Miracle-dz/UniFAR-FTUs huggingface dataset:
Heparan Sulfate Facilitates FGF and BMP Signaling to Drive Mesoderm Differentiation of Mouse Embryonic Stem Cells*

Background: HS has been implicated in regulating ESC differentiation. Results: Mouse ESCs lacking EXT1 fail to differentiate into mesoderm. Restoration of the FGF and BMP signaling each partially rescued the mesoderm differentiation defect. Conclusion: HS facilitates FGF and BMP signaling to drive mesoderm differentiation. Significance: This study shows that HS essentially promotes mesoderm differentiation of mouse ESCs. Heparan sulfate (HS) has been implicated in regulating cell fate decisions during differentiation of embryonic stem cells (ESCs) into advanced cell types. However, the necessity and the underlying molecular mechanisms of HS in early cell lineage differentiation are still largely unknown. In this study, we examined the potential of EXT1−/− mouse ESCs (mESCs), that are deficient in HS, to differentiate into primary germ layer cells. We observed that EXT1−/− mESCs lost their differentiation competence and failed to differentiate into Pax6+-neural precursor cells and mesodermal cells. More detailed analyses highlighted the importance of HS for the induction of Brachyury+ pan-mesoderm as well as normal gene expression associated with the dorso-ventral patterning of mesoderm. Examination of developmental cell signaling revealed that EXT1 ablation diminished FGF and BMP but not Wnt signaling. Furthermore, restoration of FGF and BMP signaling each partially rescued mesoderm differentiation defects. We further show that BMP4 is more prone to degradation in EXT1−/− mESCs culture medium compared with that of wild type cells. Therefore, our data reveal that HS stabilizes BMP ligand and thereby maintains the BMP signaling output required for normal mesoderm differentiation. In summary, our study demonstrates that HS is required for ESC pluripotency, in particular lineage specification into mesoderm through facilitation of FGF and BMP signaling.
Processing of emotional stimuli is reflected by modulations of beta band activity in the subgenual anterior cingulate cortex in patients with treatment resistant depression.

Deep brain stimulation (DBS) of the subgenual anterior cingulate cortex (sgACC) has emerged as a new therapeutic option in patients with treatment resistant depression (TRD). At the same time, DBS offers a unique opportunity as an innovative research tool to study brain function in vivo Indirect measures of brain function such as positron-emission-tomography imaging findings have revealed a hypermetabolism in the sgACC area in patients with TRD that normalizes in parallel with treatment response to DBS. We used direct intracranial recordings via implanted DBS electrodes to study the neuronal oscillatory activity in the sgACC area during a picture viewing task including emotional and neutral stimuli in eight patients with TRD who underwent DBS.We found a stimulus-induced decrease in beta-band and increase in gamma-band activity, with a main effect of valence for event-related desynchronisation in the beta-frequency range (14-30 Hz). Unpleasant stimuli induced the strongest and most sustained beta-power decrease. The degree of beta-band modulation upon emotional stimuli correlated with the patients' rating of stimulus valence. Our findings confirm the involvement of the sgACC area in emotional processing that was more enhanced for unpleasant stimuli. Moreover, stimulus evaluation may be encoded by modulations of beta-band activity.
Disentangling the roles of arousal and amygdala activation in emotional declarative memory.

A large body of evidence in animals and humans implicates the amygdala in promoting memory for arousing experiences. Although the amygdala can trigger threat-related noradrenergic-sympathetic arousal, in humans amygdala activation and noradrenergic-sympathetic arousal do not always concur. This raises the question how these two processes play a role in enhancing emotional declarative memory. This study was designed to disentangle these processes in a combined subsequent-memory/fear-conditioning paradigm with neutral items belonging to two conceptual categories as conditioned stimuli. Functional MRI, skin conductance (index of sympathetic activity), and pupil dilation (indirect index of central noradrenergic activity) were acquired throughout procedures. Recognition memory for individual items was tested 24 h later. We found that pupil dilation and skin conductance responses were higher on CS+ (associated with a shock) compared with CS- trials, irrespective of later memory for those items. By contrast, amygdala activity was only higher for CS+ items that were later confidently remembered compared with CS+ items that were later forgotten. Thus, amygdala activity and not noradrenergic-sympathetic arousal, predicted enhanced declarative item memory. This dissociation is in line with animal models stating that the amygdala integrates arousal-related neuromodulatory changes to alter mnemonic processes elsewhere in the brain.
The Small GTPase RhoA Regulates the Contraction of Smooth Muscle Tissues by Catalyzing the Assembly of Cytoskeletal Signaling Complexes at Membrane Adhesion Sites*

Background: RhoA GTPase regulates airway smooth muscle (SM) contraction and actin polymerization by an unknown mechanism. Results: Agonist stimulation induces the RhoA-dependent recruitment of paxillin, vinculin, FAK, and cdc42 GEFs to adhesomes, which catalyze cdc42 and N-WASP activation. Conclusion: RhoA regulates actin polymerization and SM contraction by regulating the adhesome assembly. Significance: Rho-mediated adhesome assembly is a novel mechanism for the regulation of agonist-induced SM contraction. The activation of the small GTPase RhoA is necessary for ACh-induced actin polymerization and airway smooth muscle (ASM) contraction, but the mechanism by which it regulates these events is unknown. Actin polymerization in ASM is catalyzed by the actin filament nucleation activator, N-WASp and the polymerization catalyst, Arp2/3 complex. Activation of the small GTPase cdc42, a specific N-WASp activator, is also required for actin polymerization and tension generation. We assessed the mechanism by which RhoA regulates actin dynamics and smooth muscle contraction by expressing the dominant negative mutants RhoA T19N and cdc42 T17N, and non-phosphorylatable paxillin Y118/31F and paxillin ΔLD4 deletion mutants in SM tissues. Their effects were evaluated in muscle tissue extracts and freshly dissociated SM cells. Protein interactions and cellular localization were analyzed using proximity ligation assays (PLA), immunofluorescence, and GTPase and kinase assays. RhoA inhibition prevented ACh-induced cdc42 activation, N-WASp activation and the interaction of N-WASp with the Arp2/3 complex at the cell membrane. ACh induced paxillin phosphorylation and its association with the cdc42 GEFS, DOCK180 and α/βPIX. Paxillin tyrosine phosphorylation and its association with βPIX were RhoA-dependent, and were required for cdc42 activation. The ACh-induced recruitment of paxillin and FAK to the cell membrane was dependent on RhoA. We conclude that RhoA regulates the contraction of ASM by catalyzing the assembly and activation of cytoskeletal signaling modules at membrane adhesomes that initiate signaling cascades that regulate actin polymerization and tension development in response to contractile agonist stimulation. Our results suggest that the RhoA-mediated assembly of adhesome complexes is a fundamental step in the signal transduction process in response to agonist -induced smooth muscle contraction.
Improving communication of research findings: identifying the sources of information most important to national disease control officers in low‐ and middle‐income countries

Major global health initiatives have brought new opportunities and increased funding for health programmes in countries tackling diseases, such as malaria, tuberculosis (TB), and HIV/AIDS. However, to deploy these investments effectively, health programme managers need much better access to research that assesses the advantages and disadvantages of different strategies. Communicating key findings via the sources of information that health officials use and trust helps to maximise the impact of research on policy and practice. We contacted heads of communicable disease programmes in six countries to ask them about their most important and most frequently used sources of information, as well as the source of information behind their most recent policy change. African respondents particularly emphasised the importance of the World Health Organization (WHO) to influence policy, as well as some mention of international donors. Asian respondents, however, reported being guided much more by in‐country information and surveillance. ‘Most recent’ policy changes having to do with drug treatments (particularly for malaria, but also in one TB policy) were influenced by the WHO, while other TB and HIV policy changes drew on wider sources of information, depending on the nature of the policy change considered (e.g. service structure, treatment approach or populations targeted). Our approach illustrates a first step many researchers may wish to engage in to help guide dissemination strategies to maximise potential research uptake.
The Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid

Background: Apicularen is a specific V-ATPase inhibitor that binds to the VO complex of the holoenzyme. Results: Apicularen binds at the interface of the VO subunits a and c. Conclusion: The binding site for apicularen is in the vicinity of those for bafilomycin and archazolid. Significance: We propose the first model of binding site arrangement for these three classes of V-ATPase inhibitors. The investigation of V-ATPases as potential therapeutic drug targets and hence of their specific inhibitors is a promising approach in osteoporosis and cancer treatment because the occurrence of these diseases is interrelated to the function of the V-ATPase. Apicularen belongs to the novel inhibitor family of the benzolactone enamides, which are highly potent but feature the unique characteristic of not inhibiting V-ATPases from fungal sources. In this study we specify, for the first time, the binding site of apicularen within the membrane spanning VO complex. By photoaffinity labeling using derivatives of apicularen and of the plecomacrolides bafilomycin and concanamycin, each coupled to 14C-labeled 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid, we verified that apicularen binds at the interface of the VO subunits a and c. The binding site is in the vicinity to those of the plecomacrolides and of the archazolids, a third family of V-ATPase inhibitors. Expression of subunit c homologues from Homo sapiens and Manduca sexta, both species sensitive to benzolactone enamides, in a Saccharomyces cerevisiae strain lacking the corresponding intrinsic gene did not transfer this sensitivity to yeast. Therefore, the binding site of benzolactone enamides cannot be formed exclusively by subunit c. Apparently, subunit a substantially contributes to the binding of the benzolactone enamides.
Cross-sectional and longitudinal relationships between insight and attitudes toward medication and clinical outcomes in chronic schizophrenia.

BACKGROUND We evaluated the cross-sectional and longitudinal association of measures of both insight and attitudes toward medication to outcomes that included psychopathology and community functioning. METHODS Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) was a large 18-month follow-up study pharmacotherapy of people with schizophrenia. Insight was measured using the Insight and Treatment Attitudes Questionnaire and attitudes toward medication by the Drug Attitude Inventory. Widely known scales were used to assess symptoms of schizophrenia and depression and community functioning. Medication adherence was globally assessed by the treating psychiatrist using several sources of information. Bivariate correlations and mixed model regression analyses were used to test the relationship of insight and medication attitudes to outcomes at baseline and during the follow-up period. Regression models were used to evaluate the relationship between change in insight and medication attitudes and changes outcomes. RESULTS There was a significant relationship at baseline between insight and drug attitudes and symptoms of schizophrenia and depression, as well as with community functioning. Higher levels of insight at baseline were significantly associated with lower levels of schizophrenia symptoms at follow-up while more positive medication attitudes were significantly associated with both lower symptom levels and better community functioning. Change in insight scores over time was associated with declining schizophrenia symptoms but increasing levels of depression. Change toward more positive medication attitudes was associated, independently of changes in insight, with significant decreases in psychopathology, improvement in community functioning, and greater medication compliance. CONCLUSION Greater patient understanding of their illness and more positive attitudes toward medication may improve outcomes. Educational interventions that affect these attitudes may be an important part of psychosocial rehabilitation and/or recovery-oriented services.
A Novel Mechanism Involving Four-and-a-half LIM Domain Protein-1 and Extracellular Signal-regulated Kinase-2 Regulates Titin Phosphorylation and Mechanics*

Background: Titin is critical for cardiac muscle function; however, limited knowledge exists of mechanisms important for its regulation. Results: A four-and-a-half LIM domain protein-1/extracellular signal-regulated kinase-2-associated complex modulates titin-N2B levels, phosphorylation, and mechanics. Conclusion: We reveal new mechanisms underlying titin mechano-signaling. Significance: We advance our understanding of how titin-associated complexes/mutations can impact cardiac muscle function and disease. Understanding mechanisms underlying titin regulation in cardiac muscle function is of critical importance given recent compelling evidence that highlight titin mutations as major determinants of human cardiomyopathy. We previously identified a cardiac biomechanical stress-regulated complex at the cardiac-specific N2B region of titin that includes four-and-a-half LIM domain protein-1 (Fhl1) and components of the mitogen-activated protein signaling cascade, which impacted muscle compliance in Fhl1 knock-out cardiac muscle. However, direct regulation of these molecular components in mediating titin N2B function remained unresolved. Here we identify Fhl1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics. We specifically identify titin N2B as a novel substrate of extracellular signal regulated-kinase-2 (Erk2) and demonstrate that Fhl1 directly interferes with Erk2-mediated titin-N2B phosphorylation. We highlight the critical region in titin-N2B that interacts with Fhl1 and residues that are dependent on Erk2-mediated phosphorylation in situ. We also propose a potential mechanism for a known titin-N2B cardiomyopathy-causing mutation that involves this regulatory complex. These studies shed light on a novel mechanism regulating titin-N2B mechano-signaling as well as suggest that dysfunction of these pathways could be important in cardiac disease states affecting muscle compliance.
Toad Heart Utilizes Exclusively Slow Skeletal Muscle Troponin T

Background: The heart of dry land toads has adapted to sustain circulation in a wide range of body fluid changes. Results: The toad cardiac muscle expresses exclusively slow skeletal troponin T with cardiac forms of other myofilament proteins and exhibits functional benefit. Conclusion: This finding reflects a novel adaptation of toad heart. Significance: The results indicate a molecular mechanism to improve systolic function. The three isoforms of vertebrate troponin T (TnT) are normally expressed in a muscle type-specific manner. Here we report an exception that the cardiac muscle of toad (Bufo) expresses exclusively slow skeletal muscle TnT (ssTnT) together with cardiac forms of troponin I and myosin as determined using immunoblotting, cDNA cloning, and/or LC-MS/MS. Using RT-PCR and 3′- and 5′-rapid amplification of cDNA ends on toad cardiac mRNA, we cloned full-length cDNAs encoding two alternatively spliced variants of ssTnT. Expression of the cloned cDNAs in Escherichia coli confirmed that the toad cardiac muscle expresses solely ssTnT, predominantly the low molecular weight variant with the exon 5-encoded NH2-terminal segment spliced out. Functional studies were performed in ex vivo working toad hearts and compared with the frog (Rana) hearts. The results showed that toad hearts had higher contractile and relaxation velocities and were able to work against a significantly higher afterload than that of frog hearts. Therefore, the unique evolutionary adaptation of utilizing exclusively ssTnT in toad cardiac muscle corresponded to a fitness value from improving systolic function of the heart. The data demonstrated a physiological importance of the functional diversity of TnT isoforms. The structure-function relationship of TnT may be explored for the development of new treatment of heart failure.
Dental Insurance and Dental Care: the Role of Insurance and Income

This paper analyzes the effect of dental insurance on utilization of general dentist services by adult US population aged from 25 to 64 years. Our econometric framework accommdates endogeneity of insurance and the ordered nature of the measure of dental utilization. The study finds strong evidence of endogeneity of dental insurance to utilization and identifies interesting patterns of nonlinear dependencies between the dental insurance status and individual’s age and income. The calculated average treatment effect supports the claim of adverse selection into the treated (insured) state and indicates a strong positive incentives effect of dental insurance.
Fuzzy grammar: A reader

This book brings together classic and recent papers in the philosophical and linguistic analysis of fuzzy grammar, gradience in meaning, word classes, and syntax. Issues such as how many grains make a heap, when a puddle becomes a pond, and so forth, have occupied thinkers since Aristotle and over the last two decades been the subject of increasing interest among linguists as well as in fields such as artificial intelligence and computational linguistics. The work is designed to be of use to students in all these fields. It has a substantial introduction, is divided into thematic parts, contains annotated sections of further reading, and is fully indexed.
Use of force preferences and perceived effectiveness of actions among Crisis Intervention Team (CIT) police officers and non-CIT officers in an escalating psychiatric crisis involving a subject with schizophrenia.

BACKGROUND Few studies have examined police officers' use of force toward individuals with schizophrenia, despite the widely disseminated Crisis Intervention Team (CIT) model of partnership between mental health and law enforcement that seeks to reduce use of force and enhance safety of officers and individuals with mental illnesses. This study tested the hypotheses that CIT-trained officers would select a lower level of force, identify nonphysical actions as more effective, and perceive physical force as less effective in an escalating psychiatric crisis, compared with non-CIT-trained officers. METHODS Police officers (n = 135)-48 CIT trained and 87 non-CIT trained-completed a survey containing 3 scenario-based vignettes depicting an escalating situation involving a subject with psychosis. Data were analyzed using repeated-measures analyses of variance. RESULTS Officers escalated their preferred actions across the scenarios. A significant scenario by group interaction indicated that CIT-trained officers chose less escalation (ie, opting for less force at the third scenario) than non-CIT-trained officers. Officers reported decreasing perceived effectiveness of nonphysical action across the 3 scenarios. A significant scenario by group interaction indicated that CIT-trained officers reported a lesser decline in perceived effectiveness of nonphysical actions at the third scenario. CIT-trained officers consistently endorsed lower perceived effectiveness of physical force. CONCLUSIONS Efforts are needed to reduce use of force toward individuals with psychotic disorders. These findings suggest that CIT may be an effective approach. In addition to clinical and programmatic implications, such findings demonstrate a role for clinicians, advocates, and schizophrenia researchers in promoting social justice through partnerships with diverse social sectors.
Atypical Angelman syndrome due to a mosaic imprinting defect: Case reports and review of the literature

Angelman syndrome (AS) is characterized by severe intellectual disability, limited, or absent speech and a generally happy demeanor. The four known etiological mechanisms; deletions, uniparental disomy, imprinting defects, and UBE3A mutation all affect expression of the UBE3A gene at 15q11‐q13. An atypical phenotype is seen in individuals who are mosaic for a chromosome 15q11‐q13 imprinting defect on the maternal allele. These patients present with a milder phenotype, often with hyperphagia and obesity or non‐specific intellectual disability. Unlike typical AS syndrome, they can have a vocabulary up to 100 words and speak in sentences. Ataxia and seizures may not be present, and the majority of individuals do not have microcephaly. Here we review the current literature and present three individuals with atypical AS caused by a mosaic imprinting defect to demonstrate why DNA methylation analysis at the SNRPN locus needs to be considered in a broader clinical context. © 2017 Wiley Periodicals, Inc.
Relapsing fever – a forgotten disease revealed

Borrelial relapsing fever was once a major worldwide epidemic disease that made a significant impact on Livingstone during his epic travels through Africa and throughout Europe. Indeed, the term ‘relapsing fever’ was first used to describe clinical cases of this disease in Edinburgh. During the last century, we have witnessed the demise of the louse‐borne infection, largely through improving standards of living resulting in a reduction in body lice, the vector for Borrelia recurrentis [louse‐borne relapsing fever (LBRF)]. The tick‐borne zoonotic form of the disease persists in endemic foci around the world [tick‐borne relapsing fever (TBRF)]. Indeed, TBRF is reportedly the most common bacterial infection from Senegal and listed within the top ten causes of mortality in children under five in Tanzania. In Ethiopia, LBRF is again within the top ten causes of hospital admission, associated with significant morbidity and mortality. Despite these figures, many now regard relapsing fever as an unusual tropical disease. Certainly, recent cases have been imported following travel from endemic zones. More surprisingly, cases have been reported following family reunions in Colorado, USA. A further case was reported from the Mt Wilson observatory in Los Angeles, USA. In many regions, the infection is zoonotic with natural reservoirs in several vertebrate species. In West Africa, infection is again primarily zoonotic. Whether those species found predominantly in East Africa are zoonoses or are infections of humans alone is still debated, however, the life cycle may be determined by the feeding preferences of their arthropod vectors.