Cross-species incompatibility between a DNA satellite and the Drosophila Spartan homolog poisons germline genome integrity Satellite DNA spans megabases of eukaryotic sequence and evolves rapidly. Paradoxically, satellite-rich genomic regions mediate strictly conserved, essential processes like chromosome segregation and nuclear structure. A leading resolution to this paradox posits that satellite DNA and satellite-associated chromosomal proteins coevolve to preserve these essential functions. We experimentally test this model of intra-genomic coevolution by conducting the first evolution-guided manipulation of both chromosomal protein and DNA satellite. The 359bp satellite spans an 11Mb array in D. melanogaster that is absent from its sister species, D. simulans. This species-specific DNA satellite colocalizes with the adaptively evolving, ovary-enriched protein, Maternal Haploid (MH)-the Drosophila homolog of Spartan. To determine if MH and 359 coevolve, we swapped the D. simulans version of MH ("MH[sim]") into D. melanogaster. MH[sim] triggers ovarian cell death, reduced ovary size, and loss of mature eggs. Surprisingly, the D. melanogaster mh null mutant has no such ovary phenotypes, suggesting that MH[sim] is toxic in a D. melanogaster background. Using both cell biology and genetics, we discovered that MH[sim] poisons oogenesis through a DNA damage pathway. Remarkably, deleting the D. melanogaster-specific 359 satellite array completely restores mh[sim] germline genome integrity and fertility, consistent with a history of coevolution between these two fast-evolving loci. Germline genome integrity and fertility are also restored by overexpressing Topoisomerase II (Top2), suggesting that MH[sim] interferes with Top2-mediated processing of 359. The observed 359-MH[sim] cross-species incompatibility supports a model under which ostensibly inert repetitive DNA and essential chromosomal proteins must coevolve to preserve germline genome integrity.
Paternal knockdown of tRNA (cytosine-5-)-methyltransferase (Dnmt2) increases offspring susceptibility to infection in red flour beetles Intergenerational effects from fathers to offspring are increasingly reported from diverse organisms, but the underlying mechanisms remain speculative. Paternal trans-generational immune priming (TGIP) was demonstrated in the red flour beetle Tribolium castaneum: non-infectious bacterial exposure of fathers protects their offspring against an infectious challenge for at least two generations. Epigenetic processes, such as cytosine methylation of nucleic acids, have been proposed to enable transfer of information from fathers to offspring. Here we studied a potential role in TGIP of the Dnmt2 gene (renamed as Trdmt1 in humans), which encodes a highly conserved enzyme that methylates different RNAs, including specific cytosines of a set of tRNAs. Dnmt2 has previously been reported to be involved in intergenerational epigenetic inheritance in mice and protection against viruses in fruit flies. We first studied gene expression and found that Dnmt2 is expressed in various life history stages and tissues of T. castaneum, with high expression in the reproductive organs. RNAi-mediated knockdown of Dnmt2 in fathers was systemic, slowed down offspring larval development and increased mortality of the adult offspring upon bacterial infection. However, these effects were independent of bacterial exposure of the fathers. In conclusion, our results point towards a role of Dnmt2 for paternal effects, while elucidation of the mechanisms behind paternal TGIP needs further studies.
Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition The teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching  acanthodian-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckels cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth of Acanthodopsis are borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly. Express Arm Responses Appear Bilaterally on Upper-limb Muscles in An Arm Choice Reaching Task When required, humans can generate very short latency reaches towards visual targets, like catching a falling cellphone. During such rapid reaches, express arm responses are the first wave of upper limb muscle recruitment, occurring ~80-100 ms after target appearance. There is accumulating evidence that express arm responses arise from signaling along the tecto-reticulo-spinal tract, but the involvement of the reticulo-spinal tract has not been well-studied. Since the reticulospinal tract projects bilaterally, we studied whether express arm responses would be generated bilaterally. Human participants (n = 14; 7 female) performed visually guided reaches in a modified emerging target paradigm where either arm could intercept the target. We recorded electromyographic activity bilaterally from the pectoralis major muscle. Our analysis focused on target locations where participants reached with the right arm on some trials, and the left arm on others. In support of the involvement of the reticulospinal tract, express arm responses persisted bilaterally regardless of which arm reached to the target. The latency and magnitude of the express arm response did not depend on whether the arm was chosen to reach or not. However, on the reaching arm, the magnitude of the express arm response was correlated to the level of anticipatory activity. The bilateral generation of express arm responses supports the involvement of the reticulo-spinal tract. We surmise that the correlation between anticipatory activity and the magnitude of express arm responses on the reaching arm arises from convergence of cortically-derived signals with a parallel subcortical pathway mediating the express arm response.

New and NoteworthyExpress arm responses have been proposed to arise from the tecto-reticulo-spinal tract originating within the superior colliculus, but the involvement of the reticulo-spinal tract has not been well studied. Here, we show these responses appear bilaterally in a task where either arm can reach to a newly appearing stimulus. Our results suggest that the most rapid visuomotor transformations for reaching are performed by a subcortical pathway. Rhizome trait scaling relationships are modulated by growth conditions and are linked to plant fitness Background and AimRhizomes are important organs allowing many clonal plants to persist and reproduce under stressful climates with longer rhizomes indicating enhanced ability of the plants to spread vegetatively. We do not however, know either how rhizome construction costs change with increasing length or vary with environmental conditions.

MethodsWe analysed the rhizome length vs mass scaling relationship, the plasticity in the scaling relationships, their genetic basis, and how scaling relationships are linked to plant fitness. We used data from 275 genotypes of a clonal grass Festuca rubra originating from 11 localities and cultivated under four contrasting climates. Data were analysed using standard major axis regression, mixed-effect regression models and a structural equation model.

Key ResultsRhizome construction costs increased (i.e., lower specific rhizome length) with increasing length. The trait scaling relationships were modulated by cultivation climate and its effects also interacted with the climate of origin of the experimental plants. With increasing length, increasing moisture led to a greater increase in rhizome construction costs. Plants with lower rhizome construction costs showed significantly higher fitness.

ConclusionsThis study suggests that rhizome scaling relationships are plastic, but also show genetic differentiation and are linked to plant fitness. Therefore, to persist under variable environments modulation in scaling relationships could be an important plants strategy. If Research is Not the Evidence, What is it? The Lack of Research Citations in Health Vlogs Doctor-influencers have the knowledge needed to understand scientific research, and they have the social media popularity to share it with large audiences. In this article, I explore the treatment of evidence in vlogs by Egyptian doctor-influencers: how they present it and what they use instead of it. I answer the following questions: 1) How do doctor-influencers present evidence on social media? 2) If evidence is not the research, then what is it? The data was collected through in-depth interviews with 12 Egyptian doctor-influencers from different specializations; two focus groups; and a critical discourse analysis of 48 of the influencers most popular and most engaging videos. I found that the doctor-influencers cited academic research only in the videos about medical controversies, new treatments, misinformation, or common medical mistakes. In most of their videos, the Egyptian doctor-influencers scarcely referred to medical research. This is because they believe that their audiences would not understand evidence due to their low educational attainment, weak research skills, and the language barrier (as most medical research is published in English rather than Arabic). These findings highlight the challenges of communicating science in societies with a low level of education. In these settings, communicators may need to move beyond mediating research studies on social media and instead focus on simplifying, translating, and connecting evidence-based information to the cultural context. Proteasome complexes experience profound structural and functional rearrangements throughout mammalian spermatogenesis During spermatogenesis, spermatogonia undergo a series of mitotic and meiotic divisions on their path to spermatozoa. To achieve this, a succession of processes requiring high proteolytic activity are in part orchestrated by the proteasome. The spermatoproteasome (s20S) is specific to the developing gametes, in which the gamete-specific 4s subunit replaces the 4 isoform found in the constitutive proteasome (c20S). Although the s20S is conserved across species and was shown to be crucial for germ cell development, its mechanism, function and structure remain incompletely characterized. Here, we used advanced mass spectrometry (MS) methods to map the composition of proteasome complexes and their interactomes throughout spermatogenesis. We observed that the s20S becomes highly activated as germ cells enter meiosis, mainly through a particularly extensive 19S activation and, to a lesser extent, PA200 binding. Additionally, the proteasome population shifts from c20S (98%) to s20S (>82-92%) during differentiation, presumably due to the shift from 4 to 4s expression. We demonstrated that s20S, but not c20S, interacts with components of the meiotic synaptonemal complex, where it may localize via association with the PI31 adaptor protein. In vitro, s20S preferentially binds to 19S, and displays higher trypsin- and chymotrypsin-like activities, both with and without PA200 activation. Moreover, using MS methods to monitor protein dynamics, we identified significant differences in domain flexibility between 4 and 4s. We propose that these differences induced by 4s incorporation result in significant changes in the way the s20S interacts with its partners, and dictate its role in germ cell differentiation. Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic andtargetable tissue states Glioblastoma is an aggressive diffusely infiltrating neoplasm that spreads beyond surgical resection margins, where it intermingles with non-neoplastic brain cells. This complex microenvironment harbouring infiltrating glioma and non-neoplastic brain cells is the origin of tumor recurrence. Thus, understanding the cellular and molecular features of the glioma microenvironment is therapeutically and prognostically important. Here, we used single-nucleus RNA sequencing (snRNAseq) of primary and recurrent glioma to define three compositional  tissue-states rooted in cohabitation of cell-types and transcriptional states. These comprise a state featuring A) abundant normal brain microenvironment cells, B) reactive/inflamed brain microenvironment, and C) cellular/proliferative tumor. All these states exhibited variable degrees of infiltration by glioma cells. Spatial transcriptomics confirmed that the cell-types and transcriptomics states which compositionally cohabitate tissue states also colocalize in space. Tissue states are clinically significant because they correlate with radiographic, histopathologic, and prognostic features. We found that enrichment of tissue state B signature correlated with shorter survival. Importantly, we found that our compositionally defined tissue states are enriched in distinct metabolic pathways. One such pathway is fatty acid biosynthesis, which was enriched in tissue state B - a state enriched in recurrent glioblastoma and composed of astrocyte-like/mesenchymal glioma cells, reactive astrocytes resembling those seen in neurodegeneration, and monocyte-like myeloid cells. We showed that treating acute slices of GBM with a fatty acid synthesis inhibitor is sufficient to deplete the transcriptional signature of tissue state B. Our findings define a novel compositional approach to the glioma-infiltrated tissue which allows us to discover prognostic and targetable features, paving the way to new mechanistic and therapeutic discoveries. An Essential Role of UBXN3B for B Lymphopoiesis Hematopoiesis is finely regulated to enable timely production of the right numbers and types of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential role of UBXN3B in maintenance of hematopoietic homeostasis and restriction of immunopathogenesis during respiratory viral infection. Ubxn3b deficient (Ubxn3b-/-) mice are highly vulnerable to SARS-CoV-2 and influenza A infection, characterized by more severe lung immunopathology, lower virus-specific IgG, significantly fewer B cells, but more myeloid cells than Ubxn3b+/+ littermates. This aberrant immune compartmentalization is recapitulated in uninfected Ubxn3b-/- mice. Mechanistically, UBXN3B controls precursor B-I (pre-BI) transition to pre-BII and subsequent proliferation in a cell-intrinsic manner, by maintaining BLNK protein stability and pre-BCR signaling. These results reveal an essential role of UBXN3B for the early stage of B cell development. Microbial colonization of tannin-rich tropical plants: interplay between degradability, methane production and tannin disappearance in the rumen AO_SCPLOWBSTRACTC_SCPLOWCondensed tannins in plants are found free and attached to protein and fibre but it is not known whether these fractions influence rumen degradation and microbial colonization. This study explored the rumen degradation of tropical tannins-rich plants and the relationship between condensed tannins fractions disappearance and microbial communities colonising plant particles. Leaves from Calliandra calothyrsus, Gliricidia sepium, and Leucaena leucocephala, pods from Acacia nilotica and the leaves of two agricultural by-products: Manihot esculenta and Musa spp. were incubated in situ in the rumen of dairy cows. An in vitro approach was also used to assess the effects of these plants on rumen fermentation parameters. All plants contained more than 100 g/kg of condensed tannins with a large proportion (32 to 61%) bound to proteins. Calliandra calothyrsus had the highest concentration of condensed tannins at 361 g/kg, whereas Acacia nilotica was particularly rich in hydrolysable tannins (350 g/kg). Hydrolysable and free condensed tannins from all plants completely disappeared after 24 h incubation in the rumen. Disappearance of protein-bound condensed tannins was variable with values ranging from 93% for Gliricidia sepium to 21% for Acacia nilotica. In contrast, fibre-bound condensed tannins disappearance averaged ~82% and did not vary between plants. Disappearance of bound fractions of condensed tannins was not associated with degradability of plant fractions. The presence of tannins interfered with the microbial colonisation of plants. Each plant had distinct bacterial and archaeal communities after 3 and 12 h of incubation in the rumen and distinct protozoal communities at 3 h. Adherent communities in tannin-rich plants had a lower relative abundance of fibrolytic microbes, notably Fibrobacter spp. Whereas, archaea diversity was reduced in high tannin-containing Calliandra calothyrsus and Acacia nilotica at 12 h of incubation. Concurrently, in vitro methane production was lower for Calliandra calothyrsus, Acacia nilotica and Leucaena leucocephala although for the latter total volatile fatty acids production was not affected and was similar to control. Here we show that the total amount of hydrolysable and condensed tannins contained in a plant govern the interaction with rumen microbes affecting degradability and fermentation. The effect of protein- and fibre-bound condensed tannins on degradability is less important. ConVarT: a search engine for orthologous variants and functional inference of human genetic variants The availability of genetic variants, together with phenotypic annotations from model organisms, facilitates comparing these variants with equivalent variants in humans. However, existing databases and search tools do not make it easy to scan for equivalent variants, namely "matching variants" (MatchVars) between humans and other organisms. Therefore, we developed an integrated search engine called ConVarT (http://www.convart.org/) for matching variants between humans, mice, and C. elegans. ConVarT incorporates annotations (including phenotypic and pathogenic) into variants, and these previously unexploited phenotypic MatchVars from mice and C. elegans can give clues about the functional consequence of human genetic variants. Our analysis shows that many phenotypic variants in different genes from mice and C. elegans, so far, have no counterparts in humans, and thus, can be useful resources when evaluating a relationship between a new human mutation and a disease. Modifying root/shoot ratios improves root water influxes in wheat under drought stress Drought intensity as experienced by plants depends upon soil moisture status and atmospheric variables such as temperature, radiation, and air vapour pressure deficit (VPD). Although the role of shoot architecture with these edaphic and atmospheric factors is well-characterized, the extent to which shoot and root dynamic interactions as a continuum are controlled by genotypic variation is less known. Here, we targeted these interactions using a wild emmer introgression line (IL20) with a distinct drought-induced shift in the shoot-to-root ratio and its drought-sensitive recurrent parent Svevo. Using a gravimetric platform, we show that IL20 maintained higher root water influx and gas exchange under drought stress, which supported a greater growth. Interestingly, the advantage of IL20 in root water influx and transpiration was expressed earlier during the daily diurnal cycle under lower VPD and therefore supported higher transpiration efficiency. Application of structural equation model indicates that under drought, VPD and radiation are antagonistic to transpiration rate, whereas the root water influx operates as feedback for the higher atmospheric responsiveness of leaves. Collectively, our results suggest that a drought-induced shift in root-to-shoot ratio can improve plant water uptake potential in a short preferable time window determined by both water and atmospheric parameters. Synthetic Nanobody-Functionalized Nanoparticles for Accelerated Development of Rapid, Accessible Detection of Viral Antigens Successful control of emerging infectious diseases requires accelerated development of fast, affordable, and accessible assays to be widely implemented at a high frequency. Here we present a generalizable assay platform, nanobody-functionalized nanoparticles for rapid, electronic detection (Nano2RED), demonstrated in the detection of Ebola and COVID-19 antigens. To efficiently generate high-quality affinity reagents, synthetic nanobody co-binders and mono-binders with high affinity, specificity, and stability were selected by phage display screening of a vastly diverse, rationally randomized combinatorial library, bacterially expressed and site-specifically conjugated to gold nanoparticles (AuNPs) as multivalent in-solution sensors. Without requiring fluorescent labelling, washing, or enzymatic amplification, these AuNPs reliably transduce antigen binding signals upon mixing into physical AuNP aggregation and sedimentation processes, displaying antigen-dependent optical extinction readily detectable by spectrometry or simple electronic circuitry. With nanobodies against an Ebola virus secreted glycoprotein (sGP) and a SARS-CoV-2 spike protein receptor binding domain (RBD) as targets, Nano2RED showed a high sensitivity (limit of detection of [~]10 pg/mL for sGP and [~]40 pg/mL for RBD in diluted human serum), a high specificity, and a large dynamic range ([~]7 logs). Unlike conventional assays where slow mass transport for surface binding limits the assay time, Nano2RED features fast antigen diffusion at micrometer scale, and can be accelerated to deliver results within a few minutes. The rapid detection, low material cost (estimated < $0.01 per test), inexpensive and portable readout system (< $5 and < 100 cm3), and digital data output, make Nano2RED particularly suitable for screening of patient samples with simplified operation and accelerated data transmission. Our method is widely applicable for prototyping diagnostic assays for other antigens from new emerging viruses. Discovering Rare Cell Types through Information-based Dimensionality Reduction Dimensionality reduction is crucial to summarizing the complex transcriptomic landscape of single cell datasets for downstream analyses. However, current dimensionality reduction approaches favor large cellular populations defined by many genes, at the expense of smaller and more subtly-defined populations. Here, we present surprisal component analysis (SCA), a technique that leverages the information-theoretic notion of surprisal for dimensionality reduction, and demonstrate its ability to improve the representation of clinically important populations that are indistinguishable using existing pipelines. For example, in cytotoxic T-cell data, SCA cleanly separates the gamma-delta and MAIT cell subpopulations, which are not detectable via PCA, ICA, scVI, or a wide array of specialized rare cell recovery tools. We also show that, when used instead of PCA, SCA improves downstream imputation to more accurately restore mRNA dropouts and recover important gene-gene relationships. SCAs information-theoretic paradigm opens the door to more meaningful signal extraction, with broad applications to the study of complex biological tissues in health and disease. Hematopoietic differentiation is characterized by a transient peak of entropy at a single cell level. Hematopoietic differentiation has been metaphorically represented as linear trajectories with discrete steps from hematopoietic stem cells to mature cells. While the transcriptional state of cells at the beginning or at the end of these trajectories are well described from bulk analysis, what happens in the intermediate states has remained elusive until the use of single cell approaches. Applying Shannon entropy to measure cell-to-cell variability among cells at the same stage of differentiation, we observed a transient peak of gene expression variability in all the hematopoietic differentiation pathways. Strikingly, genes with the highest entropy variation in a given differentiation pathway matched genes known as pathway-specific, whereas genes with the highest expression variation were common to all pathways. Finally, we showed that the level of cell-to-cell variation is increased in the most immature compartment of hematopoiesis in myelodysplastic syndromes. These data suggest that differentiation could be better conceptualized as a dynamical stochastic process with a transient stage of cellular indetermination. A chemical screen based on an interruption of zebrafish gastrulation identifies the HTR2C inhibitor Pizotifen as a suppressor of EMT-mediated metastasis Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in five hours. The screen tested 1280 FDA-approved drugs and identified Pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacologic and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with Pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt-signaling. In contrast, HTR2C induced epithelial to mesenchymal transition (EMT) through activation of Wnt-signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs. Ribosome actuator via the SpoT/ppGpp pathway to mitigate gene overexpression burden Gene overexpression causes a burden on ribosomes, which decreases the expression of other genes and growth rate. Here, we engineer a genetic ribosome actuator that increases gene expression rate and growth rate by over 150% and 80%, respectively. The actuator expresses the hydrolysis domain of the SpoT enzyme (SpoTH) in a bacterial strain with high basal levels of ppGpp, thus increasing ribosome availability. We use this actuator in a feedforward control arrangement, wherein SpoTH is co-expressed with a gene of interest (GOI). Without SpoTH co-expression, activation of the GOI decreases the expression of a constitutive gene and growth rate by over 80% and 40%, respectively. By contrast, with SpoTH co-expression, the ribosome binding site (RBS) of SpoTH can be tuned to achieve inappreciable change of either the expression of the constitutive gene or growth rate when the GOI is activated to the same level. We finally employ the actuator to keep growth rate constant while expressing dCas9 to a level that would otherwise decrease growth rate by more than 40% due to toxicity. This actuator will be relevant in applications where high cellular protein concentrations are desired without growth defects or global reduction of gene expression. Similarities Between Bacterial GAD and Human GAD65: Implications in Gut Mediated Autoimmune Type 1 Diabetes A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD65 and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing silico analyses, we show here that 25 GAD sequences from different human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that a majority of gut GAD sequences contain the pyroxical dependent decarboxylase domain of human GAD65 which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T-cell receptor epitopes which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities, we found between humans and bacterial GAD, these deputized immune cells may then go on to target human beta cells leading to the development of T1D. Beneficial effects of novel strains of Aureobasidium pullulans produced 1,3-1,6 β-glucans on non-esterified fatty acid levels in diabetic KKAy mice Obesity, metabolic syndrome, associated lipotoxicity and its cascade of events contribute to the majority of the burden related to non-communicable diseases globally. Preventive lifestyle changes aside, several beneficial effects have been reported in type II diabetes mellitus and dyslipidaemia patients with biological response modifier glucans (BRMG) produced as an exopolysaccharide by Aureobasidium pullulans. In this study, we compared two strains (AFO-202 and N-163) that produce beta glucans in alleviating lipotoxicity. This study was performed in obese diabetic mice model of KK-Ay mice, in four groups with six subjects in each group - Group 1: sacrificed on Day 0 for baseline values; Group 2: control (drinking water); Group 3: AFO-202 beta glucan--200 mg/kg/day; Group 4: N-163 beta glucan--300 mg/kg/day. The animals in groups 2-4 had the test solutions administered by gavage once daily for 28 consecutive days. Biochemical analyses were conducted of blood glucose, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol and non-esterified fatty acids (NEFA). Group 4 (N-163) had the lowest NEFA levels, as compared to the other groups, and marginally decreased triglyceride levels. The groups had no significant differences in blood glucose, HbA1c, triglycerides, or LDL and HDL cholesterol. N-163 produced by A. pullulans decreased NEFA in a diabetic mice model in 28 days. These results, although modest, warrant further in-depth research into lipotoxicity and associated inflammatory cascades in both healthy and disease affected subjects to develop novel strategies for prevention and management. Global diversity and distribution of prophages are lineage-specific within the Ralstonia solanacearum plant pathogenic bacterium species complex Ralstonia solanacearum is a destructive plant pathogenic bacterium and the causative agent of bacterial wilt disease, infecting over 200 plant species worldwide. In addition to chromosomal genes, its virulence is mediated by mobile genetic elements including integrated DNA of bacteriophages, i.e., prophages, which may carry fitness-associated auxiliary genes or modulate host gene expression. Although experimental studies have characterised several prophages that shape R. solanacearum virulence, the global diversity, distribution, and wider functional gene content of R. solanacearum prophages is unknown. In this study, prophages were identified in a diverse collection of 192 R. solanacearum draft genome assemblies originating from six continents. Prophages were identified bioinformatically and their diversity investigated using genetic distance measures, gene content, GC, and total length. Prophage distribution was characterised using metadata on R. solanacearum geographic origin and lineage classification (phylotypes), and their functional gene content was assessed by identifying putative prophage-encoded auxiliary genes. In total, 343 intact prophages were identified, forming ten genetically distinct clusters. These included five prophage clusters belonging to the Inoviridae, Myoviridae, and Siphoviridae phage families, and five uncharacterised clusters, possibly representing novel, previously undescribed phages. The prophages had broad geographical distribution being present across multiple continents. However, they were generally host phylogenetic lineage-specific, and overall, prophage diversity was proportional to the genetic diversity of their hosts. The prophages contained a myriad of auxiliary genes involved in metabolism and virulence of both phage and bacteria. Our results show that while R. solanacearum prophages are highly diverse globally, they make lineage-specific contributions to the R. solanacearum accessory genome, which could have resulted from shared coevolutionary history. Mouse oocytes do not contain a Balbiani body Oocytes spend the majority of their lifetime in a primordial, dormant state. Unlike many somatic cell types and mature oocytes, the cellular and molecular biology of primordial oocytes is largely unexplored. Yet, studying their cellular biology is necessary to understand the mechanisms through which oocytes maintain cellular fitness for decades, and why they eventually fail with age.

A hallmark of primordial oocytes in many species is the Balbiani body, a non-membrane bound compartment that contains the majority of mitochondria in the oocyte cytoplasm. The Balbiani body has been proposed to be essential for maintaining mitochondria in a healthy state during long-lasting dormancy, however, the architecture and function of the mammalian Balbiani body remains unknown.

Here, we develop enabling methods for live-imaging based comparative characterization of Xenopus, mouse and human primordial oocytes. We show that primordial oocytes in all three vertebrate species contain active mitochondria, Golgi apparatus and lysosomes. We further demonstrate that human and Xenopus oocytes have a Balbiani body characterized by a dense accumulation of mitochondria in their cytoplasm. However, despite previous reports, we did not find a Balbiani body in mouse oocytes. Instead, we demonstrate what was previously used as a marker for the Balbiani body in mouse primordial oocytes is in fact a ring-shaped Golgi apparatus that is not functionally associated with oocyte dormancy. Our work provides the first insights into the organisation of the cytoplasm in mammalian primordial oocytes, and clarifies relative advantages and limitations of choosing different model organisms for studying oocyte dormancy. Characterization of methylation profiles in spontaneous preterm birth placental villous tissue Preterm birth is a global public health crisis which results in significant neonatal and maternal mortality. Yet little is known regarding the molecular mechanisms of idiopathic spontaneous preterm birth, and we have few diagnostic markers for adequate assessment of placental development and function. Previous studies of placental pathology and our transcriptomics studies suggest a role for placental maturity in idiopathic spontaneous preterm birth. It is known that placental DNA methylation changes over gestation. We hypothesized that if placental hypermaturity is present in our samples, we would observe a unique idiopathic spontaneous preterm birth DNA methylation profile potentially driving the gene expression differences we previously identified in our placental samples. Our results indicate the idiopathic spontaneous preterm birth DNA methylation pattern mimics the term birth methylation pattern suggesting hypermaturity. Only seven significant differentially methylated regions fitting the idiopathic spontaneous preterm birth specific (relative to the controls) profile were identified, indicating unusually high similarity in DNA methylation between idiopathic spontaneous preterm birth and term birth samples. We identified an additional 1,718 significantly methylated regions in our gestational age matched controls were the idiopathic spontaneous preterm birth DNA methylation pattern mimics the term birth methylation pattern, again indicating a striking level of similarity between the idiopathic spontaneous preterm birth and term birth samples. Pathway analysis of these regions revealed differences in genes within the WNT and Cadherin signaling pathways, both of which are essential in placental development and maturation. Taken together, these data demonstrate that the idiopathic spontaneous preterm birth samples are molecularly more mature than expected given their respective gestational age which likely impacts birth timing. Liver Endothelium Promotes HER3-mediated Cell Survival in KRAS Wild-type and Mutant Colorectal Cancer Cells We previously showed that liver endothelial cells (ECs) secreted soluble factors in a paracrine fashion and activated human epidermal growth factor receptor 3 (HER3, also known as ERBB3) for promoting colorectal cancer (CRC) growth and chemoresistance. However, RAS proteins play a critical role in receptor tyrosine kinase signaling pathways, and KRAS mutations mediate CRC resistance to therapies targeting EGFR, another HER protein. Therefore, the role of KRAS mutation status in EC-induced HER3 activation and CRC survival was investigated as it has therapeutic implications. We used CRC cell lines and patient-derived xenografts harboring KRAS wild-type or mutant genes and demonstrated that liver EC-secreted factors promoted HER3-mediated CRC cell growth independent of KRAS mutation status. Also, blocking HER3 in CRC cells by siRNAs or a HER3 antibody seribantumab blocked EC-induced CRC survival. Our findings highlight the potential of utilizing HER3 targeted therapies for treating patients with mCRC independent of RAS mutational status. Thermodynamics and kinetics of aggregation of flexible peripheral membrane proteins Biomembrane remodeling is essential for cellular trafficking, with membrane-binding peripheral proteins playing a key role in it. Significant membrane remodeling as in endo- and exocytosis is often due to aggregates of many proteins with direct or membrane-mediated interactions. Understanding this process via computer simulations is extremely challenging: protein-membrane systems involve time- and lengthscales that make atomistic simulations impractical, while most coarse-grained models fall short in resolving dynamics and physical effects of protein and membrane flexibility. Here, we develop a coarse-grained model of the bilayer membrane bestrewed with rotationally-symmetric flexible proteins, parametrized to reflect local curvatures and lateral dynamics of proteins. We investigate the kinetics, equilibrium distributions, and the free energy landscape governing the formation and break-up of protein clusters on the surface of the membrane. We demonstrate how the flexibility of the proteins as well as their surface concentration play deciding roles in highly selective macroscopic aggregation behavior. The structurome of a Clostridium difficile phage and the remarkable accurate prediction of its novel phage receptor-binding protein As natural bacterial predators, bacteriophages have the potential to be developed to tackle antimicrobial resistance, but our exploitation of them is limited by understanding their vast uncharacterised genetic diversity1,2. Fascinatingly, this genetic diversity reflects many ways that phages can make proteins, performing similar functions that together form the familiar phage particle. Critical to infection are phage receptor-binding proteins (RBPs) that bind bacterial  receptors and initiate bacterial entry3. Here we identified and characterised Gp22, a novel RBP for phage CDHS-1 that infects pathogenic C. difficile, but that had no recognisable RBPs. We showed that Gp22 antibodies neutralised CDHS-1 infection and used immunogold-labelling and transmission electron microscopy to identify their location on the capsid. The Gp22 three-dimensional structure was resolved by X-ray crystallography revealing a new RBP class with an N-terminal L-shaped -helical superhelix domain and a C-terminal Mg2+-binding domain. The findings provide novel insights into C. difficile phage biology and phage-host interactions. This will facilitate optimal phage development and future engineering strategies4,5. Furthermore, the AlphaFold2-predicted Gp22 structure, which was strikingly accurate, paves the way for a structurome based transformation and guidance of future phage studies where many proteins lack sequence homology but have recognisable protein structures. Darwin's small and medium ground finches might have taste preferences, but not for human foods Urbanization is rapidly changing ecological niches. On the inhabited Galapagos Islands, Darwins finches consume human-introduced foods preferentially; however, it remains unclear why. Here we presented pastry with flavour profiles typical of human foods (oily, salty, sweet) to small ground finches (Geospiza fuliginosa) and medium ground finches (Geospiza fortis) to test if latent taste preferences might drive selection of human foods. If human-food flavours were consumed more than a neutral or bitter control only at sites with human foods, then we predicted tastes were acquired after urbanization; however, if no site-differences were found then this would indicate latent taste preferences. Contrary to both predictions, we found little evidence that human-food flavours were preferred compared to control flavours at any site. Instead, finches showed a weak aversion to oily foods, but only at remote (no human foods present) sites. This was further supported by behavioural responses, with beak wiping occurring more often at remote sites after finches tasted flavours associated with human foods. Our results suggest, therefore, that while Darwins finches may have acquired a tolerance to the flavours of human food, latent taste preferences are unlikely to have played a major role in their dietary response to increased urbanization.