Miracle-dz/UniFAR-FTUs huggingface dataset:
Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia

Abstract MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.
Multiple Cholesterol Recognition/Interaction Amino Acid Consensus (CRAC) Motifs in Cytosolic C Tail of Slo1 Subunit Determine Cholesterol Sensitivity of Ca2+- and Voltage-gated K+ (BK) Channels*

Background: Cholesterol regulation of large conductance, Ca2+- and voltage-gated K+ (BK) channels has widespread pathophysiological consequences. Results: Cholesterol-channel recognition involves hydrophobic and hydrophilic interactions and several cholesterol recognition/interaction amino acid consensus motifs in the BK channel long C-end. Conclusion: Cholesterol regulation of BK channels involves specific channel protein-sterol recognition. Significance: we provide for the first time the structural basis of BK channel cholesterol sensitivity. Large conductance, Ca2+- and voltage-gated K+ (BK) channel proteins are ubiquitously expressed in cell membranes and control a wide variety of biological processes. Membrane cholesterol regulates the activity of membrane-associated proteins, including BK channels. Cholesterol modulation of BK channels alters action potential firing, colonic ion transport, smooth muscle contractility, endothelial function, and the channel alcohol response. The structural bases underlying cholesterol-BK channel interaction are unknown. Such interaction is determined by strict chemical requirements for the sterol molecule, suggesting cholesterol recognition by a protein surface. Here, we demonstrate that cholesterol action on BK channel-forming Cbv1 proteins is mediated by their cytosolic C tail domain, where we identified seven cholesterol recognition/interaction amino acid consensus motifs (CRAC4 to 10), a distinct feature of BK proteins. Cholesterol sensitivity is provided by the membrane-adjacent CRAC4, where Val-444, Tyr-450, and Lys-453 are required for cholesterol sensing, with hydrogen bonding and hydrophobic interactions participating in cholesterol location and recognition. However, cumulative truncations or Tyr-to-Phe substitutions in CRAC5 to 10 progressively blunt cholesterol sensitivity, documenting involvement of multiple CRACs in cholesterol-BK channel interaction. In conclusion, our study provides for the first time the structural bases of BK channel cholesterol sensitivity; the presence of membrane-adjacent CRAC4 and the long cytosolic C tail domain with several other CRAC motifs, which are not found in other members of the TM6 superfamily of ion channels, very likely explains the unique cholesterol sensitivity of BK channels.
H ∞ approach to T-S fuzzy controller for limiting reconstruction errors

In this article, the reconstruction error between a real system to be controlled and its Takagi–Sugeno (T-S) fuzzy model is considered in the context of control system design. Accordingly, we propose an H ∞ approach to an adaptive controller that consists of two parts: one is obtained by solving certain linear matrix inequalities (fixed part) and the other is acquired using a fuzzy approximator in which the related parameters are tuned by an adaptive law (variable part). The proposed controller can guarantee a convergent and uniformly bounded control state while maintaining the stability of all the signals involved.
"Good Things Come in Lightweights": A Group Decision-Making Analysis Comparing Twitter on Mobile Communication Devices to Computer-Mediated Communication

This paper reports on a study of the effects of Twitter-enabled mobile communication devices on group decision-making and group dynamics. One hundred and sixty-seven university students formed 44 groups under two distinct communication conditions: Twitter operating on mobile communication devices (TMCD), and Google Groups online message boards (OMB) accessed through personal computers. Each group was tracked as it completed an assigned set of group decision-making tasks. The study’s results are analyzed through media synchronicity theory and its distinction between conveyance and convergence communication processes. TMCD exhibited significantly fewer conflicting (unfriendly) messages and a greater number of initiatory messages than OMB. Moreover, with tasks involving convergence communication processes, TMCD achieved significantly higher levels of conformity and satisfaction than OMB. These results imply that lightweight, portable mobile communication devices (MCDs), enabled with Twitter or another similar interface, complement conventional computer-mediated communication, offering an effective means of group decision-making.
Light and pH-induced Changes in Structure and Accessibility of Transmembrane Helix B and Its Immediate Environment in Channelrhodopsin-2*

A variant of the cation channel channelrhodopsin-2 from Chlamydomonas reinhardtii (CrChR2) was selectively labeled at position Cys-79 at the end of the first cytoplasmic loop and the beginning of transmembrane helix B with the fluorescent dye fluorescein (acetamidofluorescein). We utilized (i) time-resolved fluorescence anisotropy experiments to monitor the structural dynamics at the cytoplasmic surface close to the inner gate in the dark and after illumination in the open channel state and (ii) time-resolved fluorescence quenching experiments to observe the solvent accessibility of helix B at pH 6.0 and 7.4. The light-induced increase in final anisotropy for acetamidofluorescein bound to the channel variant with a prolonged conducting state clearly shows that the formation of the open channel state is associated with a large conformational change at the cytoplasmic surface, consistent with an outward tilt of helix B. Furthermore, results from solute accessibility studies of the cytoplasmic end of helix B suggest a pH-dependent structural heterogeneity that appears below pH 7. At pH 7.4 conformational homogeneity was observed, whereas at pH 6.0 two protein fractions exist, including one in which residue 79 is buried. This inaccessible fraction amounts to 66% in nanodiscs and 82% in micelles. Knowledge about pH-dependent structural heterogeneity may be important for CrChR2 applications in optogenetics.
SiRNA-mediated IGF-1R inhibition sensitizes human colon cancer SW480 cells to radiation

Abstract Purpose. Insulin like growth factor receptor 1 (IGF-1R) is well-documented to play a key role in radiation response and tumor radiosensitivity, thus offering an attractive clinic drug target to enhance tumor sensitivity to anti-cancer radiotherapy. Material and methods. Human colon carcinoma SW480 cells were transfected with the specific small interference RNA (siRNA) expression vector (pkD-shRNA-IGF-1R-V2) designed to target IGF-1R mRNA. The expression of IGF-1R mRNA and its protein among the transfected and untransfected cells were detected by semi-quantitative RT-PCR and ELISA assay. The changes in cell radiosensitivity were examined by MTT assay. Results. Transfection of mammalian expression vector pkD containing IGF-1R siRNA was shown to reduce IGF-1R mRNA levels by up to 95%. ELISA assay detected a similar inhibition of IGF-1R protein levels in cells transfected with IGF-1R siRNA. SW480 cells transfected with the expression vector for siRNA significantly rendered cells more sensitive to radiation and the highest radiation enhancement ratio was 2.02 ± 0.08. Conclusion. These data provide the first evidence that specific siRNA fragment (pkD-shRNA-IGF-1R-V2) targeting human IGF-1R mRNA is able to enhance colon cancer radiosensitivity. Also results indicated that, combining IGF-1R siRNA and radiation significantly enhances antitumor efficacy compared with either modality alone.
Genotype–Phenotype Correlations in Iranian Myotonic Dystrophy Type I Patients

Neda Moradin; Mojtaba Azimian; Bahareh Shojasaffar University of Social Welfare and Rehabilitation Sciences, Tehran, Iran Ana Maria Cobo, Centre de Reference Maladies Neuromusculaires GNMH, France Kaveh Alavi, Kariminejad-Najmabadi Pathology & Genetics Center Shahriar Nafisi, Shariati Hospital, Tehran, Iran Mandana Hasanzad, Seyed Mohammad Ebrahim Moosavi, Azadeh Shirazian, Hossein Najmabadi. Kimia Kahrizi University of Social Welfare and Rehabilitation Sciences, Genetics Research Center
Model of EF4-induced ribosomal state transitions and mRNA translocation

EF4, a highly conserved protein present in bacteria, mitochondria and chloroplasts, can bind to both the posttranslocation and pretranslocation ribosomal complexes. When binding to the posttranslocation state, it catalyzes backward translocation to a pretranslocation state. When binding to the pretranslocation state, it catalyzes transition to another pretranslocation state that is similar and possibly identical to that resulting from the posttranslocation state bound by EF4, and competes with EF-G to regulate the elongation cycle. However, the molecular mechanism on how EF4 induces state transitions and mRNA translocation remains unclear. Here, we present both the model for state transitions induced by EF4 binding to the posttranslocation state and that by EF4 binding to the pretranslocation state, based on which we study the kinetics of EF4-induced state transitions and mRNA translocation, giving quantitative explanations of the available experimental data. Moreover, we present some predicted results on state transitions and mRNA translocation induced by EF4 binding to the pretranslocation state complexed with the mRNA containing a duplex region.
The Obstacle-Restriction Method ( ORM ) for Reactive Obstacle Avoidance in Difficult Scenarios in Three-Dimensional

This master’s project addresses the obstacle avoidance problem in difficult scenarios in three-dimensional workspaces. The main contribution of this project is the theoretical extension of the ObstacleRestriction Method (ORM) in two dimensions to work in 3D workspaces. This master’s thesis describes a reactive obstacle avoidance technique to drive a robot in dense, cluttered and complex environments in three-dimensional workspaces. The method has two steps: First a procedure computes instantaneous sub goals in the obstacle structure, second a motion restriction is associated with each obstacle which next are managed to compute the most promising direction of motion. The advantage with the ORM, regarding the obstacle avoidance problem, is that it avoids the problems and limitations common in other obstacle avoidance methods, leading to improved navigation results in difficult scenarios. This is confirmed by simulations made in difficult scenarios in three-dimensional workspaces.
In Vivo Imaging of the Programmed Death Ligand 1 by 18F PET

Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1–binding Affibody molecule NOTA-ZPD-L1_1 with 18F and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. Methods: The affinity of the PD-L1–binding Affibody ligand ZPD-L1_1 was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of 18F-AlF. In vivo studies were performed in PD-L1–positive, PD-L1–negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by γ-counting biodistribution. Immunohistochemical staining with an antibody specific for anti–PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. Results: NOTA-ZPD-L1_1 was labeled, with a radiochemical yield of 15.1% ± 5.6%, radiochemical purity of 96.7% ± 2.0%, and specific activity of 14.6 ± 6.5 GBq/μmol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1–positive tumor, whereas the PD-L1–negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1–positive (percentage injected dose per gram [%ID/g] = 2.56 ± 0.33) and –negative (%ID/g = 0.32 ± 0.05) tumors (P = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Conclusion: Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake.
Workshop: game design for social networks

Game Design for Social Networks is a one-day workshop where the participants will learn about creating and designing game concepts for online social networking platforms, such as Facebook and Twitter. The workshop will center around exercises that enable participants to come up with new game concepts. Participants will also be able to bring existing ideas to the workshop, and have a chance to refine them through the analytical design approaches introduced throughout the day. This paper outlines the theoretical backgrounds of the workshop.
Falling and slipping detection for pedestrians using a manifold learning approach

Falling activity is a critical behavior due to the physical discomfort for elders. The prime time of rescuing is missed whenever falls accidentally happen. Fall detection in real time could save human life in video surveillance systems. Recently, digital cameras are installed everywhere. Human activities are monitored from cameras by intelligent programs. An alarm is sent to the administrator when an abnormal event occurs. In this paper, a multi-view-based manifold learning algorithm is proposed for detecting the falling events. This algorithm should be able to detect people falling down in any direction. First, the walking patterns in a normal speed are modeled by the locality preserving projection (LPP). Since the duration of falling activity is hard to be estimated from real videos, partial temporal windows are matched with the normal walking patterns. The Hausdorff distances are calculated to estimate the similarity. In the experiments, the falling events are effectively detected by the proposed method.
Optical coherence tomography angiography-based capillary velocimetry

Abstract. Challenge persists in the field of optical coherence tomography (OCT) when it is required to quantify capillary blood flow within tissue beds in vivo. We propose a useful approach to statistically estimate the mean capillary flow velocity using a model-based statistical method of eigendecomposition (ED) analysis of the complex OCT signals obtained with the OCT angiography (OCTA) scanning protocol. ED-based analysis is achieved by the covariance matrix of the ensemble complex OCT signals, upon which the eigenvalues and eigenvectors that represent the subsets of the signal makeup are calculated. From this analysis, the signals due to moving particles can be isolated by employing an adaptive regression filter to remove the eigencomponents that represent static tissue signals. The mean frequency (MF) of moving particles can be estimated by the first lag-one autocorrelation of the corresponding eigenvectors. Three important parameters are introduced, including the blood flow signal power representing the presence of blood flow (i.e., OCTA signals), the MF indicating the mean velocity of blood flow, and the frequency bandwidth describing the temporal flow heterogeneity within a scanned tissue volume. The proposed approach is tested using scattering phantoms, in which microfluidic channels are used to simulate the functional capillary vessels that are perfused with the scattering intralipid solution. The results indicate a linear relationship between the MF and mean flow velocity. In vivo animal experiments are also conducted by imaging mouse brain with distal middle cerebral artery ligation to test the capability of the method to image the changes in capillary flows in response to an ischemic insult, demonstrating the practical usefulness of the proposed method for providing important quantifiable information about capillary tissue beds in the investigations of neurological conditions in vivo.
Morphological variation in the ear region of pleistocene elephantimorpha (Mammalia, Proboscidea) from central Texas

A large sample of isolated elephantimorph petrosal bones was recovered from Pleistocene deposits in Friesenhahn Cave, Bexar County, Texas. Morphology of the middle and inner ear of the elephantimorphs is described and variation within the sample is identified. Observed variations occur in the stapedial ratio, morphology of the aquaeductus Fallopii, and connection of the crista interfenestralis to the tympanohyal on the posterior portion of the petrosal to form a foramen for passage of the stapedius muscle. The morphology of the aquaeductus Fallopii supports an ontogenetic explanation for some variation, and a sequence of ossification surrounding the aquaeductus Fallopii, from the anterior end of the canal to the posterior, is hypothesized. The stapedial ratio varies to a high degree across the sample, and such variation should be considered when the ratio is used in phylogenetic analyses. Within the inner ear, the absence of the secondary lamina suggests evolution of low‐frequency hearing in extinct proboscideans, which is known for extant elephants. The morphology of the petrosals from Friesenhahn Cave is compared to published descriptions of the ear regions of other extinct proboscideans, and the distribution and evolution of morphologic characters are discussed. J. Morphol. , 2011. © 2011 Wiley‐Liss, Inc.
Carcinoma-associated fibroblasts affect sensitivity to oxaliplatin and 5FU in colorectal cancer cells

The importance of tumor microenvironment (TME) as a relevant contributor to cancer progression and its role in the development of de novo resistance to targeted therapies has become increasingly apparent. However, the mechanisms of microenvironment-mediated drug resistance for nonspecific conventional chemotherapeutic agents, such as platinum compounds or antimetabolites, are still unclear. Here we describe a mechanism induced by soluble factors released by carcinoma-associated fibroblasts (CAFs) that induce the translocation of AKT, Survivin and P38 to the nucleus of tumor cells. These changes are guided to ensure DNA repair and the correct entrance and exit from mitosis in the presence of chemotherapy. We used conditioned media (CM) from normal-colonic fibroblasts and paired CAFs to assess dose response curves of oxaliplatin and 5-fluorouracil, separately or combined, compared with standard culture medium. We also evaluated a colony-forming assay and cell death to demonstrate the protective role of CAF-CM. Immunofluorescence confirmed the translocation of AKT, P38 and Survivin to the nucleus induced by CAF-soluble factors. We also have shown that STAT3 or P38 inhibition provides a promising strategy for overcoming microenvironment-mediated resistance. Conversely, pharmacologic AKT inhibition induces an antagonistic effect that relieves a cMET and STAT3-mediated compensatory feedback that might explain the failure of AKT inhibitors in the clinic so far.
Rapid Fusion and Syncytium Formation of Heterologous Cells upon Expression of the FGFRL1 Receptor*

The fusion of mammalian cells into syncytia is a developmental process that is tightly restricted to a limited subset of cells. Besides gamete and placental trophoblast fusion, only macrophages and myogenic stem cells fuse into multinucleated syncytia. In contrast to viral cell fusion, which is mediated by fusogenic glycoproteins that actively merge membranes, mammalian cell fusion is poorly understood at the molecular level. A variety of mammalian transmembrane proteins, among them many of the immunoglobulin superfamily, have been implicated in cell-cell fusion, but none has been shown to actively fuse cells in vitro. Here we report that the FGFRL1 receptor, which is up-regulated during the differentiation of myoblasts into myotubes, fuses cultured cells into large, multinucleated syncytia. We used luciferase and GFP-based reporter assays to confirm cytoplasmic mixing and to identify the fusion inducing domain of FGFRL1. These assays revealed that Ig-like domain III and the transmembrane domain are both necessary and sufficient to rapidly fuse CHO cells into multinucleated syncytia comprising several hundred nuclei. Moreover, FGFRL1 also fused HEK293 and HeLa cells with untransfected CHO cells. Our data show that FGFRL1 is the first mammalian protein that is capable of inducing syncytium formation of heterologous cells in vitro.