Miracle-dz/UniFAR-FTUs huggingface dataset:
Dense poly(ethylene glycol) coatings maximize nanoparticle transport across lymphatic endothelial cells and accumulate in the skindraining lymph nodes

Lymphatic vessels have recently been shown to effectively deliver immune modulatory therapies to the lymph nodes, which enhances their therapeutic efficacy. Prior work has shown that lymphatics transport 10–250 nm nanoparticles from peripheral tissues to the lymph node. However, the surface chemistry required to maximize this transport is poorly understood. Here, we determined the effect of surface poly(ethylene glycol) (PEG) density and size on nanoparticle transport across lymphatic endothelial cells (LECs) by differentially PEGylated model polystyrene nanoparticles. Using an established in-vitro lymphatic transport model, we found PEGylation improved the transport of 100 and 40 nm nanoparticles across LECs 50-fold compared to the unmodified nanoparticles and that transport is maximized when the PEG is in a dense brush conformation or high grafting density (Rf/D = 4.9). We also determined that these trends are not size-dependent. PEGylating 40 nm nanoparticles improved transport efficiency across LECs 68-fold compared to unmodified nanoparticles. We also found that PEGylated 100 nm and 40 nm nanoparticles accumulate in lymph nodes within 4 hours after intradermal injection, while unmodified nanoparticles accumulated minimally. Dense PEGylation also led nanoparticles to travel the furthest distance from the injection site. Finally, we determined that nanoparticles are transported via both paracellular and transcellular mechanisms, and that PEG conformation modulates the cellular transport mechanisms. Our results suggest that PEG conformation is crucial to maximize nanoparticle transport across LECs and into lymphatic vessels, making PEG density a crucial design. Optimizing PEG density on nanoparticle formulations has the potential to enhance immunotherapeutic and vaccine outcomes.
Gpa2, a G-Protein α Subunit Required for Hyphal Development in Candida albicans

ABSTRACT Candida albicans is able to respond to environmental changes by inducing a distinct morphological program, which is related to the ability to infect mammalian hosts. Although some of the signal transduction pathways involved in this response are known, it is not clear how the environmental signals are sensed and transmitted to these transduction cascades. In this work, we have studied the function of GPA2, a new gene from C. albicans, which encodes a G-protein α-subunit homologue. We demonstrate that Gpa2 plays an important role in the yeast-hypha dimorphic transition in the response of C. albicans to some environmental inducers. Deletion of both alleles of the GPA2 gene causes in vitro defects in morphological transitions in Spider medium and SLAD medium and in embedded conditions but not in medium containing serum. These defects cannot be reversed by exogenous addition of cyclic AMP. However, overexpression of HST7, which encodes a component of the filament-inducing mitogen-activated protein kinase (MAPK) cascade, bypasses the Gpa2 requirement. We have obtained different gain-of-function and loss-of-function mutant alleles of the GPA2 gene, which we have introduced in several C. albicans genetic backgrounds. Our results indicate that, in response to environmental cues, Gpa2 is required for the regulation of a MAPK signaling pathway.
Productivity, carbon isotope discrimination and leaf traits of trees of Eucalyptus globulus Labill. in relation to water availability

The stand basal area, carbon isotope discrimination (Δ) in tree rings and leaves, leaf area index and leaf traits of trees were measured in 6- to 8-year-old stands of Eucalyptus globulus Labill. across a gradient of rainfall of 600-1400 mm year -1 in south-western Australia to better understand the importance of leaf traits and gas-exchange as determinants of stand productivity. Δ ranged from 17‰ to 21%o. Δ and basal area were highly, positively correlated with each other and the ratio of mean annual rainfall to potential evaporation (PIPE). Leaf area index, soil water holding capacity and leaf nitrogen content were only weakly correlated with basal area. Δ and PIPE were negatively correlated with leaf nitrogen content. A was negatively correlated with leaf density but positively correlated with specific leaf area. This is consistent with the theory that larger leaf nitrogen content and smaller specific leaf area are associated with increased photosynthetic capacity and increased leaf-scale water-use-efficiency, and that A is influenced by mesophyll conductance. It is concluded that canopy conductance is a more important determinant of growth in water-limited conditions than either leaf area index or leaf traits in fertilized stands of E. globulus. Water availability was dictated more by rainfall than soil type.
Identification of a Prognostic 3-Gene Risk Prediction Model for Thyroid Cancer

Objective: We aimed to screen the genes associated with thyroid cancer (THCA) prognosis, and construct a poly-gene risk prediction model for prognosis prediction and improvement. Methods: The HTSeq-Counts data of THCA were accessed from TCGA database, including 505 cancer samples and 57 normal tissue samples. “edgeR” package was utilized to perform differential analysis, and weighted gene co-expression network analysis (WGCNA) was applied to screen the differential co-expression genes associated with THCA tissue types. Univariant Cox regression analysis was further used for the selection of survival-related genes. Then, LASSO regression model was constructed to analyze the genes, and an optimal prognostic model was developed as well as evaluated by Kaplan-Meier and ROC curves. Results: Three thousand two hundred seven differentially expressed genes (DEGs) were obtained by differential analysis and 23 co-expression genes (|COR| > 0.5, P < 0.05) were gained after WGCNA analysis. In addition, eight genes significantly related to THCA survival were screened by univariant Cox regression analysis, and an optimal prognostic 3-gene risk prediction model was constructed after genes were analyzed by the LASSO regression model. Based on this model, patients were grouped into the high-risk group and low-risk group. Kaplan-Meier curve showed that patients in the low-risk group had much better survival than those in the high-risk group. Moreover, great accuracy of the 3-gene model was revealed by ROC curve and the remarkable correlation between the model and patients' prognosis was verified using the multivariant Cox regression analysis. Conclusion: The prognostic 3-gene model composed by GHR, GPR125, and ATP2C2 three genes can be used as an independent prognostic factor and has better prediction for the survival of THCA patients.
Executive dysfunction in different subtypes of vascular cognitive impairment

Objective To investigate the executive function features of different subtypes of vascular cognitive impairment (VCI). Methods Sixty-four subjects with subcortical ischaemic vascular disease (SIVD) presumed by medical history and neuroimaging (cranial MRI) were recruited. The clinical and neuropsychological features of the 4 groups were compared: cognitive normal control (n=25), simple executive impairment of VCI-ND (s-VCI-ND, n=16), multi-domain impairment of VCI-ND (m-VCI-ND, n=26) and vascular dementia (VaD) patients (n=22). All participants underwent neuropsychological tests covering global cognitive function, executive function, memory function, language function and visual spatial skills. The executive tests included 15 independent subtest reflect set shifting, inhibition of prepotent responses, working memory, concept formation and fluency. Results Tower of Hanoi, self ordered pointing test and paced auditory serial addition test were not suitable for identification of VCI-ND because their finish rates were less 50%. Performance of trail making test (216.5±69.3 vs 137.4±37.9), Stroop color words test (115.4±30.1 vs 72.9±17.5), California cards sorting test-Chinese version (1.9±1.4 vs 2.7±1.2)and animal category fluency test(14.2±2.3 vs 17.7±4.4) had significant difference between s-VCI-ND group and cognitive normal control group (t=4.73, 5.72, 2.04 and 3.53, all P<0.05) and these tests were applicable and sensitive assessment tools in all executive tests. Time-consuming index showed more sensitivity than correct index in executive function. Neuropsychological deficits of m-VCI-ND patients showed lower than that of s-VCI-ND group and better than that of VaD patients. It was likely that the m-VCI-ND was a transition state between normal aging and VaD. Conclusion Executive dysfunction of VCI caused by SIVD is short of specificity. Some tests may appear earlier in screening of VCI-ND. Key words: Dementia, vascular; Cognition disorders; Neuropsychological tests
Prion Amyloid Polymorphs – The Tag Might Change It All

Sup35p is a protein from Saccharomyces cerevisiae. It can propagate using a prion-like mechanism, which means that it can recruit non-prion soluble Sup35p into insoluble fibrils. Sup35p is a large protein showing three distinct domains, N, M and an extended globular domain. We have previously studied the conformations of the full-length and truncated NM versions carrying poly-histidine tags on the N-terminus. Comparison with structural data from C-terminally poly-histidine tagged NM from the literature surprisingly revealed discrepancies. Here we investigated fibrils from the untagged, as well as a C-terminally poly-histidine tagged NM construct, using solid-state NMR. We find that the conformation of untagged NM is very close to the N-terminally tagged NM and confirms our previous findings. The C-terminal poly-histidine tag, in contrast, drastically changes the NM fibril structure, and yields data consistent with results obtained previously on this construct. We conclude that the C-terminally located Sup35p globular domain influences the structure of the fibrillar core at the N domain, as previously shown. We further conclude, based on the present data, that small tags on NM C-terminus have a substantial, despite different, impact. Modifications at this remote localization thus shows an unexpected influence on the fibril structure, and importantly also its propensity to induce [PSI+].
Mesoporous Bioactive Glass Nanoparticles Promote Odontogenesis and Neutralize Pathophysiological Acidic pH

Pathophysiological acidic-pH hinders the dental biomaterial-based pulp-dentin regeneration. Bioactive glass (BG) synthesized by sol-gel methods had shown odontogenic and pulp regeneration potential. However, the pathophysiological acidic-pH neutralizing potential of BG has not been tested yet. In this study, we aimed to design mesoporous BG-nanoparticles by a well-established sol-gel method and test its odontogenic and acidic-pH neutralizing potential. BG-nanoparticles were synthesized and further characterized by SEM, EDS, XRD, and FTIR. Mono-dispersed and spherical mesoporous BG-nanoparticles with size 300–500 nm were successfully fabricated. Effect of BG ionic extraction in DMEM with 0.1–2.5 g/L BG concentrations on proliferation and odontogenic differentiation of stem cells from human exfoliated deciduous teeth (SHED) was analyzed. All the BG ionic extractions did not affect SHEDs proliferation at early time points (day 1 and 3). BG ionic extraction 0.5 g/L robustly enhanced odontogenic differentiation of SHEDs, as shown by the expression pattern of ALP, Col1, DSPP, and matrix mineralization results. The chemical composition of the BG ionic extraction-induced mineralized matrix resembled natural dentin. BG-nanoparticles/alginate paste neutralized the butyric acid solution (pH 5.4) and buffered within pH 8.3 for a month. Our findings showed the odontogenic and pathophysiological acidic-pH neutralizing potential of BG-nanoparticles, indicating its possible application in pulp-dentin regeneration under pathophysiologically challenged acidic environment.
FuseGAN: Learning to Fuse Multi-Focus Image via Conditional Generative Adversarial Network

We study the problem of multi-focus image fusion, where the key challenge is detecting the focused regions accurately among multiple partially focused source images. Inspired by the conditional generative adversarial network (cGAN) to image-to-image task, we propose a novel FuseGAN to fulfill the images-to-image for multi-focus image fusion. To satisfy the requirement of dual input-to-one output, the encoder of the generator in FuseGAN is designed as a Siamese network. The least square GAN objective is employed to enhance the training stability of FuseGAN, resulting in an accurate confidence map for focus region detection. Also, we exploit the convolutional conditional random fields technique on the confidence map to reach a refined final decision map for better focus region detection. Moreover, due to the lack of a large-scale standard dataset, we synthesize a large enough multi-focus image dataset based on a public natural image dataset PASCAL VOC 2012, where we utilize a normalized disk point spread function to simulate the defocus and separate the background and foreground in the synthesis for each image. We conduct extensive experiments on two public datasets to verify the effectiveness of the proposed method. Results demonstrate that the proposed method presents accurate decision maps for focus regions in multi-focus images, such that the fused images are superior to 11 recent state-of-the-art algorithms, not only in visual perception, but also in quantitative analysis in terms of five metrics.
RobMixReg: an R package for robust, flexible and high dimensional mixture regression

Motivation Mixture regression has been widely used as a statistical model to untangle the latent subgroups of the sample population. Traditional mixture regression faces challenges when dealing with: 1) outliers and versatile regression forms; and 2) the high dimensionality of the predictors. Here, we develop an R package called RobMixReg, which provides comprehensive solutions for robust, flexible as well as high dimensional mixture modeling. Availability and Implementation RobMixReg R package and associated documentation is available at CRAN: https://CRAN.R-project.org/package=RobMixReg.
Orange is the new white: taxonomic revision of Antarctic Tritonia species (Gastropoda: Nudibranchia)

Among nudibranch molluscs, the family Tritoniidae gathers taxa with unclear phylogenetic position, such as some species of the genus Tritonia Cuvier, 1798. Currently, 35 valid species belong to this genus and only three of them are found in the Southern Ocean, namely T. challengeriana Bergh, 1884, T. dantarti Ballesteros & Avila, 2006, and T. vorax (Odhner, 1926). In this study, we shed light on the long-term discussed systematics and taxonomy of Antarctic Tritonia species using morpho-anatomical and molecular techniques. Samples from the Weddell Sea and Bouvet Island were dissected and prepared for scanning electron microscopy. The three molecular markers COI, 16S, and H3 were sequenced and analysed through maximum likelihood and Bayesian methods. The phylogenetic analyses and species delimitation tests clearly distinguished two species, T. challengeriana and T. dantarti, being widely-spread in the Southern Ocean, and endemic to Bouvet Island, respectively. Coloration seemed to be an unreliable character to differentiate among species since molecular data revealed both species can either have orange or white colour-morphotypes. This variability could be explained by pigment sequestration from the soft coral species they feed on. Morphological analyses reveal differences between Antarctic and Magellanic specimens of T. challengeriana, thus, we suggest the resurrection of T. antarctica Martens & Pfeffer, 1886 to encompass exclusively the Antarctic species. To progress further, additional molecular data from Magellanic specimens are required to definitely resolve their taxonomy and systematics.
PTPN11/SHP2 negatively regulates growth in breast epithelial cells: implications on tumorigenesis

PTPN11/SHP2, a non-receptor protein tyrosine phosphatase is a prominent target of the receptor tyrosine kinase that participates in positive feedback signalling of the human epidermal growth factor receptors and helps in growth and migration. PTPN11/SHP2 is widely believed to be an oncoprotein, although it’s possible tumor-suppressor role is also reported. Our analysis of breast cancer metadata shows, PTPN11/SHP2 copy number loss in luminal A subtype is correlated to poor disease-specific survival and late-stage cancer at diagnosis. Analysis of the level 4 Reverse Phase Protein Array (RPPA) data available on the TCGA database resulted in positive correlations between the lower expression levels of constitutively active variant, the phospho-SHP2-Y542, of PTPN11/SHP2 and larger tumor size and lymph node positivity. We experimentally examined possible negative regulation of growth by PTPN11/SHP2 using MCF10A, a normal breast epithelial cell line. Knock-down of PTPN11/SHP2 resulted in increased cell migration, cell shape changes to mesenchymal morphology, and increased survival in cells treated with epirubicin, a DNA-damaging drug. However, it did not alter the rate of cell proliferation. It is possible that PTPN11/SHP2 might function as a tumor suppressor by potentiating proliferating cells with increased cell migration and resistance to apoptosis. Statement of Significance Molecules like PTPN11/SHP2, among many others that show dual specificity in tumorigenesis in the same tissue depending on the upstream signaling cues, present challenges in the field of targeted drug therapy. This study puts forth the importance of understanding the mechanism of one of the two outcomes and thereby helps better clinical management of a subgroup of cancer.
Single cell transcriptomics reveal disrupted kidney filter cell-cell interactions after early and selective podocyte injury

The health of the kidney filtration barrier requires communication between podocytes, endothelial cells and mesangial cells. Disruption of these cell-cell interactions is thought to contribute to disease progression in chronic kidney diseases (CKD). We recently demonstrated that podocyte ablation via doxycycline-inducible deletion of an essential endogenous molecule, CTCF (iCTCFpod-/-), is sufficient to drive progressive CKD. However, the earliest events connecting podocyte injury to disrupted intercellular communication within the kidney filter remain unclear. Here we performed single-cell RNA sequencing of kidney tissue from iCTCFpod-/- mice after one week of doxycycline induction to generate a map of the earliest transcriptional effects of podocyte injury on cell-cell interactions at single cell resolution. A subset of podocytes showed the earliest signs of injury due to disrupted gene programs for cytoskeletal regulation and mitochondrial function. Surviving podocytes upregulated Col4a5, causing reactive changes in integrin expression in endothelial populations and mesangial cells. Intercellular interaction analysis revealed several receptor-ligand-target gene programs as drivers of endothelial cell injury and abnormal matrix deposition. This analysis reveals the earliest disruptive changes within the kidney filter, pointing to new, actionable targets within a therapeutic window that may allow us to maximize the success of much needed therapeutic interventions for CKD.
A genetic probe for visualizing glutamatergic synapses and vesicles by 3D electron microscopy

Communication between neurons relies on the release of diverse neurotransmitters, which represent a key-defining feature of a neuron’s chemical and functional identity. Neurotransmitters are packaged into vesicles by specific vesicular transporters. However, tools for labeling and imaging synapses and synaptic vesicles based on their neurochemical identity remain limited. We developed a genetically encoded probe to identify glutamatergic synaptic vesicles at the levels of both light and electron microscopy (EM) by fusing the mini singlet oxygen generator (miniSOG) probe to an intra-lumenal loop of the vesicular glutamate transporter-2. We then used a 3D imaging method, serial block face scanning EM, combined with a deep learning approach for automatic segmentation of labeled synaptic vesicles to assess the subcellular distribution of transporter-defined vesicles at nanometer scale. These tools represent a new resource for accessing the subcellular structure and molecular machinery of neurotransmission and for transmitter-defined tracing of neuronal connectivity.
CSPα reduces aggregates and rescues striatal dopamine release in α-synuclein transgenic mice

αSynuclein aggregation at the synapse is an early event in Parkinson’s disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSPα) and αsynuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSPα is a member of the DNAJ/HSP40 family of co-chaperones and like αsynuclein, chaperones the SNARE complex assembly and neurotransmitter release. αSynuclein can rescue neurodegeneration in CSPαKO mice. However, whether αsynuclein aggregation alters CSPα expression and function is unknown. Here we show that αsynuclein aggregation at the synapse induces a decrease in synaptic CSPα and a reduction in the complexes that CSPα forms with HSC70 and STGa. We further show that viral delivery of CSPα rescues in vitro the impaired vesicle recycling in PC12 cells with αsynuclein aggregates and in vivo reduces synaptic αsynuclein aggregates restoring normal dopamine release in 1-120hαsyn mice. These novel findings reveal a mechanism by which αsynuclein aggregation alters CSPα at the synapse, and show that CSPα rescues αsynuclein aggregation-related phenotype in 1-120hαsyn mice similar to the effect of αsynuclein in CSPαKO mice. These results implicate CSPα as a potential therapeutic target for the treatment of early-stage PD.
SLO2.1 and NALCN form a functional complex to modulate myometrial cell excitability

At the end of pregnancy, the uterus transitions from a quiescent state to an excitable, contractile state. These changes are linked to depolarization of the myometrial smooth muscle cell (MSMC) resting membrane potential. The membrane potential is primarily determined by the balance between an outward potassium (K+) leak current and an inward sodium (Na+) leak current. We recently described a Na+-activated K+ channel (SLO2.1) and a non-selective Na+ leak channel (NALCN) in human MSMCs. Here, we asked whether these channels function together. We show that SLO2.1 currents are activated by an inward NALCN-dependent Na+ leak current, leading to MSMC hyperpolarization. The regulation of the membrane potential by NALCN/SLO2.1 activity modulates both Ca2+ entry through VDCCs, and myometrial contractility. Finally, NALCN and SLO2.1 are in proximity to one another in human MSMCs. We conclude that SLO2.1 and NALCN function together to regulate human MSMC membrane potential and excitability.