed to interrogate possible resistance mechanisms in a physiological context. Here, we provide evidence that the NMR presents as a novel model of tumor initiation. We developed an endogenous lung cancer model in NMRs, driven by an oncogenic Eml4-Alk fusion protein introduced through CRISPR- mediated genome editing. While this is sufficient to drive tumorigenesis in mice, the development of progressive disease in NMRs required the additional loss of key tumor suppressors. Our results show that tumor initiation in NMRs more closely recapitulates that of human tumors. This suggests that the proposed “resistance” of NMRs to cancer development may stem from tumor initiation events that are likely to be comparable to the mechanisms in human cells.

One-Sentence Summary

Tumor development in the cancer-resistant naked mole-rat more accurately represents the tumor initiation process in humans.
Simian Immunodeficiency Virus and Storage Buffer: Field-friendly preservation methods for RNA viral detection in primate feces
Authors: Wilde Tessa H.C. , Shukla Rajni Kant , Madden Christopher , Vodovotz Yael , Sharma Amit , Mcgraw W. Scott , Hale Vanessa L.
Published: August 2023

Wild non-human primates carry many types of RNA viruses, including simian immunodeficiency virus (SIV), simian foamy virus, simian T-cell leukemia virus, and hepatitis C virus. These viruses can also infect humans via zoonotic transmission through handling and consumption of primate bushmeat. Characterizing viral prevalence and shedding in natural hosts is critical to understand infection and transmission risks within and between primate species. Here, we sought to identify a robust “field-friendly” method (i.e., without freezing or refrigeration) for preserving viral RNA, specifically SIV, in primate fecal samples. Fecal samples were collected from a mantled guereza colobus (Colobus guereza) housed at the Columbus Zoo and Aquarium. Samples were homogenized and inoculated with three concentrations (low, medium, high) of inactivated SIV virus and preserved in four different storage buffers (DNA/RNA Shield, RNAlater, 95% Ethanol, and Viral Transport Medium). SIV viral RNA was then extracted from samples at four time points (1 week, 4 weeks, 8 weeks, and 12 weeks) to determine the efficacy of each buffer for preserving SIV RNA. Quantitative RT-PCR was used for detection and quantification of viral RNA. At all concentrations, DNA/RNA Shield yielded the highest average SIV virion concentrations. We then successfully validated this approach using fecal samples from known SIV-positive and SIV-negative sooty mangabeys (Cercocebus atys) housed at Emory National Primate Research Center. Our results indicate that DNA/RNA shield is an optimal “field-friendly” buffer for preserving SIV RNA in fecal samples over time, and may also be effective for preserving other RNA viruses in feces.

Importance

Human immunodeficiency virus (HIV) was introduced into human populations through zoonotic transmission of SIV from African primates, leading to a global epidemic and ongoing worldwide public health issue. SIV occurs naturally in over 40 primate species in sub-Saharan Africa and these viruses have crossed species barriers on multiple occasions, leading to the spread of HIV-1 and HIV-2. Quantifying RNA viruses in wild primate populations can be challenging as invasive sampling is often not feasible, and many field stations lack ready access to a freezer for storing biological samples. This study compares SIV RNA preservation and recovery across multiple storage buffers to identify a robust field-friendly option for RNA viral detection in noninvasively collected feces. Our results will inform future fieldwork and facilitate improved approaches to characterizing prevalence, shedding, and transmission of RNA viruses like SIV in natural hosts including wild-living nonhuman primates.
OpgH is an essential regulator ofCaulobactermorphology
Authors: Daitch Allison K. , Goley Erin D.
Published: August 2023

Bacterial growth and division rely on intricate regulation of morphogenetic complexes to remodel the cell envelope without compromising envelope integrity. Significant progress has been made in recent years towards understanding the regulation of cell wall metabolic enzymes. However, other cell envelope components play a role in morphogenesis as well. Components required to maintain osmotic homeostasis are among these understudied envelope-associated enzymes that may contribute to cell morphology. A primary factor required to protect envelope integrity in low osmolarity environments is OpgH, the synthase of osmoregulated periplasmic glucans (OPGs). Here, we demonstrate that OpgH is essential in the ⍺-proteobacteriumCaulobacter crescentus. Unexpectedly, depletion of OpgH results in striking asymmetric bulging and cell lysis, accompanied by misregulation of cell wall insertion and mislocalization of morphogenetic complexes. The enzymatic activity of OpgH is required for normal cell morphology as production of an OpgH mutant that disrupts a conserved glycosyltransferase motif phenocopies the depletion. Our data establish a surprising function for an OpgH homolog in morphogenesis and reveal an essential role of OpgH in maintaining proper cell morphology during normal growth and division inCaulobacter.

Significance

Bacteria must synthesize and fortify the cell envelope in a tightly regulated manner to orchestrate growth and adaptation. Osmoregulated periplasmic glucans (OPGs) are important, but poorly understood, constituents of Gram-negative cell envelopes that contribute to envelope integrity and protect against osmotic stress. Here, we determined that the OPG synthase OpgH plays a surprising, essential role in morphogenesis inCaulobacter crescentus. Loss of OpgH causes asymmetric cell bulging and lysis via misregulation of the localization and activity of morphogenetic complexes. Because cell envelope integrity is critical for bacterial survival, understanding how OpgH activity contributes to morphogenesis could aid in the development of antibiotic therapies.
UPP affects chloroplast development by interfering with chloroplast proteostasis
Authors: Scherer Vanessa , Bellin Leo , Schwenkert Serena , Lehmann Martin , Rinne Jannis , Witte Claus-Peter , Jahnke Kathrin , Richter Andreas , Pruss Tobias , Lau Anne , Leister Dario , Möhlmann Torsten
Published: August 2023

Arabidopsis uracil phosphoribosyltransferase (UPP) has been identified as an essential protein with a previously unknown moonlighting activity. By analysis of UPP amiRNA mutants, we first confirmed a vital function of UPP in chloroplast development and growth which seems unrelated to nucleotide homeostasis since nucleotide levels were not altered in the mutants. Impaired photosynthesis and reductions in carbohydrate contents in these mutants resulted in an inability to induce flavonoid biosynthesis after high light (HL) treatment. Additionally, levels of raffinose, proline and fumarate, acting as osmoprotectants and carbon-stores were reduced as well. Proteomic analysis suggests a role of UPP in chloroplast proteostasis, particularly under HL, and this was confirmed by immunoblots. PetC, the iron-sulfur protein of the Cytb6f complex, was identified as putative UPP target that is massively reduced in UPP knock-down and knock-out plants, resulting in blocked photosynthetic electron transport, seen by increased unregulated energy dissipation and subsequent damage to the D1 protein of PSII. Proteases, including thylakoid-bound FtsHs, were up-regulated together with components of the chloroplast protein import machinery. We hypothesize that the UPP assists in the targeting of PetC and further interacting proteins to the thylakoid and when this mechanism is impaired in corresponding mutants chloroplast proteases are upregulated as a countermeasure.
Chemogenetic inhibition of IST1-CHMP1B interaction impairs endosomal recycling and promotes unconventional LC3 lipidation at stalled endosomes
Authors: Knyazeva Anastasia , Li Shuang , Corkery Dale P. , Shankar Kasturika , Herzog Laura K. , Zhang Xuepei , Singh Birendra , Niggemeyer Georg , Grill David , Gilthorpe Jonathan D. , Gaetani Massimiliano , Carlson Lars-Anders , Waldmann Herbert , Wu Yao-Wen
Published: August 2023

The Endosomal Sorting Complex Required for Transport (ESCRT) machinery constitutes a multisubunit protein complex that plays an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, encompassing cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair and autophagy. Given the versatile functionality of ESCRTs and the intricate organizational structure of the ESCRT complex, the targeted modulation of distinct ESCRT-mediated membrane deformations for functional dissection poses a considerable challenge. This study presents a pseudo-natural product targeting IST1-CHMP1B within the ESCRT-III complex. This compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting and exosome biogenesis, it rapidly hinders transferrin receptor (TfR) recycling in cells, resulting in the accumulation of transferrin in perinuclear endosomal recycling tubules. Stalled recycling endosomes acquire unconventional LC3 lipidation, establishing a link between non-canonical LC3 lipidation and endosomal recycling.
The protective function of an immunity protein against thecis-toxic effects of aXanthomonasType IV Secretion System Effector
Authors: Oka Gabriel U. , Souza Diorge P. , Sgro Germán G. , Guzzo Cristiane R. , Dunger German , Farah Chuck S.
Published: August 2023

Many bacterial species use specialized secretion systems to translocate proteinaceous toxic effectors into target bacterial cells. In most cases, effectors are encoded in bicistronic operons with their cognate immunity proteins. The current model is that immunity proteins could, in principle, provide protection in two different ways: i) by avoiding self-intoxication (suicide orcis-intoxication) or ii) by inhibiting intoxication due to “friendly-fire” translocation from neighboring sister cells (fratricide ortrans-intoxication). Here, we set out to distinguish between these two protection mechanisms in the case of the bactericidalXanthomonas citriType IV Secretion System (X-T4SS), where killing is due to the action of a cocktail of secreted effectors (X-Tfes) that are inhibited by their cognate immunity proteins (X-Tfis). We use a set ofX. citrimutants lacking multiple X-Tfe/X-Tfi pairs to show that X-Tfis are not absolutely required to protect againsttrans-intoxication. Our investigation then focused on thein vivofunction of the lysozyme-like effector X-TfeXAC2609and its cognate immunity protein X-TfiXAC2610. We observe the accumulation of damage in theX. citricell envelope and inhibition of biofilm formation due to the action of X-TfeXAC2609in the absence of X-TfiXAC2610. We show that X-TfeXAC2609toxicity is independent of an active X-T4SS and that X-TfiXAC2610protects the cell colony against X-TfeXAC2609-inducedcis-intoxication via autolysis.In vitroassays employing X-TfiXAC2610mutants were used to test and validate an AlphaFold2-derived model of the X-TfeXAC2609-X-TfiXAC2610complex which presents topological similarities with the distantly related Tse1/Tsi1 complex fromP. aeruginosaand the the i-type lysozyme fromMeretrix lusoria(MI-iLys) in complex with PliI-Ah fromAeromonas hydrophila. While immunity proteins in other systems have been shown to protect against attacks by sister cells (trans-intoxication), this is the first description of an antibacterial secretion system in which the immunity proteins are dedicated to protecting cells againstcis-intoxication.
Microbe transmission from pet shop to lab-reared zebrafish reveals a pathogenic birnavirus
Authors: Rice Marlen C. , Elde Nels C. , Gagnon James A. , Balla Keir M.
Published: August 2023

Zebrafish are popular research organisms selected for laboratory use due in part to widespread availability from the pet trade. Many contemporary colonies of laboratory zebrafish are maintained in aquaculture facilities that monitor and aim to curb infections that can negatively affect colony health and confound experiments. The impact of laboratory control on the microbial constituents associated with zebrafish in research environments compared to the pet trade are unclear. Diseases of unknown causes are common in both environments. We conducted a metagenomic survey to broadly compare the zebrafish-associated microbes in pet trade and laboratory environments. We detected many microbes in animals from the pet trade that were not found in laboratory animals. Co-housing experiments revealed several transmissible microbes including a newly described non-enveloped, double-stranded RNA virus in the Birnaviridae family we name Rocky Mountain birnavirus (RMBV). Infections were detected in asymptomatic animals from the pet trade, but when transmitted to laboratory animals RMBV was associated with pronounced antiviral responses and hemorrhagic disease. These experiments highlight the pet trade as a distinct source of diverse microbes that associate with zebrafish and establish a paradigm for the discovery of newly described pathogenic viruses and other infectious microbes that can be developed for study in the laboratory.
Spatial patterning regulates neuron numbers in theDrosophilavisual system
Authors: Malin Jennifer A. , Chen Yen-Chung , Simon Félix , Keefer Evelyn , Desplan Claude
Published: August 2023

Neurons must be made in the correct proportions to communicate with the appropriate synaptic partners and form functional circuits. In theDrosophilavisual system, multiple subtypes of Distal medulla (Dm) inhibitory interneurons are made in distinct, reproducible numbers—from 5 to 800 per optic lobe. These neurons are born from a crescent-shaped neuroepithelium called the Outer Proliferation Center (OPC), which can be subdivided into specific domains based on transcription factor expression. We fate mapped Dm neurons and found that more abundant neural types are born from larger neuroepithelial subdomains, while less abundant subtypes are born from smaller ones. Additionally, morphogenetic Dpp/BMP signaling provides a second layer of patterning that subdivides the neuroepithelium into smaller domains to provide more granular control of cell proportions. Apoptosis appears to play a minor role in regulating Dm neuron abundance. This work describes an underappreciated mechanism for the regulation of neuronal stoichiometry.
Application of fluorescence lifetimes to multi-imaging analysis in plant cells
Authors: Aoyama Tsuyoshi , Sugimoto Nagisa , Sato Yoshikatsu
Published: August 2023

Multi-imaging analysis has become an indispensable technique to visualize multiple target proteins and intracellular components simultaneously. While current multi-imaging analysis relies on the differences in emission spectra of fluorescent molecules, the use of fluorescence lifetime imaging microscopy (FLIM), which exploits the differences in fluorescence lifetimes of fluorescent proteins, in multi-imaging analysis is quite limited. In this study, we successfully discriminated fluorescent proteins with similar colors but different fluorescence lifetimesin vitroandin planta. We found that four fluorescent proteins with similar emission spectra could be distinguished by FLIM. In addition, we found that FLIM could clearly separate fluorescent proteins if they differ by at least 0.2 ns. In a proof-of-concept experiments for plant live imaging, we transiently expressed fluorescent proteins with different subcellular localization tags inPhyscomitrium patensby particle bombardment. Each fluorescent protein exhibited its fluorescence lifetime at the subcellular localization corresponding to the localization tag inP. patenswith little or no effect of chlorophyll autofluorescence. Our results demonstrate the effectiveness of FLIM in revealing the spatiotemporal dynamics of a large number of fluorescent proteins in living plant cells.
Supply chain finance, firm performance and industry competition: empirical evidence from Pakistan
Authors: Sajid Memoona , Safdar Raheel
Published: August 2023

Purpose

This study empirically tests the relationship between supply chain finance (SCF) and firm performance. Moreover, this study also investigates the potential role of industry competition in the proposed relationship between SCF and firm performance.

Design/methodology/approach

A conceptual framework is developed and tested using secondary data collected from 122 non-financial listed firms on the Pakistan Stock Exchange (PSX) for the period of ten years (2012–2021). Ordinary least squares (OLS) regression analysis is performed in STATA to validate the proposed relationships.

Findings

The results highlight that SCF has a positive impact on firm performance. Moreover, industry competition positively moderates the relationship between SCF and firm performance.

Practical implications

This study would help firms in assessing the value of operational financing to their financially constrained suppliers/customers by adopting supply chain finance practices. Furthermore, this study will help understand the role of the competitive environment in supply chain finance decision-making.

Originality/value

The findings will help core firms better understand how implementing SCF benefits firm performance under high product competition, especially in emerging markets.