Mass spectrometry imaging of levofloxacin distribution in TB-infected pulmonary lesions by MALDI-MSI and continuous liquid microjunction surface sampling

A multi-modal mass spectrometry imaging (MSI) and profiling approach has been applied to assess the partitioning of the anti-TB fluoroquinolone levofloxacin into pulmonary lesions. Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and a commercial liquid microjunction surface sampling technology (LMJ-SSP), or flowprobe, have been used to both spatially profile and image drug distributions in lung tissue sections from TB-infected rabbits following oral administration of a single human-equivalent dose., Levofloxacin levels were highest at 6 h post-dose in normal lung, cellular granuloma, and necrotic caseum compartments. The drug accumulated in the cellular granuloma regions with lower amounts partitioning into central caseous compartments. Flowprobe imaging at 630 μm (limited by the probe tip diameter) enabled visualization of drug distribution into lesion compartments, including limited differentiation of relative drug abundance in cellular versus caseous regions of the lesions., MALDI-MSI analysis at 75 μm provided more detailed drug distribution, which clearly accumulated in the cellular region immediately surrounding the central caseum core. Imaging and profiling data acquired by flowprobe and MALDI-MSI were validated by quantitative LC/MS/MS analysis of lung and granuloma homogenates taken from the same animals., The results of the investigation show flowprobe imaging and sampling as a rapid and sensitive alternative to MALDI-MSI for profiling drug distributions into tissues when spatial resolution of data below the threshold of the probe diameter is not required

Disorder-Induced Critical Phenomena in Hysteresis: Numerical Scaling in Three and Higher Dimensions

We present numerical simulations of avalanches and critical phenomena associated with hysteresis loops, modeled using the zero-temperature random-field Ising model. We study the transition between smooth hysteresis loops and loops with a sharp jump in the magnetization, as the disorder in our model is decreased. In a large region near the critical point, we find scaling and critical phenomena, which are well described by the results of an epsilon expansion about six dimensions. We present the results of simulations in 3, 4, and 5 dimensions, with systems with up to a billion spins (1000^3).Comment: Condensed and updated version of cond-mat/9609072,``Disorder-Induced Critical Phenomena in Hysteresis: A Numerical Scaling Analysis'

Investigating health service availability and readiness for antenatal testing and treatment for HIV and syphilis in Papua New Guinea

Background Papua New Guinea (PNG) has one of the highest burdens of HIV and syphilis in pregnancy in the Asia-Pacific region. Timely and effective diagnosis can alleviate the burden of HIV and syphilis and improve maternal and newborn health. Supply-side factors related to implementation and scale up remain problematic, yet few studies have considered their impact on antenatal testing and treatment for HIV and syphilis. This study explores health service availability and readiness for antenatal HIV and/or syphilis testing and treatment in PNG. Methods Using data from two sources, we demonstrate health service availability and readiness. Service availability is measured at a province level as the average of three indicators: infrastructure, workforce, and antenatal clinic utilization. The readiness score comprises 28 equally weighted indicators across four domains; and is estimated for 73 health facilities. Bivariate and multivariate robust linear regressions explore associations between health facility readiness and the proportion of antenatal clinic attendees tested and treated for HIV and/or syphilis. Results Most provinces had fewer than one health facility per 10 000 population. On average, health worker density was 11 health workers per 10 000 population per province, and approximately 22% of pregnant women attended four or more antenatal clinics. Most health facilities had a composite readiness score between 51% and 75%, with urban health facilities faring better than rural ones. The multivariate regression analysis, when controlling for managing authority, catchment population, the number of clinicians employed, health facility type and residence (urban/rural) indicated a weak positive relationship between health facility readiness and the proportion of antenatal clinic attendees tested and treated for HIV and/or syphilis. Conclusion This study adds to the limited evidence base for the Asia-Pacific region. There is a need to improve antenatal testing and treatment coverage for HIV and syphilis and reduce healthcare inequalities faced by rural and urban communities. Shortages of skilled health workers, tests, and medicines impede the provision of quality antenatal care. Improving service availability and health facility readiness are key to ensuring the effective provision of antenatal care interventions

Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus

Pathological mechanisms underlying Down syndrome (DS)/Trisomy 21, including dysregulation of essential signalling processes remain poorly understood. Combining bioinformatics with RNA and protein analysis, we identified downregulation of the Wnt/β-catenin pathway in the hippocampus of adult DS individuals with Alzheimer’s disease and the ‘Tc1’ DS mouse model. Providing a potential underlying molecular pathway, we demonstrate that the chromosome 21 kinase DYRK1A regulates Wnt signalling via a novel bimodal mechanism. Under basal conditions, DYRK1A is a negative regulator of Wnt/β-catenin. Following pathway activation, however, DYRK1A exerts the opposite effect, increasing signalling activity. In summary, we identified downregulation of hippocampal Wnt/β-catenin signalling in DS, possibly mediated by a dose dependent effect of the chromosome 21-encoded kinase DYRK1A. Overall, we propose that dosage imbalance of the Hsa21 gene DYRK1A affects downstream Wnt target genes. Therefore, modulation of Wnt signalling may open unexplored avenues for DS and Alzheimer’s disease treatment

Divergent clonal evolution of blastic plasmacytoid dendritic cell neoplasm and chronic myelomonocytic leukemia from a shared TET2-mutated origin

From Springer Nature via Jisc Publications RouterHistory: received 2020-11-25, rev-recd 2021-02-15, accepted 2021-03-11, registration 2021-03-12, pub-electronic 2021-04-08, online 2021-04-08, pub-print 2021-11Publication status: PublishedFunder: Oglesby Charitable TrustFunder: Pickering family donationFunder: Blood Cancer UK Clinician Scientist Fellowship (15030) Oglesby Charitable Trus

Allogeneic Lymphocytes Persist and Traffic in Feral MHC-Matched Mauritian Cynomolgus Macaques

Thus far, live attenuated SIV has been the most successful method for vaccinating macaques against pathogenic SIV challenge; however, it is not clear what mechanisms are responsible for this protection. Adoptive transfer studies in mice have been integral to understanding live attenuated vaccine protection in models like Friend virus. Previous adoptive transfers in primates have failed as transferred cells are typically cleared within hours after transfer.Here we describe adoptive transfer studies in Mauritian origin cynomolgus macaques (MCM), a non-human primate model with limited MHC diversity. Cells transferred between unrelated MHC-matched macaques persist for at least fourteen days but are rejected within 36 hours in MHC-mismatched macaques. Cells trafficked from the blood to peripheral lymphoid tissues within 12 hours of transfer.MHC-matched MCM provide the first viable primate model for adoptive transfer studies. Because macaques infected with SIV are the best model for HIV/AIDS pathogenesis, we can now directly study the correlates of protective immune responses to AIDS viruses. For example, plasma viral loads following pathogenic SIV challenge are reduced by several orders of magnitude in macaques previously immunized with attenuated SIV. Adoptive transfer of lymphocyte subpopulations from vaccinated donors into SIV-naïve animals may define the immune mechanisms responsible for protection and guide future vaccine development

Self-Compassion and Its Relation to Nonsuicidal Self-Injury

There have been relatively few studies that have empirically explored the relationship between self-compassion and nonsuicidal self-injury (NSSI). Previous studies have found that engagement in self-injurious behaviors is closely related to being self-critical (Glassman, Weierich, Hooley, Deliberto, & Nock, 2007; Hooley, Ho, Slater, & Lockshin, 2010).Therefore, it has been suggested that higher levels of self-compassion may be associated with less engagement in NSSI. The current study explored the relationship between self-reported self-compassion and past self-reported occurrences of NSSI. This study used Neff\u27s (2003a) 12 item Self-Compassion Scale- Short Form (SCS-SF) to measure one\u27s level of self-compassion and a Client Information/Demographics Questionnaire (SDS-CCMH) to determine past occurrences of NSSI. It was hypothesized that there would be significant mean differences in self-reported self-compassion scores in individuals who have self-reported occurrences of self-injury than those with no self-reported occurrences. Participants were divided into two groups: those who reported past occurrences of self-injury and those who reported no self-injury. This study involved two main analyses. The first analysis was a biserial Pearson\u27s r correlation in order to determine if there was a significant association between NSSI (e.g. self-injury versus no self-injury) and self-compassion. The second analysis was an independent t-test to allow a direct examination of the hypothesis. Results from the study supported the hypothesis as those who reported past occurrences of self-injury had significantly lower self-compassion scores than those who reported no past occurrence of self-injury. The findings demonstrate and provide empirical data that one\u27s level of self-compassion may play a significant role in one\u27s decision to engage in self-injury

Self-Compassion and Its Relation to Nonsuicidal Self-Injury

There have been relatively few studies that have empirically explored the relationship between self-compassion and nonsuicidal self-injury (NSSI). Previous studies have found that engagement in self-injurious behaviors is closely related to being self-critical (Glassman, Weierich, Hooley, Deliberto, & Nock, 2007; Hooley, Ho, Slater, & Lockshin, 2010).Therefore, it has been suggested that higher levels of self-compassion may be associated with less engagement in NSSI. The current study explored the relationship between self-reported self-compassion and past self-reported occurrences of NSSI. This study used Neff\u27s (2003a) 12 item Self-Compassion Scale- Short Form (SCS-SF) to measure one\u27s level of self-compassion and a Client Information/Demographics Questionnaire (SDS-CCMH) to determine past occurrences of NSSI. It was hypothesized that there would be significant mean differences in self-reported self-compassion scores in individuals who have self-reported occurrences of self-injury than those with no self-reported occurrences. Participants were divided into two groups: those who reported past occurrences of self-injury and those who reported no self-injury. This study involved two main analyses. The first analysis was a biserial Pearson\u27s r correlation in order to determine if there was a significant association between NSSI (e.g. self-injury versus no self-injury) and self-compassion. The second analysis was an independent t-test to allow a direct examination of the hypothesis. Results from the study supported the hypothesis as those who reported past occurrences of self-injury had significantly lower self-compassion scores than those who reported no past occurrence of self-injury. The findings demonstrate and provide empirical data that one\u27s level of self-compassion may play a significant role in one\u27s decision to engage in self-injury