Efficient Dynamic Approximate Distance Oracles for Vertex-Labeled Planar Graphs

Let $G$ be a graph where each vertex is associated with a label. A Vertex-Labeled Approximate Distance Oracle is a data structure that, given a vertex $v$ and a label $\lambda$, returns a $(1+\varepsilon)$-approximation of the distance from $v$ to the closest vertex with label $\lambda$ in $G$. Such an oracle is dynamic if it also supports label changes. In this paper we present three different dynamic approximate vertex-labeled distance oracles for planar graphs, all with polylogarithmic query and update times, and nearly linear space requirements

The association between childhood trauma and emotion recognition is reduced or eliminated when controlling for alexithymia and psychopathy traits

Data availability: The dataset generated and analysed during the current study and a fully programmed version of the experiment is available on Open Science Framework: (https://osf.io/vhwxj/?view_only=f6776204f42d4368b4a7a262d0fc8139).Emotion recognition shows large inter-individual variability, and is substantially affected by childhood trauma as well as modality, emotion portrayed, and intensity. While research suggests childhood trauma influences emotion recognition, it is unclear whether this effect is consistent when controlling for interrelated individual differences. Further, the universality of the effects has not been explored, most studies have not examined differing modalities or intensities. This study examined childhood trauma’s association with accuracy, when controlling for alexithymia and psychopathy traits, and if this varied across modality, emotion portrayed, and intensity. An adult sample (N = 122) completed childhood trauma, alexithymia, and psychopathy questionnaires and three emotion tasks: faces, voices, audio-visual. When investigating childhood trauma alone, there was a significant association with poorer accuracy when exploring modality, emotion portrayed, and intensity. When controlling for alexithymia and psychopathy, childhood trauma remained significant when exploring emotion portrayed, however, it was no longer significant when exploring modality and intensity. In fact, alexithymia was significant when exploring intensity. The effect sizes overall were small. Our findings suggest the importance of controlling for interrelated individual differences. Future research should explore more sensitive measures of emotion recognition, such as intensity ratings and sensitivity to intensity, to see if these follow accuracy findings.Partially funded by internal funding awarded to RB by Brunel University London (BRIEF award 1086)

Assessment and risk reduction of infectious pathogens on chiropractic treatment tables

<p>Abstract</p> <p>Background</p> <p>To investigate the presence of pathogenic microbes on chiropractic treatment tables in one outpatient teaching clinic. Additional aims were to test inexpensive disinfectants on tables that may kill microbes and suggest infection control measures for chiropractic offices, clinics and classrooms. The aim of the study was to assess the presence of pathogenic microbes on treatment tables in one outpatient teaching clinic and determine a simple behavioral model for infection control including table disinfection and accepted hand washing and sanitizing protocols.</p> <p>Methods</p> <p>10 treatment tables were selected and sampled for possible microbial flora on face and hand pieces. Samples were cultured on MacConky's agar and mannitol salt agar, labeled and incubated for up to 48 hours. Confirmatory testing of microbes to determine if drug resistant flora were present was performed. Among tables tested, 5 were selected to test disinfectants. One-half of the face piece and 1 hand piece were treated with two different wipes and then post-tested for microbes.</p> <p>Results</p> <p>Pathogenic microbes were present on chiropractic treatment tables including methicillin-resistant <it>Staph aureus</it>. Simple disinfectants neutralized the pathogens. A rudimentary disinfection procedure and infection control measures are suggested based on the findings.</p> <p>Conclusion</p> <p>Pathogenic microbes may be present on chiropractic treatment tables and can be effectively killed with proper disinfecting. Hand washing/sanitizing is an important measure in infection control as is table disinfecting. Rudimentary behavioral changes to improve chiropractic clinic infection control are needed. More comprehensive behavioral models are needed. All teaching clinics and private chiropractic offices should adopt infection control practices including routine table disinfecting and hand sanitizing. Effective measures can be put in place at minimal costs. Accrediting bodies of chiropractic institutions should mandate an infection control plan for member institutions immediately.</p

GoLoco motif proteins binding to Gαi1: insights from molecular simulations

Molecular dynamics simulations, computational alanine scanning and sequence analysis were used to investigate the structural properties of the Gαi1/GoLoco peptide complex. Using these methodologies, binding of the GoLoco motif peptide to the Gαi1 subunit was found to restrict the relative movement of the helical and catalytic domains in the Gαi1 subunit, which is in agreement with a proposed mechanism of GDP dissociation inhibition by GoLoco motif proteins. In addition, the results provide further insights into the role of the “Switch IV” region located within the helical domain of Gα, the conformation of which might be important for interactions with various Gα partners

Regulator of G-Protein Signaling 14 (RGS14) Is a Selective H-Ras Effector

Background: Regulator of G-protein signaling (RGS) proteins have been well-described as accelerators of Ga-mediated GTP hydrolysis (‘‘GTPase-accelerating proteins’’ or GAPs). However, RGS proteins with complex domain architectures are now known to regulate much more than Ga GTPase activity. RGS14 contains tandem Ras-binding domains that have been reported to bind to Rap- but not Ras GTPases in vitro, leading to the suggestion that RGS14 is a Rap-specific effector. However, more recent data from mammals and Drosophila imply that, in vivo, RGS14 may instead be an effector of Ras.Methodology/Principal Findings: Full-length and truncated forms of purified RGS14 protein were found to bind indiscriminately in vitro to both Rap- and Ras-family GTPases, consistent with prior literature reports. In stark contrast, however, we found that in a cellular context RGS14 selectively binds to activated H-Ras and not to Rap isoforms. Co- transfection / co-immunoprecipitation experiments demonstrated the ability of full-length RGS14 to assemble a multiprotein complex with components of the ERK MAPK pathway in a manner dependent on activated H-Ras. Small interfering RNA-mediated knockdown of RGS14 inhibited both nerve growth factor- and basic fibrobast growth factor- mediated neuronal differentiation of PC12 cells, a process which is known to be dependent on Ras-ERK signaling.Conclusions/Significance: In cells, RGS14 facilitates the formation of a selective Ras?GTP-Raf-MEK-ERK multiprotein complex to promote sustained ERK activation and regulate H-Ras-dependent neuritogenesis. This cellular function for RGS14 is similar but distinct from that recently described for its closely-related paralogue, RGS12, which shares the tandem Ras- binding domain architecture with RGS14

Normally preordered spaces and utilities

In applications it is useful to know whether a topological preordered space is normally preordered. It is proved that every $k_\omega$-space equipped with a closed preorder is a normally preordered space. Furthermore, it is proved that second countable regularly preordered spaces are perfectly normally preordered and admit a countable utility representation.Comment: 17 pages, 1 figure. v2 contains a second proof to the main theorem with respect to the published version. The last section of v1 is not present in v2. It will be included in a different wor

Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes

<p>Abstract</p> <p>Background</p> <p>Methylmalonic acidemia (MMA), a common organic aciduria, is caused by deficiency of the mitochondrial localized, 5'deoxyadenosylcobalamin dependent enzyme, methylmalonyl-CoA mutase (MUT). Liver transplantation in the absence of gross hepatic dysfunction provides supportive therapy and metabolic stability in severely affected patients, which invites the concept of using cell and gene delivery as future treatments for this condition.</p> <p>Methods</p> <p>To assess the effectiveness of gene delivery to restore the defective metabolism in this disorder, adenoviral correction experiments were performed using murine <it>Mut </it>embryonic fibroblasts and primary human methylmalonyl-CoA mutase deficient hepatocytes derived from a patient who harbored two early truncating mutations, E224X and R228X, in the <it>MUT </it>gene. Enzymatic and expression studies were used to assess the extent of functional correction.</p> <p>Results</p> <p>Primary hepatocytes, isolated from the native liver after removal subsequent to a combined liver-kidney transplantation procedure, or <it>Mut </it>murine fibroblasts were infected with a second generation recombinant adenoviral vector that expressed the murine methylmalonyl-CoA mutase as well as eGFP from distinct promoters. After transduction, [1-¹⁴C] propionate macromolecular incorporation studies and Western analysis demonstrated complete correction of the enzymatic defect in both cell types. Viral reconstitution of enzymatic expression in the human methylmalonyl-CoA mutase deficient hepatocytes exceeded that seen in fibroblasts or control hepatocytes.</p> <p>Conclusion</p> <p>These experiments provide proof of principle for viral correction in methylmalonic acidemia and suggest that hepatocyte-directed gene delivery will be an effective therapeutic treatment strategy in both murine models and in human patients. Primary hepatocytes from a liver that was unsuitable for transplantation provided an important resource for these studies.</p

Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype.</p> <p>Methods</p> <p>To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function.</p> <p>Results</p> <p>Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens.</p> <p>Conclusion</p> <p>The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.</p

'HepCheck Dublin': An Intensified Hepatitis C Screening Programme in a Homeless Population Demonstrates the Need for Alternative Models of Care

Background: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease worldwide. Prevalence of HCV in homeless populations ranges from 3.9% to 36.2%. The HepCheck study sought to investigate and establish the characterisation of HCV burden among individuals who attended an intensified screening programme for HCV in homeless services in Dublin, Ireland. Methods: The HepCheck study was conducted as part of a larger European wide initiative called HepCare Europe. The study consisted of three phases; 1) all subjects completed a short survey and were offered a rapid oral HCV test; 2) a convenience sample of HCV positive participants from phase 1 were selected to complete a survey on health and social risk factors and 3) subjects were tracked along the referral pathway to identify whether they were referred to a specialist clinic, attended the specialist clinic, were assessed for cirrhosis by transient elastography (Fibroscan) and were treated for HCV. Results: 597 individuals were offered HCV screening, 73% were male and 63% reported having had a previous HCV screening. We screened 538 (90%) of those offered screening, with 37% testing positive. Among those who tested positive, 112 (56%) were ‘new positives’ and 44% were ‘known positives’. Undiagnosed HCV was prevalent in 19% of the study sample. Active past 30-day drug use was common, along with attendance for drug treatment. Unstable accommodation was the most common barrier to attending specialist appointments and accessing treatment. Depression and anxiety, dental problems and respiratory conditions were common reported health problems. 46 subjects were referred to specialised services and two subjects completed HCV treatment. Conclusions: This study demonstrates that the current hospital-based model of care is inadequate in addressing the specific needs of a homeless population and emphasises the need for a community-based treatment approach. Findings are intended to inform HepCare Europe in their development of a community-based model of care in order to engage with homeless individuals with multiple co-morbidities including substance abuse, who are affected by or infected with HCV