Neurodegenerative disorders, such as Huntington's diseases and spinocerebellar ataxias (SCAs), are driven by proteins with expanded polyglutamine (polyQ) tracts. Recently, coiled-coil structures in polyQ regions of such proteins were shown to facilitate aggregate formation and ultimately lead to cell death. However, the molecular mechanism linking these structural domains to neuronal toxicity of polyQ proteins remains elusive. Here, we demonstrate that coiled-coil structures in the Q repeat region of SCA type 3 (SCA3) polyQ proteins confer protein toxicity in Drosophila neurons. To functionally characterize coiled-coil structures in the Q repeat regions, we generated three structural variants of SCA3 polyQ proteins: (i) MJDtr-76Q, containing both α-helical coiled-coil and β-sheet hairpin structures in the Q repeat region; (ii) MJDtr-70Q_cc0, possessing only α-helical coiled-coil structures due to the incorporation of β-sheet-breaking residues (Q-to-N or Q-to-E mutations); and (iii) MJDtr-70Q_pQp, with no secondary structure due to the introduced proline residues (Q-to-P mutations). Through comparative analysis of these variants, we found that coiled-coil structures facilitated nuclear localization of SCA3 polyQ proteins and induced dendrite defects in Drosophila dendritic arborization neurons. Furthermore, genetic and functional screening identified the transcription factor Foxo as a target of polyQ proteins, and coiled-coil-mediated interactions of Foxo and polyQ proteins in the nucleus resulted in the observed dendrite and behavioral defects in Drosophila These results demonstrate that coiled-coil structures of polyQ proteins are crucial for their neuronal toxicity, which is conferred through coiled-coil to coiled-coil interactions with the nuclear targets of these proteins.

Polyunsaturated fatty acids (PUFAs) have important industrial, physiological, and nutritional properties. Plants use the sequential activities of FAD2 and FAD3 desaturases to convert 18:1Δ9 to the important PUFA 18:3Δ9,12,15, whereas the fungus Fusarium verticillioides 7600 uses the bifunctional desaturase Fm1 for both reactions. Here, we used a combination of sequence comparisons, structural modeling, and mutagenesis experiments to investigate Fm1's regioselectivity and identified two functionally relevant clusters of residues that contribute to Fm1 activity. We found that cluster I (Leu153, Phe157, and His194), located near the catalytic iron ions, predominantly affects activity, whereas cluster II (Tyr280, His284, and Leu287), located in a helix forming the entrance to the substrate-binding pocket, mainly specifies 15-desaturation. Individual or combined substitutions of cluster II residues substantially reduced 15-desaturation. The combination of F157W from cluster I with Y280L, H284V, and L287T from cluster II created an increased-activity variant that almost completely lost the ability to desaturate at C15 and acted almost exclusively as a 12-desaturase. No variants were identified in which 15-desaturation occurred in the absence of 12-desaturation. Fm1 displayed only traces of activity with C16 substrate, but several cluster I variants exhibited increased activity with both 18:1 and 16:1 substrates, converting 16:1Δ9 to 16:3Δ9,12,15, consistent with Fm1 performing sequential v + 3 desaturation reactions at C12 and then C15. We propose that cluster II residues interact with the substrate headgroup when the acyl chain contains both Δ9 and Δ12 double bonds, in which case C15 becomes positioned adjacent to the di-iron site enabling a second v + 3 desaturation.

Kenya has a rich mammalian fauna. We reviewed recently published books and papers including the six volumes of Mammals of Africa to develop an up-to-date annotated checklist of all mammals recorded from Kenya. A total of 390 species have been identified in the country, including 106 species of rodents, 104 species of bats, 63 species of even-toed ungulates (including whales and dolphins), 36 species of insectivores and carnivores, 19 species of primates, five species of elephant shrews, four species of hyraxes and odd-toed ungulates, three species of afrosoricids, pangolins, and hares, and one species of aardvark, elephant, sirenian and hedgehog. The number of species in this checklist is expected to increase with additional surveys and as the taxonomic status of small mammals (e.g., bats, shrews and rodents) becomes better understood.

To understand neural circuits that control limbs, one must measure their activity during behavior. Until now this goal has been challenging, because limb premotor and motor circuits have been largely inaccessible for large-scale recordings in intact, moving animals-a constraint that is true for both vertebrate and invertebrate models. Here, we introduce a method for 2-photon functional imaging from the ventral nerve cord (VNC) of behaving adult Drosophila melanogaster. We use this method to reveal patterns of activity across nerve cord populations during grooming and walking and to uncover the functional encoding of moonwalker ascending neurons (MANs), moonwalker descending neurons (MDNs), and a previously uncharacterized class of locomotion-associated A1 descending neurons. Finally, we develop a genetic reagent to destroy the indirect flight muscles and to facilitate experimental access to the VNC. Taken together, these approaches enable the direct investigation of circuits associated with complex limb movements.

Visual neurons respond more vigorously to an attended stimulus than an unattended one. How the brain prepares for response gain in anticipation of that stimulus is not well understood. One prominent proposal is that anticipation is characterized by gain-like modulations of spontaneous activity similar to gains in stimulus responses. Here we test an alternative idea: anticipation is characterized by a mixture of both increases and decreases of spontaneous firing rates. Such a strategy would be adaptive as it supports a simple linear scheme for disentangling internal, modulatory signals from external, sensory inputs. We recorded populations of V4 neurons in monkeys performing an attention task, and found that attention states are signaled by different mixtures of neurons across the population in the presence or absence of a stimulus. Our findings support a move from a stimulation-invariant account of anticipation towards a richer view of attentional modulation in a diverse neuronal population.

We have previously reported that microRNA-10 family could disturb normal development of granulosa cells (GC) during follicle formation. In the current study, the effect of miR-10a on granulosa cell tumor (GCT), a subtype of ovarian cancer, was examined. Strong miR-10a signal was detected in tissues from malignant GCT patients. Forced expression of miR-10a significantly promoted cell proliferation, migration, invasion, ovarian hormone production, and repressed anticancer drug-induced apoptosis in vitro. The oncogenic role of miR-10a was further validated in an orthotopic GCT model in vivo. In addition, by using CRISPR-Cas9 system, the aggressive phenotype was repressed in miR-10a knockout cancer GC. By using a heterotopic mice model, the oncogenic role of miR-10a was confirmed in vivo. RNA-seq, FISH, western blot, luciferase reporter assay were used to identified PTEN, a well-known anti-GCT gene, as direct functional target of miR-10a in cancer GC; Akt and Wnt were also found as two associated oncogenic pathways of miR-10a in cancer GC. Taken together, our results demonstrate that the miR-10a could promote GCT development via synergistically regulating PTEN, Akt, and Wnt pathways.

Robust proliferation and apoptosis inhibition of tumor cells are responsible for the high mortality and poor outcome of patients with high-grade gliomas. miR-29a/b/c have been reported to be important suppressors in several human tumor types. However, their exact roles in gliomagenesis and their relevance to patient prognosis remain unclear. In this study, using 187 human glioma specimens and 20 nontumoral brain tissues, we demonstrated that the expression of miR-29a/b/c decreased progressively as the grade of glioma and the Ki-67 index increased. However, the expression of TRAF4, the functional target of miR-29a/b/c, exhibited the inverse trend, and its level was inversely correlated with the levels of miR-29a/b/c. A Kaplan-Meier analysis demonstrated that the miR-29a/b/c and TRAF4 levels were closely associated with patient survival even in patients with the same tumor grade and identical IDH gene status. A functional study verified that miR-29a/b/c induced apoptosis and suppressed the proliferation of glioma cells by directly targeting TRAF4. An investigation of the mechanism revealed that miR-29a/b/c promoted apoptosis through the TRAF4/AKT/MDM2 pathway in a p53-dependent manner, while miR-29a/b/c induced G1 arrest and inhibited tumor cell proliferation by blocking the phosphorylation of AKT and GSK-3β, and the expression of cyclin D1 and c-Myc. Furthermore, TRAF4-knockdown perfectly simulated the anti-glioma effects of miR-29a/b/c. These findings enrich our understanding of gliomagenesis, highlight the prognostic value of miR-29a/b/c and TRAF4, and imply their potential therapeutic roles in malignant gliomas.

Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. We show that testicular endothelial cells (TECs) are part of the SSC niche producing glial cell line-derived neurotrophic factor (GDNF) and other factors to support human and mouse SSCs in long-term culture. We demonstrate that FGF-2 binding to FGFR1 on TECs activates the calcineurin pathway to produce GDNF. Comparison of the TEC secretome to lung and liver endothelial cells identified 5 factors sufficient for long-term maintenance of human and mouse SSC colonies in feeder-free cultures. Male cancer survivors after chemotherapy are often infertile since SSCs are highly susceptible to cytotoxic injury. Transplantation of TECs alone restores spermatogenesis in mice after chemotherapy-induced depletion of SSCs. Identifying TECs as a niche population necessary for SSC self-renewal may facilitate fertility preservation for prepubertal boys diagnosed with cancer.

The liver is the largest solid organ in the body and is critical for metabolic and immune functions. However, little is known about the cells that make up the human liver and its immune microenvironment. Here we report a map of the cellular landscape of the human liver using single-cell RNA sequencing. We provide the transcriptional profiles of 8444 parenchymal and non-parenchymal cells obtained from the fractionation of fresh hepatic tissue from five human livers. Using gene expression patterns, flow cytometry, and immunohistochemical examinations, we identify 20 discrete cell populations of hepatocytes, endothelial cells, cholangiocytes, hepatic stellate cells, B cells, conventional and non-conventional T cells, NK-like cells, and distinct intrahepatic monocyte/macrophage populations. Together, our study presents a comprehensive view of the human liver at single-cell resolution that outlines the characteristics of resident cells in the liver, and in particular provides a map of the human hepatic immune microenvironment.

The oxygen consumption rate (OCR) and cytochrome c oxidase (CcO) activity of respiratory complex IV (CIV) in brain mitochondria significantly decline in middle-aged male mice compared to younger male mice. To explore the mechanisms underlying the regulation of brain mitochondrial function, we examined CIV-associated proteins, and identified actin inside the isolated brain mitochondria. Inhibiting actin polymerization using cytochalasin B (CB) significantly enhanced the OCR and CcO activity of CIV in the mitochondria. These changes were accompanied by a significant reduction in the amount of CIV-bound cytochrome c (cyt c). Actin was also associated with respiratory complex III (CIII); however, the amount of CIII-bound cyt c increased significantly after treatment of the mitochondria with CB. In contrast, no significant alteration in the assembly or the CcO activity of CIV in CIV-containing supercomplexes or CIV monomers was induced by CB. These results suggest that mitochondrial actin plays a crucial role in the regulation of the CcO activity and OCR of CIV with modification of the retention of cyt c between CIV and CIII.

Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by modulating amyloid-β pathology. APOE ε4 is also shown to exacerbate neurodegeneration and neuroinflammation in a tau transgenic mouse model. To further evaluate the association of APOE genotype with the presence and severity of tau pathology, we express human tau via an adeno-associated virus gene delivery approach in human APOE targeted replacement mice. We find increased hyperphosphorylated tau species, tau aggregates, and behavioral abnormalities in mice expressing APOE ε2/ε2. We also show that in humans, the APOE ε2 allele is associated with increased tau pathology in the brains of progressive supranuclear palsy (PSP) cases. Finally, we identify an association between the APOE ε2/ε2 genotype and risk of tauopathies using two series of pathologically-confirmed cases of PSP and corticobasal degeneration. Our data together suggest APOE ε2 status may influence the risk and progression of tauopathy.

The Hippo pathway is involved in intestinal epithelial homeostasis with Wnt, BMP, Notch, and EGF signaling. We investigated the relationship between Hippo and other signaling pathways and the role of MOB kinase activator 1A/1B (MOB1A/B) in intestinal homeostasis. Mice with intestinal epithelial cell (IEC)-specific depletion of MOB1A/B showed hyperproliferation in IECs, defects in secretory lineage differentiation and loss of intestinal stem cells and eventually died at 10-12 days after tamoxifen treatment. In MOB1A/B-depleted IECs, expression of Wnt target genes were downregulated but Bmp2 and Tgfbr2 were transcriptionally activated with enhanced YAP activity. In in vivo and in vitro experiments with several signaling inhibitors, it has been shown that the BMP inhibitor LDN193189 or TGF-β inhibitor SB431542 had effects on partial restoration of the intestinal degenerative phenotype. Treatment with these inhibitors restored differentiation of secretory lineage cells in MOB1A/B-deficient mice, but not ISC pools in the crypt region. These studies reveal that IEC-specific depletion of MOB1A/B induced overexpression of Bmp2 and Tgfbr2 and inhibited Wnt activity, finally leading to loss of ISCs and functional epithelia in the mouse intestine. These results suggest that MOB1A/B has an essential function for intestinal epithelial homeostasis by regulating YAP, Wnt activity, and BMP/TGF-β signaling.

A new type of all-solid, photonic bandgap fiber exhibiting a wavelength dependent guidance mechanism and second harmonic generation capabilities is presented. A silica glass microstructured optical fiber was infiltrated with 2-methyl 4-nitroaniline for creating the composite material optical fiber. This optical fiber was characterized over a broad wavelength range, revealing that a transition from photonic bandgap guidance to modified total internal reflection propagation occurs from short to longer wavelengths, attributed to the dispersion characteristics of the low Abbe number nitroaniline. Annealing post-processing was used for tuning the morphology of the solidified nitroaniline inside the capillaries of the silica glass microstructured optical fiber which increased the extinction ratio of the transmission bandgaps. This composite material optical fiber also exhibits second harmonic generation capabilities under 1064 nm laser excitation, with conversion characteristics dependent upon the packing of the nitroaniline inside the optical fiber capillaries. As the pump and generated light fall into different guidance regimes of the optical fiber, such a device could be potentially used as an all optical gate or light conversion device.

Studies on the microbial communities in non-human primate hosts provide unique insights in both evolution and function of microbes related to human health and diseases. Using 16S rRNA gene amplicon profiling, we examined the oral, anal and vaginal microbiota in a group of non-captive rhesus macaques (N = 116) and compared the compositions with the healthy communities from Human Microbiome Project. The macaque microbiota was dominated by Bacteroidetes, Firmicutes and Proteobacteria; however, there were marked differences in phylotypes enriched across body sites indicative of strong niche specialization. Compared to human gut microbiota where Bacteroides predominately enriched, the surveyed macaque anal community exhibited increased abundance of Prevotella. In contrast to the conserved human vaginal microbiota extremely dominated by Lactobacillus, the macaque vaginal microbial composition was highly diverse while lactobacilli were rare. A constant decrease of the vaginal microbiota diversity was observed among macaque samples from juvenile, adult without tubectomy, and adult with tubectomy, with the most notable distinction being the enrichment of Halomonas in juvenile and Saccharofermentans in contracepted adults. Both macaque and human oral microbiota were colonized with three most common oral bacterial genera: Streptococcus, Haemophilus and Veillonella, and shared relatively conserved communities to each other. A number of bacteria related to human pathogens were consistently detected in macaques. The findings delineate the range of structure and diversity of microbial communities in a wild macaque population, and enable the application of macaque as an animal model for future characterization of microbes in transmission, genomics and function.

Amyloid precursor protein (APP) is ubiquitously expressed in various types of cells including bone cells. Mutations in App gene result in early-onset Alzheimer's disease (AD). However, little is known about its physiological function in bone homeostasis. Here, we provide evidence for APP's role in promoting bone formation. Mice that knocked out App gene (APP-/-) exhibit osteoporotic-like deficit, including reduced trabecular and cortical bone mass. Such a deficit is likely due in large to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption was detected in the mutant mice. Further mechanical studies of APP-/- OBs showed an impairment in mitochondrial function, accompanied with increased reactive oxygen species (ROS) and apoptosis. Intriguingly, these deficits, resemble to those in Tg2576 animal model of AD that expresses Swedish mutant APP (APPswe), were diminished by treatment with an anti-oxidant NAC (n-acetyl-l-cysteine), uncovering ROS as a critical underlying mechanism. Taken together, these results identify an unrecognized physiological function of APP in promoting OB survival and bone formation, implicate APPswe acting as a dominant negative factor, and reveal a potential clinical value of NAC in treatment of AD-associated osteoporotic deficits.

Long-noncoding RNAs (lncRNAs) have been shown to participate in oncogenesis across a variety of cancers and may represent novel therapeutic targets. However, little is known about the role of lncRNAs in basal-like breast cancer (BLBC), the aggressive form of breast cancer with no molecularly defined therapeutic target. To examine whether altered lncRNA expression contributes to the aggressive phenotype characteristic of BLBC, we performed a comparative analysis of BLBC versus non-BLBC using microarray profiling and RNA sequencing of primary breast cancer. We identified RP11-19E11.1 as a significantly up-regulated lncRNA in BLBC tumors and named it Basal-Like breast cancer Associated Transcript 1 (BLAT1). Analysis of pan-cancer datasets showed the highest expression of BLAT1 in BLBC tumors compared to all other cancers. Depletion of BLAT1 in breast cancer cells led to significantly increased apoptosis, partly because of accumulation of DNA damage. Mechanistically, BLAT1 expression is regulated at the epigenetic level via DNA methylation at CpG islands in the promoter. Concordantly, patients harboring tumors with BLAT1 hypomethylation showed decreased overall survival. Our results suggest that increased expression of BLAT1 via CpG site hypomethylation may contribute to the aggressive phenotype of BLBC, raising a possibility of new biomarkers for prognosis of aggressive BLBC tumors.

Magnetic resonance imaging (MRI) studies have demonstrated that patients with myotonic dystrophy type 1 (DM1) exhibit gray and white matter abnormalities that are correlated with various genetic and neuropsychological measures. However, few MRI studies have focused on the correlations between brain abnormalities and overall motor function including gait performance. Here, we investigated the correlations between brain abnormalities, as assessed with MRI including diffusion tensor imaging (DTI), and motor performance, as assessed with the Medical Research Council sum score (MRCSS), 6-minute walk test (6MWT), and hand grip power, in patients with DM1. Eighteen patients with DM1 and twenty healthy controls participated in this study. The MRCSS and 6MWT reflect patients' general motor performance, particularly gait, while hand grip reflects the presence of myotonia. We found significant relationships between DTI parameters in the corticospinal tract (CST) and genetic factors and motor performance in patients with DM1. These findings suggest that CST involvement reflecting deterioration of the motor tracts may play a significant role in clinical myotonia. Further, a direct relationship between the cortical gray matter volume and DTI measures in the CST suggests that white matter abnormalities in the CST are strongly associated with volume reductions in the sensorimotor cortex of patients with DM1.

Data on the diversity and relative abundance of elasmobranchs (sharks and rays) in the Arabian Gulf have been limited to fishery-dependent monitoring of landing sites. Understanding the diversity and abundance of sharks and rays is, however, crucial to inform policy and management plans. Baited Remote Underwater Video Surveys (BRUVS) were conducted in 2015-2016 across the United Arab Emirates Arabian Gulf waters encompassing a range of depths and habitat types. Data from 278 BRUVS (757 hours soak time) were analysed to gather information on diversity, relative abundance, species distribution, and habitat associations. Surveys recorded 213 individuals from 20 species of sharks and rays at 129 stations. The frequency of occurrence of species usually discarded by fishers such as the Arabian carpetshark (Chiloscyllium arabicum) and stingrays (Himantura spp.) was high, accounting for 60.5% of observed elasmobranchs. Despite the large survey area covered and extensive sampling effort, the relative abundance of sharks and rays was low at 0.28 elasmobranchs per hour, 0.13 sharks per hour, and 0.15 rays per hour. This CPUE was reduced to one of lowest recorded abundance on BRUVS from around the world when removing the two discarded species from the analysis (0.11 elasmobranchs per hour). These results likely reflect the intense fishing pressure and habitat loss contributing to population declines of many elasmobranchs in the Arabian Gulf. Findings provide a baseline for future work and can support the design of conservation strategies for sharks and rays in the UAE.

Animals strategically scan the environment to form an accurate perception of their surroundings. Here we investigated the neuronal representations that mediate this behavior. Ca2+ imaging and selective optogenetic manipulation during an active sensing task reveals that layer 5 pyramidal neurons in the vibrissae cortex produce a diverse and distributed representation that is required for mice to adapt their whisking motor strategy to changing sensory cues. The optogenetic perturbation degraded single-neuron selectivity and network population encoding through a selective inhibition of active dendritic integration. Together the data indicate that active dendritic integration in pyramidal neurons produces a nonlinearly mixed network representation of joint sensorimotor parameters that is used to transform sensory information into motor commands during adaptive behavior. The prevalence of the layer 5 cortical circuit motif suggests that this is a general circuit computation.

To evaluate the long-term predictability, stability, safety, and efficacy of the V4c Visian implantable collamer lens (ICL) with central hole to correct myopia.