bluuebunny/crossref_metadata_2025 huggingface dataset:
Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice
Authors: Rashidieh Behnam , Bain Amanda Louise , Tria Simon Manuel , Sharma Sowmya , Stewart Cameron Allan , Simmons Jacinta Ley , Apaja Pirjo M. , Duijf Pascal H.G. , Finnie John , Khanna Kum Kum
Published: July 2022

αB-Crystallin is a heat shock chaperone protein which binds to misfolded proteins to prevent their aggregation. It is overexpressed in a wide-variety of cancers. Previous studies using human cancer cell lines and human xenograft models have reported tumor suppressor or tumor promoter (oncogene) roles for αB-Crystallin depending on cellular context and environmental conditions. To determine the causal relationship between CRYAB overexpression and cancer, we generated a Cryab overexpression knock-in mouse model. This model revealed that constitutive overexpression of Cryab results in the formation of a variety of lethal spontaneous primary and metastatic tumors in mice. In vivo, the overexpression of Cryab correlated with the upregulation of epithelial-to-mesenchymal (EMT) markers, angiogenesis and some oncogenic proteins including Basigin. In vitro, using E1A/Ras transformed mouse embryonic fibroblasts (MEFs), we observed that the overexpression of Cryab led to the promotion of cell survival via upregulation of Akt signaling and downregulation of pro-apoptotic pathway mediator JNK, with subsequent attenuation of apoptosis as assessed by cleaved caspase-3. Overall, through the generation and characterization of Cryab overexpression model, we provide evidence supporting the role of αB-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis.
Challenges and considerations for reproducibility of STARR-seq assays
Authors: Das Maitreya , Hossain Ayaan , Banerjee Deepro , Praul Craig Alan , Girirajan Santhosh
Published: July 2022

High-throughput methods such as RNA-seq, ChIP-seq and ATAC-seq have well-established guidelines, commercial kits, and analysis pipelines that enable consistency and wider adoption for understanding genome function and regulation. STARR-seq, a popular assay for directly quantifying activity of thousands of enhancer sequences simultaneously, has seen limited standardization across studies. The assay is long with >250 steps, and frequent customization of the protocol and variations in bioinformatics methods raise concerns for reproducibility of STARR-seq studies. Here, we assess each step of the protocol and analysis pipelines from published sources and in-house assays, and identify critical steps and QC checkpoints necessary for reproducibility of the assay. We also provide guidelines for experimental design, protocol scaling, customization, and analysis pipelines for better adoption of the assay. These resources will allow better optimization of STARR-seq for specific research needs, enable comparisons and integration across studies, and improve reproducibility of results.
Impairments in the mechanical effectiveness of reactive balance control strategies during walking in people post-stroke
Authors: Liu Chang , McNitt-Gray Jill L. , Finley James
Published: August 2022

People post-stroke have an increased risk of falls compared to neurotypical individuals, partly resulting from an inability to generate appropriate reactions to restore balance. However, few studies investigated the effect of paretic deficits on the mechanics of reactive control strategies following forward losses of balance during walking. Here, we characterized the biomechanical consequences of reactive control strategies following perturbations induced by the treadmill belt accelerations. Thirty-eight post-stroke participants and thirteen age-matched and speed-matched neurotypical participants walked on a dual-belt treadmill while receiving perturbations that induced a forward loss of balance. We computed whole-body angular momentum and angular impulse using segment kinematics and reaction forces to quantify the effect of impulse generation by both the leading and trailing limbs in response to perturbations in the sagittal plane. We found that perturbations to the paretic limb led to larger increases in forward angular momentum during the perturbation step than perturbations to the non-paretic limb or to neurotypical individuals. To recover from the forward loss of balance, neurotypical individuals coordinated reaction forces generated by both legs to decrease the forward angular impulse relative to the pre-perturbation step. They first decreased the forward pitch angular impulse during the perturbation step. Then, during the first recovery step, they increased the backward angular impulse by the leading limb and decreased the forward angular impulse by the trailing limb. In contrast to neurotypical participants, people post-stroke did not reduce the forward angular impulse generated by the stance limb during the perturbed step. They also did not increase leading limb angular impulse or decrease the forward trailing limb angular impulse using their paretic limb during the first recovery step. Lastly, post-stroke individuals who scored poorer on clinical assessments of balance and had greater motor impairment made less use of the paretic limb to reduce forward momentum. Overall, these results suggest that paretic deficits limit the ability to recover from forward loss of balance. Future perturbation-based balance training targeting reactive stepping response in stroke populations may benefit from improving the ability to modulate paretic ground reaction forces to better control whole-body dynamics.
Room-temperature serial synchrotron crystallography of apo PTP1B
Authors: Sharma Shivani , Ebrahim Ali , Keedy Daniel A.
Published: July 2022

Room-temperature X-ray crystallography provides unique insights into protein conformational heterogeneity, but a common hurdle is obtaining sufficiently large protein crystals. Serial synchrotron crystallography (SSX) helps address this hurdle by allowing the use of many medium- to small-sized crystals. We have used a recently introduced serial sample support chip system to obtain the first SSX structure of a human phosphatase, specifically Protein Tyrosine Phosphatase 1B (PTP1B) in the unliganded (apo) state. In previous apo room-temperature structures, the active site and allosteric sites adopted alternate conformations, including open and closed conformations for the active-site WPD loop and for a distal allosteric site. By contrast, in our SSX structure, the active site is best fit with a single conformation, but the distal allosteric site is best fit with alternate conformations. This observation argues for additional nuance in interpreting the nature of allosteric coupling in this protein. Overall, our results illustrate the promise of serial methods for room-temperature crystallography, as well as future avant-garde crystallography experiments, for PTP1B and other proteins.
Defining the optimal intranasal administration strategy for inactivated poliovirus vaccine
Authors: Kraan Heleen , Willems Geert-Jan , Soema Peter C.
Published: July 2022

Mucosal immunity plays a pivotal role in protection against infection and the transmission of pathogens from person to person. Ideally, novel vaccines should be easy and safe to administer, provide mucosal immunity, be safe to manufacture, and be affordable for low-income countries. Alternative delivery strategies, such as the intranasal route, may fulfill at least some of these preferred vaccine characteristics. Moreover, vaccination via mucosal routes has the potential to evoke strong mucosal immunity at the entry site.

In the current study, the potential of the intranasal route was investigated for an inactivated polio vaccine based on Sabin strains (sIPV). Different vaccination regimes for intranasal administration of sIPV were evaluated by measuring both systemic and mucosal immune responses in mice. Heterologous prime-boost schedules using a combination of parenteral and mucosal administration showed to elicit virus neutralizing antibody titers in serum and polio-specific IgA titers at different mucosal sites in mice that were vaccinated with sIPV. Moreover, the inclusion of an adjuvant was able to further enhance immune responses. Intranasal administration of adjuvanted sIPV combined with a regular intramuscular sIPV vaccination can significantly improve mucosal immune responses while maintaining systemic immune responses, which can lead to better protection against polio infection and possibly prevent virus transmission. An intranasally delivered inactivated polio vaccine might be of value for use in routine vaccination or outbreak control, and therefore, a helpful tool towards polio-eradication.
Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells
Authors: Donnelly Hannah , Ross Ewan , Xiao Yinbo , Hermantara Rio , Taqi Aqeel , Sebastian Doherty-Boyd W. , Cassels Jennifer , Tsimbouri Penelope. M. , Dunn Karen M , Hay Jodie , Cheng Annie , Jain Nikhil , West Christopher , Wheadon Helen , Michie Alison M , Peault Bruno , West Adam G. , Salmeron-Sanchez Manuel , Dalby Matthew J.
Published: July 2022

Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via allogeneic stem cell transplantation (alloSCT), to engraft and repopulate the blood system. The very low abundance of LT-HSCs and their rapid differentiation duringin vitroculture hinders their clinical utility. Previous developments using stromal feeder layers, defined media cocktails, and bioengineering have enabled HSC expansion in culture, but of mostly short-term HSCs (ST-HSC) and progenitor populations at the expense of naïve LT-HSCs. Here, we report the creation of a bioengineered LT-HSC maintenance niche that recreates physiological extracellular matrix organisation, using soft collagen type-I hydrogels to drive nestin expression in perivascular stromal cells (PerSCs or pericytes). We demonstrate that nestin, which is expressed by HSC-supportive bone marrow stromal cells, is cytoprotective and, via regulation of metabolism, is important for HIF-1α expression in PerSCs. When CD34+veHSCs were added to the bioengineered niches comprising nestin/HIF-1α expressing PerSCs, LT-HSC numbers were maintained with normal clonal andin vivoreconstitution potential, without media supplementation. We provide proof-of-concept that our bioengineered niches can support the survival of CRISPR edited HSCs. Successful editing of LT-HSCs ex vivo can have potential impact on the treatment of blood disorders.
Hitchhiking of bactericidal/permeability-increasing protein-like gene with the fibromelanosis locus in Kadaknath black-bone-chicken
Authors: Shinde Sagar Sharad , Sharma Ashutosh , Vijay Nagarjun
Published: August 2022

Black-bone-chicken (BBC) meat is popular for its distinctive taste and texture. A complex chromosomal rearrangement at the fibromelanosis (Fm) locus on the 20th chromosome results in increased expression of the endothelin-3 (EDN3) gene and is responsible for melanin hyperpigmentation in BBC. We use public long-read sequencing data of the silkie breed to resolve high-confidence haplotypes at theFmlocus spanning both Dup1 and Dup2 regions and establish that theFm_2scenario is correct of the three possible scenarios of the complex chromosomal rearrangement. The relationship between Chinese and Korean BBC breeds with Kadaknath native to India is underexplored. Our data from whole-genome re-sequencing establishes that all BBC breeds, including Kadaknath, share the complex chromosomal rearrangement junctions at the fibromelanosis (Fm) locus. We also identify twoFmlocus proximal regions (∼70Kb and ∼300 Kb) with signatures of selection unique to Kadaknath. These regions harbor several genes with protein-coding changes, with the Bactericidal/permeability-increasing-protein-like (BPIL) gene having two Kadaknath-specific changes within protein domains. Our results indicate that protein-coding changes in theBPILgene hitchhiked with theFmlocus in Kadaknath due to close physical linkage. Identifying thisFmlocus proximal selective sweep sheds light on the genetic distinctiveness of Kadaknath compared to other BBC.
The Effects of Depression on The Neural Correlates of Reward Sensitivity in Poverty
Authors: Perera-W.A. Hiran , Khairuddin Rozainee , Salehuddin Khazriyati
Published: August 2022

Existing studies have identified that depression and depressive symptoms are associated with reduced sensitivity to feedback processing, which is a core ability that determines the success of human actions. However, a key individual difference which is the socioeconomic status (SES) has been largely ignored in this field because the recent trend of research has suggested how it relates to various cognitive domain-specific neural systems. Because depression is a widespread mental health condition that is more prevalent among the poor, it can potentially play a role in the association between poverty and feedback processing. With a sample of 80 adults recruited from low to high-income communities, the current study examined the role of depression on the relationship between poverty and feedback processing by using feedback negativity (FN) event-related potential (ERP), which is a well-known ERP component that is indexed by response feedback indicating losses versus gains. Consistent with previous studies, high depressive symptoms were associated with reduced FN amplitude across our sample. SES was negatively associated with FN and depressive symptoms, which indicates reduced reward sensitivity to feedback among the low-SES individuals who are also mostly depressed. However, no association between SES and reward sensitivity was observed when it was controlled for depression. Findings in this study suggest the importance of partial out the variance accounted for by depression when studying responses to reward sensitivity in poverty.
The 3D Structural Architecture of the Human Hand Area is Non-Topographic
Authors: Doehler Juliane , Northall Alicia , Liu Peng , Fracasso Alessio , Chrysidou Anastasia , Speck Oliver , Lohmann Gabriele , Wolbers Thomas , Kuehn Esther
Published: August 2022

The functional topography of the human primary somatosensory cortex (S1) hand area is a widely studied model system to understand sensory organization and plasticity. It is so far unclear whether or not the underlying 3D structural architecture also shows a topographic organization. We used 7T MRI data to quantify layer-specific myelin, iron and mineralization in relation to population receptive field maps of individual finger representations in Brodman area 3b (BA 3b) of human S1 in female and male younger adults. This 3D description allowed us to identify a characteristic profile of layer-specific myelin and iron deposition in the BA 3b hand area, but revealed an absence of structural differences, an absence of low-myelin borders, and high similarity of 3D microstructure profiles between individual fingers. However, structural differences and borders were detected between the hand and face areas. We conclude that the 3D structural architecture of the human hand area is non-topographic, unlike in some monkey species, which suggests a high degree of flexibility for functional finger organization and a new perspective on human topographic plasticity.

Significance Statement

Using ultra-high field MRI, we provide the first comprehensivein vivodescription of the 3D structural architecture of the human BA 3b hand area in relation to functional population receptive field (pRF) maps. High similarity of precise finger-specific 3D profiles, together with an absence of structural differences and an absence of low-myelin borders between individual fingers, reveal the 3D structural architecture of the human hand area to be non-topographic. This suggests reduced structural limitations to cortical plasticity and reorganization, and allows for shared representational features across fingers.
Genome-wide epistasis analysis in Parkinson’s disease between populations with different genetic ancestry reveals significant variant-variant interactions
Authors: Cisterna-Garcia Alejandro , Bustos Bernabe I. , Bandres-Ciga Sara , Leal Thiago P. , Sarihan Elif I. , Jok Christie , Blauwendraat Cornelis , Nalls Mike A. , Krainc Dimitri , Singleton Andrew B. ,   International Parkinson’s Disease Genomics Consortium (IPDGC), Mata Ignacio F. , Lubbe Steven J. , Botia Juan A.
Published: August 2022

Genome-wide association studies (GWAS) have increased our understanding of Parkinson’s disease (PD) genetics through the identification of common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained by epistasis. Here, we developed a genome-wide non-exhaustive epistasis screening pipeline calledVariant-variant interaction through variable thresholds(VARI3) and applied it to diverse PD GWAS cohorts. First, as a discovery cohort, we used 14 cohorts of European ancestry (14,671 cases and 17,667 controls) to identify candidate variant-variant interactions. Next, we replicated significant results in a cohort with a predominately Latino genetic ancestry (807 cases and 690 controls). We identified 14 significant epistatic signals in the discovery stage, with genes showing enrichment in PD-relevant ontologies and pathways. Next, we successfully replicated two of the 14 interactions, where the signals were located nearbySNCAand withinMAPTandWNT3. Finally, we determined that the epistatic effect on PD of those variants was similar between populations. In brief, we identified several epistatic signals associated with PD and replicated associations despite differences in the genetic ancestry between cohorts. We also observed their biological relevance and effect on the phenotype usingin silicoanalysis.
Enhanced viral infectivity and reduced interferon production are associated with high pathogenicity for influenza viruses
Authors: Li Ke , McCaw James M. , Cao Pengxing
Published: July 2022

Epidemiological and clinical evidence indicates that humans infected with the 1918 pandemic influenza virus and highly pathogenic avian H5N1 influenza viruses often displayed severe lung pathology. High viral load and extensive infiltration of macrophages are the hallmarks of highly pathogenic (HP) influenza viral infections. However, it remains unclear what biological mechanisms primarily determine the observed difference in the kinetics of viral load and macrophages between HP and low pathogenic (LP) viral infections, and how the mechanistic differences are associated with viral pathogenicity. In this study, we develop a mathematical model of viral dynamics that includes the dynamics of different macrophage populations and interferon. We fit the model to in vivo kinetic data of viral load and macrophage level from BALB/c mice infected with an HP or LP strain of H1N1/H5N1 virus using Bayesian inference. Our primary finding is that HP viruses has a higher viral infection rate, a lower interferon production rate and a lower macrophage recruitment rate compared to LP viruses, which are strongly associated with more severe tissue damage (quantified by a higher percentage of epithelial cell loss). We also quantify the relative contribution of macrophages to viral clearance and find that macrophages do not play a dominant role in direct clearance of free virus although their role in mediating immune responses such as interferon production is crucial. Our work provides new insight into the mechanisms that convey the observed difference in viral and macrophage kinetics between HP and LP infections and establishes an improved model fitting framework to enhance the analysis of new data on viral pathogenicity.

Author Summary

Infections with highly pathogenic (HP) influenza virus (e.g., the 1918 pandemic virus) often lead to serious morbidity and mortality. HP influenza virus infection is characterised by rapid viral growth rate, high viral load and excessive infiltration of macrophages to the lungs. Despite extensive study, we do not yet fully understand what biological processes leading to the observed viral and macrophage dynamics and therefore viral pathogenicity. Experimental studies have previously suggested that bot viral factors (e.g., viral proteins) and host factors (e.g., the host immune response) play a role to enhance viral pathogenicity. Here, we utilise in vivo kinetic data of viral load and macrophages and fit a viral dynamic model the data. Our model allow us to explore the biological mechanisms that contribute to the difference viral and macrophage dynamics between HP and LP infections. This study improves our understanding of the role of interferon on distinguishing immunodynamics between HP and LP infections. Our findings may contribute to the development of next-generation treatment which rely upon an understanding of the host different immunological response to HP influenza viruses.
Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis
Authors: Jia Minxue , Rosas Lorena , Kapetanaki Maria G. , Tabib Tracy , Sebrat John , Cruz Tamara , Bondonese Anna , Mora Ana L. , Lafyatis Robert , Rojas Mauricio , Benos Panayiotis .V.
Published: August 2022

Background

Idiopathic Pulmonary Fibrosis (IPF) is an age-associated progressive lung disease with accumulation of scar tissue impairing gas exchange. Previous high-throughput studies elucidated the role of cellular heterogeneity and molecular pathways in advanced disease. However, critical pathogenic pathways occurring in the transition of fibroblasts from normal to profibrotic have been largely overlooked.

Methods

We used single cell transcriptomics (scRNA-seq) from lungs of healthy controls and IPF patients (lower and upper lobes). We identified fibroblast subclusters, genes and pathways associated to early disease. Immunofluorescence assays validated the role of MOXD1 early in fibrosis.

Findings

We identified four distinct fibroblast subgroups, including one marking the normal-to-profibrotic state transition. Our results show for the first time that global downregulation of ribosomal proteins and significant upregulation of the majority of copper-binding proteins, including MOXD1, mark the IPF transition. We find no significant differences in gene expression in IPF upper and lower lobe samples, which were selected to have low and high degree of fibrosis, respectively.

Interpretation

Early events during IPF onset in fibroblasts include dysregulation of ribosomal and copper-binding proteins. Fibroblasts in early stage IPF have already acquired a profibrotic phenotype while hallmarks of advanced disease, including fibroblast foci and honeycomb formation, are still not evident. The new transitional fibroblasts we discover could prove very important for studying the role of fibroblast plasticity in disease progression and help develop early diagnosis tools and therapeutic interventions targeting earlier disease states.
New genetic tools enable dissection of a global stress response in the early-branching speciesFusobacterium nucleatum
Authors: Ponath Falk , Zhu Yan , Cosi Valentina , Vogel Jörg
Published: July 2022

Fusobacterium nucleatum, long known as a common oral microbe, has recently garnered attention for its ability to colonize tissues and tumors elsewhere in the human body. Clinical and epidemiological research has now firmly establishedF. nucleatumas an oncomicrobe associated with several major cancer types. However, with the current research focus on host associations, little is known about gene regulation inF. nucleatumitself, including global stress response pathways that typically ensure the survival of bacteria outside their primary niche. This is due to the phylogenetic distance of Fusobacteriota to most model bacteria, their limited genetic tractability, and paucity of known gene functions. Here, we characterize a global transcriptional stress response network governed by the extracytoplasmic function sigma factor, σE. To this aim, we developed several new genetic tools for this anaerobic bacterium, including four different fluorescent marker proteins, inducible gene expression, scarless gene deletion, and transcriptional and translational reporter systems. Using these tools, we identified a σEresponse partly reminiscent of phylogenetically distant Proteobacteria but induced by exposure to oxygen. AlthoughF. nucleatumlacks canonical RNA chaperones such as Hfq, we uncovered conservation of the non-coding arm of the σEresponse in form of the non-coding RNA FoxI. This regulatory small RNA (sRNA) acts as an mRNA repressor of several membrane proteins, thereby supporting the function of σE. In addition to the characterization of a global stress response inF. nucleatum, the genetic tools developed here will enable further discoveries and dissection of regulatory networks in this early-branching bacterium.

SIGNIFICANCE STATEMENT

Fusobacterium nucleatumis an abundant member of the oral microbiome that can spread throughout the body and colonize secondary sites, including cancer tissues where it promotes tumor progression. Understanding howF. nucleatumis able to adapt to this new environment might open new therapeutic opportunities, but we currently lack basic molecular knowledge of gene regulation in this phylogenetically distinct bacterium. We developed much-needed genetic tools for use inF. nucleatumand with their aid uncovered a stress response mediated by the transcriptional activator σEand an associated small RNA. Our findings in an early-branching bacterium reveal surprising parallels to and differences from the σEresponse in well-characterized model bacteria and provide a framework that will accelerate research into the understudied phylum Fusobacteriota.
TraC of the conjugative plasmid pKM101 is secreted as a monomer in outer membrane vesicles and stimulates conjugation
Authors: Amro Jaafar , Baron Christian
Published: July 2022

Gram-negative bacteria use membrane-bound type IV secretion systems to assemble pili on the cell surface, followed by cell-cell contact with recipient cells and transfer of plasmid DNA. The process at the cell-cell contact stage of conjugative DNA transfer is not well understood. We here present a biochemical and genetic characterization of the TraC protein that is a minor component of the pili determined by the IncN plasmid pKM101 from Escherichia coli. The cellular and secreted forms of TraC are monomers, TraC preferentially localizes at the cell poles and it is also detected in extracellular membrane vesicles. Purified TraC does not impact the infection with bacteriophages, but we detect binding of TraC to recipient cells and partial complementation of a traC deletion strain by the addition of purified TraC. These results suggest that the protein contributes to conjugation at the cell-cell contact stage.
Crowding-induced phase separation and solidification by co-condensation of PEG in NPM1-rRNA condensates
Authors: André Alain A.M. , Yewdall N. Amy , Spruijt Evan
Published: July 2022

The crowdedness of the cell calls for adequate intracellular organization. Biomolecular condensates, formed by liquid-liquid phase separation of intrinsically disordered proteins and nucleic acids, are important organizers of cellular fluids. To underpin the molecular mechanisms of protein condensation, cell-free studies are often used where the role of crowding is not investigated in detail. Here, we investigate the effects of macromolecular crowding on the formation and material properties of a model heterotypic biomolecular condensate, consisting of nucleophosmin (NPM1) and ribosomal RNA (rRNA). We studied the effect of the macromolecular crowding agent PEG, which is often considered an inert crowding agent. We observed that PEG could induce both homotypic and heterotypic phase separation of NPM1 and NPM1-rRNA, respectively. Crowding increases the condensed concentration of NPM1 and decreases its equilibrium dilute phase concentration, while no significant change in the concentration of rRNA in the dilute phase was observed. Interestingly, the crowder itself is concentrated in the condensates, suggesting that co-condensation rather than excluded volume interactions underlie the enhanced phase separation by PEG. Fluorescence recovery after photobleaching (FRAP) measurements indicated that both NPM1 and rRNA become immobile at high PEG concentrations, indicative of a liquid-to-gel transition. Together, these results shed new light onto the role of synthetic crowding agents in phase separation, and demonstrate that condensate properties determined in vitro depend strongly on the addition of crowding agents.

STATEMENT OF SIGNIFICANCE

Liquid-liquid phase separation of proteins and nucleic acids leads to the formation of biomolecular condensates. To mimic biomolecular condensates in vitro, polymeric crowding agents, such as PEG, are often added. Such crowding agents are considered to make in vitro solutions more physiologically relevant, by mimicking the high cellular macromolecule concentrations. However, these crowding agents are commonly selected for their commercial availability and solubility in water, and their influence on phase separation and the physicochemical properties of condensates are seldom studied. Here we use biophysical methods to show that PEG induces phase separation of a model condensate through co-condensation rather than volume exclusion. As a consequence, crowding changes the partitioning, concentrations and viscoelastic properties of the condensates significantly, which sheds new light onto studies aimed at quantifying the material properties of biomolecular condensates.
ID1 functions as an autonomous phosphate (Pi) regulator upstream of the miR399-ZmPHO2 signaling module in maize
Authors: Wang Xufeng , Yuan Dan , Liu Yanchun , Liang Yameng , He Juan , Yang Xiaoyu , Hang Runlai , Jia Hong , Mo Beixin , Tian Feng , Chen Xuemei , Liu Lin
Published: July 2022

The macronutrient phosphorus is essential for plant growth and development. Plants have evolved multiple strategies to increase the efficiency of Pi acquisition to protect themselves from Pi starvation. However, the crosstalk between Pi homeostasis and plant development remains to be explored. Here, we report that overexpressing microRNA399 in maize induced a premature aging syndrome after pollination. Knockout of ZmPHO2, one of the miR399 targets, resulted in a similar premature aging phenotype. Strikingly, we found that INDETERMINATE1 (ID1), a floral transition regulator, inhibits the transcription of ZmMIR399 genes by directly binding to their promoters, alleviating the repression of ZmPHO2 by miR399 and ultimately contributing to the maintenance of Pi homeostasis in maize. Unlike ZmMIR399 genes, whose expression is induced by Pi deficiency, ID1 expression is independent of the Pi status, indicating that ID1 is an autonomous regulator of Pi homeostasis. Furthermore, we found that ZmPHO2 was under selection during maize domestication, resulting in a more sensitive response to phosphate starvation in temperate maize than in tropical maize. Our study reveals a direct functional link between Pi-deprivation sensing by the miR399-ZmPHO2 regulatory module and plant developmental regulation by ID1.
Sex-biased infections scale to population impacts for an emerging wildlife disease
Authors: Kailing Macy J. , Hoyt Joseph R. , White J. Paul , Kaarakka Heather M. , Redell Jennifer A. , Leon Ariel E. , Rocke Tonie E. , DePue John E. , Scullon William H. , Parise Katy L. , Foster Jeffrey T. , Kilpatrick A. Marm , Langwig Kate E.
Published: August 2022

Demographic factors are fundamental in shaping infectious disease dynamics. Aspects of populations that create structure, like age and sex, can affect patterns of transmission, infection intensity and population outcomes. However, studies rarely link these processes from individual to population-scale effects. Moreover, the mechanisms underlying demographic differences in disease are frequently unclear. Here, we explore sex-biased infections for a multi-host fungal disease of bats, white-nose syndrome, and link disease-associated mortality between sexes, the distortion of sex ratios, and the potential mechanisms underlying sex differences in infection. We collected data on host traits, infection intensity, and survival of five bat species at 42 sites across seven years. We found females were more infected than males for all five species. Females also had lower apparent survival over winter and accounted for a smaller proportion of populations over time. Notably, female-biased infections were evident by early hibernation and likely driven by sex-based differences in autumn mating behavior. Male bats were more active during autumn which likely reduced replication of the cool-growing fungus. Higher disease impacts in female bats may have cascading effects on bat populations beyond the hibernation season by limiting recruitment and increasing the risk of Allee effects.
Obesity promotes breast epithelium DNA damage in BRCA mutation carriers
Authors: Bhardwaj Priya , Iyengar Neil M. , Zahid Heba , Carter Katharine M. , Byun Dong Jun , Choi Man Ho , Sun Qi , Savenkov Oleksandr , Louka Charalambia , Liu Catherine , Piloco Phoebe , Acosta Monica , Bareja Rohan , Elemento Olivier , Foronda Miguel , Dow Lukas E. , Oshchepkova Sofya , Giri Dilip D. , Pollak Michael , Zhou Xi Kathy , Hopkins Benjamin D. , Laughney Ashley M. , Frey Melissa K. , Ellenson Lora Hedrick , Morrow Monica , Spector Jason A. , Cantley Lewis C. , Brown Kristy A.
Published: August 2022

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelium of BRCA mutation carriers is positively correlated with body mass index and with biomarkers of metabolic dysfunction. Additionally, RNA-sequencing reveals significant obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which impacts neighboring breast epithelial cells. We found that blockade of estrogen biosynthesis or estrogen receptor activity decreases DNA damage, whereas treatment with leptin or insulin increases DNA damage in BRCA heterozygous epithelial cells. Furthermore, we show that increased adiposity is associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between bodyweight and breast cancer development in BRCA mutation carriers and suggests that maintaining a healthy bodyweight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.

One Sentence Summary

Elevated bodyweight is positively associated with DNA damage in breast epithelium of BRCA mutation carriers
Spatial distribution and predictive factors of antenatal care in Burundi: a multilevel analysis and spatial baseline for the third Burundian demographic health survey
Authors: Barankanira Emmanuel , Iradukunda Arnaud , Ntakaburimvo Nestor , Ahishakiye Willy , Nsavyimana Jean Claude , Odjidja Emmanuel Nene
Published: August 2022

Background

The use of antenatal care by pregnant women enables them to receive good pregnancy monitoring. This monitoring includes counseling, health instructions, examinations and tests to avoid pregnancy-related complications or death during childbirth. To avoid these complications, the World Health Organization (WHO) recommends at least four antenatal visits. Therefore, this study sought to understand the spatial distribution and predictive factors of antenatal care (ANC) among women aged 15 to 49 years with a medical doctor in Burundi.

Methods

We used data from the Second Burundi Demographic and Health Survey (DHS). A descriptive and spatial analysis of ANC prevalence were done. The ANC prevalence was mapped by region and by province. In unsampled data points, a cluster based interpolation of ANC prevalence was done using the kernel method with an adaptive window. Predictive factors of ANC were assessed using a fixed effects binary logistic regression. The dependent variable was antenatal care with a medical doctor and the explanatory variables were place of residence, age, education level, religion, marital status of the woman, household wealth index and delivery place of the woman. Data processing and data analysis were done using R software, version 3.5.0.

Results

The ANC prevalence varied from 0.0 to 16.2% with a median of 0.5%. A highest predicted ANC prevalence was observed at Muyinga and Kirundo provinces’ junction. Low prevalence was observed in several locations in all regions and provinces. The woman’s education level and delivery place were significantly associated with antenatal care with a medical doctor.

Conclusion

Globally, the ANC prevalence is low in Burundi. It varies across the country. There is an intra-regional or intra-provincial heterogeneity in term of ANC prevalence. Woman’s education level and delivery place are significantly associated antenatal care.
Short report: A trend analysis of attitudes towards early diagnosis of dementia in Germany
Authors: Zülke Andrea E. , Luppa Melanie , Luck Tobias , Riedel-Heller Steffi G.
Published: August 2022

Background

Early detection of dementia provides numerous benefits for those living with dementia and their relatives and healthcare systems at large. Methods available for early diagnosis have improved significantly over the past years. Therefore, we examined whether openness towards early diagnosis for dementia and preferred sources of support have changed in Germany over the last decade.

Method

We compared findings from two representative telephone surveys conducted among older adults in Germany (≥ 60 years of age) in 2011 and 2022, assessing attitudes towards and willingness to pursue an early diagnosis of dementia in a sample of n = 879 individuals (mean age: 72.9, % female: 58.8). Group comparisons using Chi2- and t-tests and multivariable regression analyses were conducted, assessing factors linked to willingness to be examined for an early diagnosis of dementia.

Results

Openness towards early diagnosis of dementia was high both in 2011 and 2022, but slightly declined over time (b=.62; 95% CI: .45; .86). Belief in preventability of dementia was linked to greater openness towards an early diagnosis of dementia (b=1.52; 95% CI: 1.12; 2.07).

Conclusion

Willingness to pursue an early diagnosis of dementia is high in the older German public, but slightly lower than reported previously. Improving knowledge on modifiable risk factors and better understanding of individual motives underlying endorsement or refusal of an early diagnosis may further increase acceptance in the general public.
Comprehensive analysis using DNA metabarcoding, PCR, and HPLC unveils the adulteration in Brahmi herbal products
Authors: Shah Abhi P. , Travadi Tasnim , Sharma Sonal , Pandit Ramesh , Joshi Chaitanya , Joshi Madhvi
Published: August 2022

Background

The herbal products market is expanding and creating a bottleneck for raw materials. Hence, economically motivated adulteration has a high prevalence. DNA barcoding and species-specific PCR assays are now revolutionising the molecular identification of herbal products and are included in a number of pharmacopoeias for the identification of raw materials. High-throughput sequencing with barcoding advances toward metabarcoding, which enables the identification of unintentionally or intentionally unlabelled plant material present in herbal products. Brahmi is one of the most commercially significant and nootropic botanicals, with great controversy over the terms “Brahmi” being used to describe both Bacopa monneri (BM) and Centella asiatica (CA) species.

Purpose

This study evaluates DNA-based methods for Brahmi herbal products with the traditional HPLC-based analytical approach in order to assess their effectiveness.

Methods

We employed a species-specific PCR assay, DNA metabarcoding using rbcL minibarcode, and HPLC to detect the presence of the Brahmi (either BM or CA) in eighteen market samples. All the methods have been validated using in-house blended formulations.

Results

Comprehensive analysis of all three methods revealed the presence of 22.2%, 55.6%, and 50.0% of Brahmi by PCR assay, DNA metabarcoding, and HPLC, respectively, in Brahmi market formulations, whereas blended formulations only exhibited targeted plant species with all three methods.

Conclusion

Species-specific PCR can be used as a cost-effective and rapid method to detect the presence of the Brahmi, while in high-throughput methods, DNA metabarcoding can be used to detect the presence of widespread adulterated botanicals, and further, bioactive compounds could be detected by HPLC. These results emphasise the need for quality control of the marketed Brahmi herbal products as well as the implementation of all methodologies in accordance with fit for purpose.
Recombinant Human ACE2-Fc : A promising therapy for SARS-CoV2 infection
Authors: Smitha P.K , Shandil R.K. , Suresh Pushkarni , Biswas Kunal , Rudramurthy G.R. , Naveenkumar C.N. , Bharathkumar K. , Battula Naga Puspha , Chowdhury Suprabuddha Datta , Sinha Sakshi , Dutta Sarmistha , Dhar Sujan K. , Narayanan Shridhar , Das Manjula
Published: August 2022

SARS-CoV2 entry is mediated by binding of viral spike-protein(S) to the transmembrane Angiotensin-Converting Enzyme-2 (ACE2) of the host cell. Thus, to prevent transmission of disease, strategies to abrogate the interaction are important. However, ACE2 cannot be blocked since its normal function is to convert the Angiotensin II peptide to Angiotensin(1-7) to reduce hypertension. This work reports a recombinant cell line secreting soluble ACE2-ectopic domain (MFcS2), modified to increase binding and production efficacy and fused to human immunoglobulin-Fc. While maintaining its enzymatic activity, the molecule trapped and neutralized SARS CoV2 virus in vitro with an IC50 of 64 nM. In vivo, with no pathology in the vital organs, it inhibited the viral load in lungs in SARS-CoV2 infected Golden-Syrian-hamster. The Intravenous pharmacokinetic profiling of MFcS2 in hamster at a dose of 5 mg/Kg presented a maximum serum concentration of 23.45 µg/mL with a half-life of 29.5 hrs. These results suggest that MFcS2 could be used as an effective decoy based therapeutic strategy to treat COVID19. This work also reports usage of a novel oral-cancer cell line as in vitro model of SARS-Cov2 infection, validated by over expressing viral-defence pathways upon RNA-seq analysis and over-expression of ACE2 and TMPRSS upon growth in hyperglycaemic condition.
Altered global modular organization of intrinsic functional connectivity in autism arises from atypical node-level processing
Authors: Sigar Priyanka , Uddin Lucina Q. , Roy Dipanjan
Published: August 2022

Autistic spectrum disorder (ASD) is a neurodevelopmental condition characterized by restricted interests and repetitive behaviors as well as social-communication deficits. These traits are associated with atypicality of functional brain networks. Modular organization in the brain plays a crucial role in network stability and adaptability for neurodevelopment. Previous neuroimaging research demonstrates discrepancies in studies of functional brain modular organization in ASD. These discrepancies result from the examination of mixed age groups. Furthermore, recent findings suggest while much attention has been given to deriving atlases and measuring the connections between nodes, the within nodes information may be crucial in determining altered modular organization in ASD compared with TD. However, altered modular organization originating from systematic nodal changes are yet to be explored in younger children with ASD. Here, we used graph-theoretical measures to fill this knowledge gap. To this end, we utilized multicenter resting-state BOLD fMRI data collected from 5–10-year-old children - 34 ASD and 40 typically developing obtained from the Autism Brain Image Data Exchange (ABIDE) I and II. We demonstrated alterations in the topological roles and modular cohesiveness are the two key properties of the brain regions anchored in default mode, sensorimotor, and salience networks primarily relates to social and sensory deficits in ASD children. These results demonstrate atypical global network organization in ASD children arise from nodal role changes and contribute to the growing body of literature suggesting that there is interesting information within nodes providing critical marker of functional brain networks in Autistic children.
Engram Stability and Maturation During Systems Consolidation Underlies Remote Memory
Authors: Refaeli Ron , Kreisel Tirzah , Groysman Maya , Adamsky Adar , Goshen Inbal
Published: August 2022

Remote memories play an important role in how we perceive the world and are rooted in ensembles in the CA1 and ACC, however the evolution of these components during systems consolidation has not yet been comprehensively addressed. By applying transgenic approaches for ensemble identification, CLARITY, retro-AAV and rabies virus for circuit mapping, and chemogenetics for functional interrogation, we addressed the dynamics of CA1-ACC ensembles and their connectivity as well as the contribution of astrocytes to the process. We found that the CA1 engrams remain stable between recent and remote recall, and, the inhibition of the engram for recent recall during remote recall functionally impairs memory. We also found that the new cells in the remote recall engram in the CA1 are not added randomly, but differ according to their connections: First, the anterograde CA1 → ACC engram cell projection grows larger. Second, in the retrograde projections, the ACC reduces input to CA1 engram cells, while input from the entorhinal cortex and paraventricular nucleus of the thalamus increases. Finally, we found that activating CA1 astrocytes during acquisition improves recent but not remote recall, and that CA1 → ACC projecting cells are recruited earlier when the astrocytes are stimulated. Our results shine fresh light on systems consolidation by providing a deeper understanding of engram stability and maturation in the transition from recent to remote memory.
Why slow axonal transport is bidirectional – can axonal transport of tau protein rely only on motor-driven anterograde transport?
Authors: Kuznetsov Ivan A. , Kuznetsov Andrey V.
Published: August 2022

Slow axonal transport (SAT) moves multiple proteins from the soma, where they are synthesized, to the axon terminal. Due to the great lengths of axons, SAT almost exclusively relies on active transport, which is driven by molecular motors. The puzzling feature of slow axonal transport is its bidirectionality. Although the net direction of SAT is anterograde, from the soma to the terminal, experiments show that it also contains the retrograde component. One of the proteins transported by SAT is microtubule-associated protein tau. To better understand why the retrograde component in tau transport is needed, we used the perturbation technique. We analyzed the simplification of the full tau SAT model for the case when retrograde motor-driven transport and diffusion-driven transport of tau are negligible, and tau is driven only by anterograde (kinesin) motors. The solution of the simplified equations shows that the tau concentration along the axon length stays almost uniform (decreases very slightly), which is inconsistent with the tau concentration at the outlet boundary (at the axon tip). Thus kinesin-driven transport alone is not enough to explain the experimentally observed distribution of tau, and the retrograde motor-driven component in SAT is needed.