Twist Angle Tuning of Moiré Exciton Polaritons in van der Waals Heterostructures.

Twisted atomically thin semiconductors are characterized by moiré excitons. Their optical signatures and selection rules are well understood. However, their hybridization with photons in the strong coupling regime for heterostructures integrated in an optical cavity has not been the focus of research yet. Here, we combine an excitonic density matrix formalism with a Hopfield approach to provide microscopic insights into moiré exciton polaritons. In particular, we show that exciton-light coupling, polariton energy, and even the number of polariton branches can be controlled via the twist angle. We find that these new hybrid light-exciton states become delocalized relative to the constituent excitons due to the mixing with light and higher-energy excitons. The system can be interpreted as a natural quantum metamaterial with a periodicity that can be engineered via the twist angle. Our study presents a significant advance in microscopic understanding and control of moiré exciton polaritons in twisted atomically thin semiconductors.

Observations of hypomelanosis in the nurse shark Ginglymostoma cirratum.

Hypomelanosis refers to a suite of skin pigment abnormalities, including albinism, leucism and piebaldism. While documented across many vertebrate species, examples of hypomelanosis are rarely seen in chondrichthyans, with little insight into the potential effects on survival. Here, we report the first observation of abnormal skin pigmentation indicative of piebaldism in the Atlantic nurse shark Ginglymostoma cirratum, representing only the second reported case of skin aberrations for this species. This extremely rare observation is discussed in the broader context of fitness variation and long-term survival.

The need for an integrated multi-OMICs approach in microbiome science in the food system.

Microbiome science as an interdisciplinary research field has evolved rapidly over the past two decades, becoming a popular topic not only in the scientific community and among the general public, but also in the food industry due to the growing demand for microbiome-based technologies that provide added-value solutions. Microbiome research has expanded in the context of food systems, strongly driven by methodological advances in different -omics fields that leverage our understanding of microbial diversity and function. However, managing and integrating different complex -omics layers are still challenging. Within the Coordinated Support Action MicrobiomeSupport (https://www.microbiomesupport.eu/), a project supported by the European Commission, the workshop "Metagenomics, Metaproteomics and Metabolomics: the need for data integration in microbiome research" gathered 70 participants from different microbiome research fields relevant to food systems, to discuss challenges in microbiome research and to promote a switch from microbiome-based descriptive studies to functional studies, elucidating the biology and interactive roles of microbiomes in food systems. A combination of technologies is proposed. This will reduce the biases resulting from each individual technology and result in a more comprehensive view of the biological system as a whole. Although combinations of different datasets are still rare, advanced bioinformatics tools and artificial intelligence approaches can contribute to understanding, prediction, and management of the microbiome, thereby providing the basis for the improvement of food quality and safety.

High SARS-CoV-2 Viral Load in Urine Sediment Correlates with Acute Kidney Injury and Poor COVID-19 Outcome.

BACKGROUND: AKI is a complication of coronavirus disease 2019 (COVID-19) that is associated with high mortality. Despite documented kidney tropism of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there are no consistent reports of viral detection in urine or correlation with AKI or COVID-19 severity. Here, we hypothesize that quantification of the viral load of SARS-CoV-2 in urine sediment from patients with COVID-19 correlates with occurrence of AKI and mortality. METHODS: The viral load of SARS-CoV-2 in urine sediments (U-viral load) was quantified by qRT-PCR in 52 patients with PCR-confirmed COVID-19 diagnosis, who were hospitalized between March 15 and June 8, 2020. Immunolabeling of SARS-CoV-2 proteins Spike and Nucleocapsid was performed in two COVID-19 kidney biopsy specimens and urine sediments. Viral infectivity assays were performed from 32 urine sediments. RESULTS: A total of 20 patients with COVID-19 (39%) had detectable SARS-CoV-2 U-viral load, of which 17 (85%) developed AKI with an average U-viral load four-times higher than patients with COVID-19 who did not have AKI. U-viral load was highest (7.7-fold) within 2 weeks after AKI diagnosis. A higher U-viral load correlated with mortality but not with albuminuria or AKI stage. SARS-CoV-2 proteins partially colocalized with the viral receptor ACE2 in kidney biopsy specimens in tubules and parietal cells, and in urine sediment cells. Infective SARS-CoV-2 was not detected in urine sediments. CONCLUSION: Our results further support SARS-CoV-2 kidney tropism. A higher SARS-CoV-2 viral load in urine sediments from patients with COVID-19 correlated with increased incidence of AKI and mortality. Urinary viral detection could inform the medical care of patients with COVID-19 and kidney injury to improve prognosis.

Enhanced cartilage repair in 'healer' mice-New leads in the search for better clinical options for cartilage repair.

Adult articular cartilage has a poor capacity to undergo intrinsic repair. Current strategies for the repair of large cartilage defects are generally unsatisfactory because the restored cartilage does not have the same resistance to biomechanical loading as authentic articular cartilage and degrades over time. Recently, an exciting new research direction, focused on intrinsic cartilage regeneration rather than fibrous repair by external means, has emerged. This review explores the new findings in this rapidly moving field as they relate to the clinical goal of restoration of structurally robust, stable and non-fibrous articular cartilage following injury.

INPPL1 gene mutations in opsismodysplasia.

The INPPL1 (inositol polyphosphate phosphatase-like 1) gene encodes the inositol phosphatase, SHIP2 (for src homology 2 domain-containing inositol phosphatase 2). SHIP2 functions to dephosphorylate, and negatively regulate, the lipid second messenger phosphatidylinositol (3,4,5)P3. SHIP2 has been well studied in the area of insulin resistance and obesity but has roles in cancer and other disorders. Recently, it was reported that mutations in INPPL1 cause opsismodysplasia, a rare, autosomal recessive severe skeletal dysplasia. This review focuses on the mutations associated with opsismodysplasia and explores the role of INPPL1/ SHIP2 in skeletal development.

Novel Fermentates Can Enhance Key Immune Responses Associated with Viral Immunity.

Fermented foods have long been known to have immunomodulatory capabilities, and fermentates derived from the lactic acid bacteria of dairy products can modulate the immune system. We have used skimmed milk powder to generate novel fermentates using Lb. helveticus strains SC234 and SC232 and we demonstrate here that these fermentates can enhance key immune mechanisms that are critical to the immune response to viruses. We show that our novel fermentates, SC234 and SC232, can positively impact on cytokine and chemokine secretion, nitric oxide (NO) production, cell surface marker expression, and phagocytosis in macrophage models. We demonstrate that the fermentates SC234 and SC232 increase the secretion of cytokines IL-1ß, IL-6, TNF-α, IL-27, and IL-10; promote an M1 pro-inflammatory phenotype for viral immunity via NO induction; decrease chemokine expression of Monocyte Chemoattractant Protein (MCP); increase cell surface marker expression; and enhance phagocytosis in comparison to their starting material. These data suggest that these novel fermentates have potential as novel functional food ingredients for the treatment, management, and control of viral infection.

Novel Dairy Fermentates Have Differential Effects on Key Immune Responses Associated with Viral Immunity and Inflammation in Dendritic Cells.

Fermented foods and ingredients, including furmenties derived from lactic acid bacteria (LAB) in dairy products, can modulate the immune system. Here, we describe the use of reconstituted skimmed milk powder to generate novel fermentates from Lactobacillus helveticus strains SC232, SC234, SC212, and SC210, and from Lacticaseibacillus casei strains SC209 and SC229, and demonstrate, using in vitro assays, that these fermentates can differentially modulate cytokine secretion via bone-marrow-derived dendritic cells (BMDCs) when activated with either the viral ligand loxoribine or an inflammatory stimulus, lipopolysaccharide. Specifically, we demonstrate that SC232 and SC234 increase cytokines IL-6, TNF-α, IL-12p40, IL-23, IL-27, and IL-10 and decrease IL-1ß in primary bone-marrow-derived dendritic cells (BMDCs) stimulated with a viral ligand. In contrast, exposure of these cells to SC212 and SC210 resulted in increased IL-10, IL-1ß, IL-23, and decreased IL-12p40 following activation of the cells with the inflammatory stimulus LPS. Interestingly, SC209 and SC229 had little or no effect on cytokine secretion by BMDCs. Overall, our data demonstrate that these novel fermentates have specific effects and can differentially enhance key immune mechanisms that are critical to viral immune responses, or can suppress responses involved in chronic inflammatory conditions, such as ulcerative colitis (UC), and Crohn's disease (CD).

The expanded collagen VI family: new chains and new questions.

Collagen VI is a component of the extracellular matrix of almost all connective tissues, including cartilage, bone, tendon, muscles and cornea, where it forms abundant and structurally unique microfibrils organized into different suprastructural assemblies. The precise role of collagen VI is not clearly defined although it is most abundant in the interstitial matrix of tissues and often found in close association with basement membranes. Three genetically distinct collagen VI chains, α1(VI), α2(VI) and α3(VI), encoded by the COL6A1. COL6A2 and COL6A3 genes, were first described more than 20 years ago. Their molecular assembly and role in congenital muscular dystrophy has been broadly characterized. In 2008, three additional collagen VI genes arrayed in tandem at a single gene locus on chromosome 3q in humans, and chromosome 9 in mice, were described. Following the naming scheme for collagens the new genes were designated COL6A4. COL6A5 and COL6A6 encoding the α4(VI), α5(VI) and α6(VI) chains, respectively. This review will focus on the current state of knowledge of the three new chains.

Heritability of articular cartilage regeneration and its association with ear wound healing in mice.

OBJECTIVE: Emerging evidence suggests that genetic components contribute significantly to cartilage degeneration in osteoarthritis pathophysiology, but little information is available on the genetics of cartilage regeneration. Therefore, this study was undertaken to investigate cartilage regeneration in genetic murine models using common inbred strains and a set of recombinant inbred (RI) lines generated from LG/J (healer of ear wounds) and SM/J (nonhealer) inbred mouse strains. METHODS: An acute full-thickness cartilage injury was introduced in the trochlear groove of 8-week-old mice (n=265) through microsurgery. Mouse knee joints were sagittally sectioned and stained with toluidine blue to evaluate regeneration. For the ear wound phenotype, a bilateral 2-mm through-and-through puncture was created in 6-week-old mice (n=229), and healing outcomes were measured after 30 days. Broad-sense heritability and genetic correlations were calculated for both phenotypes. RESULTS: Time-course analysis of the RI mouse lines showed no significant regeneration until 16 weeks after surgery; at that time, the strains could be segregated into 3 categories: good, intermediate, and poor healers. Analysis of heritability (H2) showed that both cartilage regeneration (H2=26%; P=0.006) and ear wound closure (H2=53%; P<0.00001) were significantly heritable. The genetic correlations between the two healing phenotypes for common inbred mouse strains (r=0.92) and RI mouse lines (r=0.86) were found to be extremely high. CONCLUSION: Our findings indicate that articular cartilage regeneration in mice is heritable, the differences between the mouse lines are due to genetic differences, and a strong genetic correlation between the two phenotypes exists, indicating that they plausibly share a common genetic basis. We therefore surmise that LG/J by SM/J intercross mice can be used to dissect the genetic basis of variation in cartilage regeneration.

Vertical habitat stratification in Aedes triseriatus and Aedes hendersoni (Diptera: Culicidae): complications associated with sloped and flood-prone landscapes.

For the sibling mosquito species Aedes triseriatus Say and Ae. hendersoni Cockerell, success of offspring is highly dependent on oviposition site selection by gravid females, and the dynamics of that selection process have been the subject of much investigation. Patterns of vertical oviposition stratification were examined in this study by placing basal and canopy level oviposition traps in relatively steep and flat terrains, as well as in flood-prone riverbank vs upland settings. Strong stratification existed in both steep and flat terrains, with Ae. triseriatus favoring basal ovitraps and Ae. hendersoni favoring canopy ovitraps. Contrary to expectations, Ae. hendersoni displayed even more marked preference for canopy ovitraps in steeper terrain. Both species avoided basal ovitraps in flood-prone locations, where Ae. triseriatus oviposited only in canopy ovitraps and greatly outnumbered Ae. hendersoni in canopy ovitraps. In contrast, the expected stratification was found in nearby upland habitats.

Methods to mitigate Escherichia coli blooms in human ex vivo colon model experiments using the high throughput micro-Matrix bioreactor fermentation system.

Ex vivo colon model experiments are frequently employed as a means to assess the gut microbiome modulating potential of different foods, food ingredients and dietary supplements. A number of useful models already exist; however, they tend to be relatively low in terms of throughput (3-4 samples per experiment) with a long experiment duration of one to a number of weeks. Therefore, a need for a high-throughput system with a short duration time is required to enable screening of large numbers of samples. Therefore, we report here on the development of a system based on the Applikon micro-Matrix bioreactor which has the capacity to run 24 samples with an experiment duration of 48 h. However, Escherichia coli blooms are a common problem encountered in this model. Here, we describe the factors that contribute to such blooms and provide approaches to address them, providing:•Step by step optimisation of processes involved in conducting ex vivo distal colon experiments using the micro-Matrix bioreactor fermentation platform•Recommended steps for users on how to attenuate E. coli blooms in such ex vivo colon model experiments.

Akkermansia muciniphila reduces susceptibility to Listeria monocytogenes infection in mice fed a high-fat diet.

A high-fat (HF) diet reduces resistance to the foodborne pathogen Listeria monocytogenes. We demonstrate that short-term gavage with A. muciniphila increases resistance to oral and systemic L. monocytogenes infection in mice fed a HF diet. A. muciniphila reduced inflammation in the gut and liver of mice fed a high-fat diet prior to infection and reduced inflammatory cell infiltration in the ileum to levels similar to mice fed a low-fat (LF) diet. Akkermansia administration had minimal impacts upon the microbiota and microbial metabolites and did not affect individual taxa or impact the Bacteroidetes to Firmicutes ratio. In summary, A. muciniphila increased resistance to L. monocytogenes infection in mice fed a HF diet by moderating immune/physiological effects through specific interaction between A. muciniphila and the host gut.

Improved gut microbiome recovery following drug therapy is linked to abundance and replication of probiotic strains.

Probiotics have been used for decades to alleviate the negative side-effects of oral antibiotics, but our mechanistic understanding on how they work is so far incomplete. Here, we performed a metagenomic analysis of the fecal microbiota in participants who underwent a 14-d Helicobacter pylori eradication therapy with or without consumption of a multi-strain probiotic intervention (L. paracasei CNCM I-1518, L. paracasei CNCM I-3689, L. rhamnosus CNCM I-3690, and four yogurt strains) in a randomized, double-blinded, controlled clinical trial. Using a strain-level analysis for detection and metagenomic determination of replication rate, ingested strains were detected and replicated transiently in fecal samples and in the gut during and following antibiotic administration. Consumption of the fermented milk product led to a significant, although modest, improvement in the recovery of microbiota composition. Stratification of participants into two groups based on the degree to which their microbiome recovered showed i) a higher fecal abundance of the probiotic L. paracasei and L. rhamnosus strains and ii) an elevated replication rate of one strain (L. paracasei CNCMI-1518) in the recovery group. Collectively, our findings show a small but measurable benefit of a fermented milk product on microbiome recovery after antibiotics, which was linked to the detection and replication of specific probiotic strains. Such functional insight can form the basis for the development of probiotic-based intervention aimed to protect gut microbiome from drug treatments.

Gut Steroids and Microbiota: Effect of Gonadectomy and Sex.

Sex steroids, derived mainly from gonads, can shape microbiota composition; however, the impact of gonadectomy and sex on steroid production in the gut (i.e., gut steroids), and its interaction with microbiota composition, needs to be clarified. In this study, steroid environment and gut steroidogenesis were analysed by liquid chromatography tandem mass spectrometry and expression analyses. Gut microbiota composition as branched- and short-chain fatty acids were determined by 16S rRNA gene sequence analysis and gas chromatography flame ionisation detection, respectively. Here, we first demonstrated that levels of pregnenolone (PREG), progesterone (PROG), and isoallopregnanolone (ISOALLO) were higher in the female rat colon, whereas the level of testosterone (T) was higher in males. Sexual dimorphism on gut steroidogenesis is also reported after gonadectomy. Sex, and more significantly, gonadectomy, affects microbiota composition. We noted that a number of taxa and inferred metabolic pathways were associated with gut steroids, such as positive associations between Blautia with T, dihydroprogesterone (DHP), and allopregnanolone (ALLO), whereas negative associations were noted between Roseburia and T, ALLO, PREG, ISOALLO, DHP, and PROG. In conclusion, this study highlights the novel sex-specific association between microbiota and gut steroids with possible relevance for the gut-brain axis.

Changes in visual receptive fields with microstimulation of frontal cortex.

The influence of attention on visual cortical neurons has been described in terms of its effect on the structure of receptive fields (RFs), where multiple stimuli compete to drive neural responses and ultimately behavior. We stimulated the frontal eye field (FEF) of passively fixating monkeys and produced changes in V4 responses similar to known effects of voluntary attention. Subthreshold FEF stimulation enhanced visual responses at particular locations within the RF and altered the interaction between pairs of RF stimuli to favor those aligned with the activated FEF site. Thus, we could influence which stimulus drove the responses of individual V4 neurons. These results suggest that spatial signals involved in saccade preparation are used to covertly select among multiple stimuli appearing within the RFs of visual cortical neurons.

WARP: A Unique Extracellular Matrix Component of Cartilage, Muscle, and Endothelial Cell Basement Membranes.

The von Willebrand factor A-domain-related protein (WARP) encoded by the VWA1 gene, is an orphan extracellular matrix protein that is expressed in a subset of ECM structures but whose function is poorly understood. Here, recent advances on understanding VWA1/WARP will be reviewed including analysis of VWA1 reporter and global knock-out mice, interaction studies, and recent transcriptome analyses. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.

Applications of CRISPR for musculoskeletal research.

The ability to edit DNA at the nucleotide level using clustered regularly interspaced short palindromic repeats (CRISPR) systems is a relatively new investigative tool that is revolutionizing the analysis of many aspects of human health and disease, including orthopaedic disease. CRISPR, adapted for mammalian cell genome editing from a bacterial defence system, has been shown to be a flexible, programmable, scalable, and easy-to-use gene editing tool. Recent improvements increase the functionality of CRISPR through the engineering of specific elements of CRISPR systems, the discovery of new, naturally occurring CRISPR molecules, and modifications that take CRISPR beyond gene editing to the regulation of gene transcription and the manipulation of RNA. Here, the basics of CRISPR genome editing will be reviewed, including a description of how it has transformed some aspects of molecular musculoskeletal research, and will conclude by speculating what the future holds for the use of CRISPR-related treatments and therapies in clinical orthopaedic practice. Cite this article: Bone Joint Res 2020;9(7):351-359.

A Deep Intronic Variant Activates a Pseudoexon in the MTM1 Gene in a Family with X-Linked Myotubular Myopathy.

We report a novel intronic variant in the MTM1 gene in 4 males in a family with severe X-linked myotubular myopathy. The A>G variant in deep intronic space activates a cryptic 5' donor splice site resulting in the inclusion of a 48-bp pseudoexon into the mature MTM1 mRNA. The variant is present in all affected males, absent in unaffected males, and heterozygous in the mother of the affected males. The included intronic sequence contains a premature stop codon, and experiments using a translational inhibitor indicate that the mutant mRNAs undergo nonsense-mediated decay. We conclude that affected males produce no, or low, levels of MTM1 mRNA likely leading to a significant reduction of myotubularin-1 protein resulting in the severe neonatal myopathy present in this family. The study highlights the need to consider noncoding variants in genomic screening in families with X-linked myotubular myopathy.

Holding and Mobility of Pediatric Patients With Transthoracic Intracardiac Catheters.

BACKGROUND: Nursing care of pediatric patients after cardiac surgery consists of close hemodynamic monitoring, often through transthoracic intracardiac catheters, requiring patients to remain on bed rest and limiting holding and mobility. OBJECTIVES: The primary aim of this quality improvement project was to determine the feasibility of safely mobilizing pediatric patients with transthoracic intracardiac catheters out of bed. Once feasibility was established, the secondary aim was to increase the number of days such patients were out of bed. METHODS AND INTERVENTIONS: New standards and procedures were implemented in July 2015 for pediatric patients with transthoracic intracardiac catheters. After initiation of the new policies, complications were tracked prospectively. Nursing documentation of activity and positioning for all patients with transthoracic intracardiac catheters was extracted from electronic health records for 2 fiscal years before and 3 fiscal years after the new policies were implemented. The Cochran-Armitage test for trend was used to determine whether patterns of out-of-bed documentation changed over time. RESULTS: A total of 1358 patients (approximately 250 to 300 patients each fiscal year) had activity and positioning documented while transthoracic intracardiac catheters were in place. The Cochran-Armitage test for trend revealed that out-of-bed documentation significantly increased after the new policies and procedures were initiated (P < .001). No major complications were noted resulting from patient mobility with transthoracic intracardiac catheters. CONCLUSION: Pediatric patients with transthoracic intracardiac catheters can be safely held and mobilized out of bed.