Müller glia activation in response to inherited retinal degeneration is highly varied and disease-specific

Despite different aetiologies, most inherited retinal disorders culminate in photoreceptor loss, which induces concomitant changes in the neural retina, one of the most striking being reactive gliosis by Müller cells. It is typically assumed that photoreceptor loss leads to an upregulation of glial fibrilliary acidic protein (Gfap) and other intermediate filament proteins, together with other gliosis-related changes, including loss of integrity of the outer limiting membrane (OLM) and deposition of proteoglycans. However, this is based on a mix of both injury-induced and genetic causes of photoreceptor loss. There are very few longitudinal studies of gliosis in the retina and none comparing these changes across models over time. Here, we present a comprehensive spatiotemporal assessment of features of gliosis in the degenerating murine retina that involves Müller glia. Specifically, we assessed Gfap, vimentin and chondroitin sulphate proteoglycan (CSPG) levels and outer limiting membrane (OLM) integrity over time in four murine models of inherited photoreceptor degeneration that encompass a range of disease severities (Crb1rd8/rd8, Prph2+/Δ307, Rho-/-, Pde6brd1/rd1). These features underwent very different changes, depending upon the disease-causing mutation, and that these changes are not correlated with disease severity. Intermediate filament expression did indeed increase with disease progression in Crb1rd8/rd8 and Prph2+/Δ307, but decreased in the Prph2+/Δ307 and Pde6brd1/rd1 models. CSPG deposition usually, but not always, followed the trends in intermediate filament expression. The OLM adherens junctions underwent significant remodelling in all models, but with differences in the composition of the resulting junctions; in Rho-/- mice, the adherens junctions maintained the typical rod-Müller glia interactions, while in the Pde6brd1/rd1 model they formed predominantly between Müller cells in late stage of degeneration. Together, these results show that gliosis and its associated processes are variable and disease-dependent

Increasing Multiyear Sea Ice Loss in the Beaufort Sea: A New Export Pathway for the Diminishing Multiyear Ice Cover of the Arctic Ocean

Historically, multiyear sea ice (MYI) covered a majority of the Arctic and circulated through the Beaufort Gyre for years. However, increased ice melt in the Beaufort Sea during the early 2000s was proposed to have severed this circulation. Constructing a regional MYI budget from 1997 to 2021 reveals that MYI import into the Beaufort Sea has increased year-round, yet less MYI now survives through summer and is transported onwards in the Gyre. Annual average MYI loss quadrupled over the study period and increased from ∼7% to ∼33% of annual Fram Strait MYI export, while the peak in 2018 (385,000 km2) was similar in magnitude to Fram Strait MYI export. The ice-albedo feedback coupled with the transition toward younger thinner MYI is responsible for the increased MYI loss. MYI transport through the Beaufort Gyre has not been severed, but it has been reduced so severely to prevent it from being redistributed throughout the Arctic Ocean

Inhibition of neurite outgrowth in differentiating mouse N2a neuroblastoma cells by phenyl saligenin phosphate: Effects on MAP kinase (ERK 1/2) activation, neurofilament heavy chain phosphorylation and neuropathy target esterase activity

Sub-lethal concentrations of the organophosphate phenyl saligenin phosphate (PSP) inhibited the outgrowth of axon-like processes in differentiating mouse N2a neuroblastoma cells (IC50 2.5 μM). A transient rise in the phosphorylation state of neurofilament heavy chain (NFH) was detected on Western blots of cell extracts treated with 2.5 μM PSP for 4 h compared to untreated controls, as determined by a relative increase in reactivity with monoclonal antibody Ta51 (anti-phosphorylated NFH) compared to N52 (anti-total NFH). However, cross-reactivity of PSP-treated cell extracts was lower than that of untreated controls after 24 h exposure, as indicated by decreased reactivity with both antibodies. Indirect immunofluorescence analysis with these antibodies revealed the appearance of neurofilament aggregates in the cell bodies of treated cells and reduced axonal staining compared to controls. By contrast, there was no significant change in reactivity with anti-a tubulin antibody B512 at either time point. The activation state of the MAP kinase ERK 1/2 increased significantly after PSP treatment compared to controls, particularly at 4 h, as indicated by increased reactivity with monoclonal antibody E-4 (anti-phosphorylated MAP kinase) but not with polyclonal antibody K-23 (anti-total MAP kinase). The observed early changes were concomitant with almost complete inhibition of the activity of neuropathy target esterase (NTE), one of the proposed early molecular targets in organophosphate-induced delayed neuropathy (OPIDN)

Scaling and Asymptotic Scaling in the SU(2) Gauge Theory

We determine the critical couplings for the deconfinement phase transition in $SU(2)$ gauge theory on $N_\tau \times N_\sigma^3$ lattices with $N_\tau = 8$ and 16 and $N_\sigma$ varying between 16 and 48. A comparison with string tension data shows scaling of the ratio $T_c / \sqrt{\sigma}$ in the entire coupling regime $\beta =2.30-2.75$, while the individual quantities still exhibit large scaling violations. We find $T_c / \sqrt{\sigma}=0.69(2)$. We also discuss in detail the extrapolation of $T_c / Lambda_{\rm{\bar{M} \bar{S}}}$ and $\sqrt{\sigma} / Lambda_{\rm{\bar{M}\bar{S}}}$ to the continuum limit. Our result, which is consistent with the above ratio, is $T_c / Lambda_{\rm{\bar{M}\bar{S}}} = 1.23(11)$ and $\sqrt{\sigma} / Lambda_{\rm{\bar{M}\bar{S}}} = 1.79(12)$. We also comment upon corresponding results for $SU(3)$ gauge theory and four flavour QCD.Comment: 27 pages with 9 postscript figures included. Plain TeX file (needed macros are included). BI-TP 92-26, FSU-SCRI-92-103, HLRZ-92-39 (Quote of UKQCD string tension, and accordingly Figs. 5 and 7a, plus a few typo's corrected.

Proteomic quantification of perturbation to pharmacokinetic target proteins in liver disease

Model-based assessment of drug pharmacokinetics in liver disease requires quantification of abundance and disease-related changes in hepatic enzymes and transporters. This study aimed to assess performance of three label-free methods [high N (HiN), intensity-based absolute quantification (iBAQ) and total protein approach (TPA)] against QconCAT-based targeted data in healthy and diseased (cancer and cirrhosis) liver tissue. Measurements were compared across methods and disease-to-control ratios provided a ‘disease perturbation factor’ (DPF) for each protein. Mean label-free measurements of targets correlated well (Pearson\u27s coefficient, r = 0.91–0.98 p \u3c 0.001) and with targeted data (r = 0.65–0.95, p \u3c 0.001). Concordance with targeted data was generally moderate (Lin\u27s concordance coefficient, ρc = 0.46–0.92), depending on methodology. Moderate precision and accuracy were observed for label-free methods (average fold error, AFE = 1.44–1.68; absolute average fold error, AAFE = 2.44–3.23). The DPF reconciled the data and indicated downregulated expression in cancer and cirrhosis, consistent with an inflammatory effect. HiN estimated perturbation consistently with targeted data (AFEHiN = 1.07, AAFEHiN = 1.57), whereas iBAQ overestimated (AFEiBAQ = 0.81, AAFEiBAQ = 1.67) and TPA underestimated (AFETPA = 1.37, AAFETPA = 1.65) disease effect. Progression from mild to severe cirrhosis was consistent with progressive decline in expression, reproduced by HiN but overestimated by iBAQ and underestimated by TPA (AFEHiN = 0.98, AFEiBAQ = 0.60, AFETPA = 1.24). DPF data confirmed non-uniform disease effect on drug-elimination pathways and progressive impact of disease severity

The role of parental achievement goals in predicting autonomy-supportive and controlling parenting

Although autonomy-supportive and controlling parenting are linked to numerous positive and negative child outcomes respectively, fewer studies have focused on their determinants. Drawing on achievement goal theory and self-determination theory, we propose that parental achievement goals (i.e., achievement goals that parents have for their children) can be mastery, performance-approach or performance-avoidance oriented and that types of goals predict mothers' tendency to adopt autonomy-supportive and controlling behaviors. A total of 67 mothers (aged 30-53 years) reported their goals for their adolescent (aged 13-16 years; 19.4 % girls), while their adolescent evaluated their mothers' behaviors. Hierarchical regression analyses showed that parental performance-approach goals predict more controlling parenting and prevent acknowledgement of feelings, one autonomy-supportive behavior. In addition, mothers who have mastery goals and who endorse performance-avoidance goals are less likely to use guilt-inducing criticisms. These findings were observed while controlling for the effect of maternal anxiety

Direct Extraction of QCD Lambda MS-bar from e+e- Jet Observables

We directly fit the QCD dimensional transmutation parameter, Lambda MS-bar, to experimental data on e+e- jet observables, making use of next-to-leading order (NLO) perturbative calculations. In this procedure there is no need to mention, let alone to arbitrarily vary, the unphysical renormalisation scale mu, and one avoids the spurious and meaningless ``theoretical error'' associated with standard alpha_s determinations. PETRA, SLD, and LEP data are considered in the analysis. An attempt is made to estimate the importance of uncalculated next-NLO and higher order perturbative corrections, and power corrections, by studying the scatter in the values of Lambda MS-bar obtained for different observables.Comment: 46 pages, 22 figure

How sukuk shapes firm performance

Peer reviewedPostprin

Development, feasibility, and acceptability of an intervention to improve care for agitation in people living in nursing homes with dementia nearing the end-of-life

OBJECTIVES: To develop a staff training intervention for agitation in people with severe dementia, reaching end-of-life, residing in nursing homes (NHs), test feasibility, acceptability, and whether a trial is warranted. DESIGN: Feasibility study with pre- and post-intervention data collection, qualitative interviews, and focus groups. SETTING: Three NHs in South East England with dementia units, diverse in terms of size, ownership status, and location. PARTICIPANTS: Residents with a dementia diagnosis or scoring ≥2 on the Noticeable Problems Checklist, rated as "severe" on Clinical Dementia Rating Scale, family carers, and staff (healthcare assistants and nurses). INTERVENTION: Manualized training, delivered by nonclinical psychology graduates focusing on agitation in severe dementia, underpinned by a palliative care framework. MEASUREMENTS: Main outcomes were feasibility of recruitment, data collection, follow-up, and intervention acceptability. We collected resident, family carer, and staff demographics. Staff provided data on resident's agitation, pain, quality of life, and service receipt. Staff reported their sense of competence in dementia care. Family carers reported on satisfaction with end-of-life care. In qualitative interviews, we explored staff and family carers' views on the intervention. RESULTS: The target three NHs participated: 28 (49%) residents, 53 (74%) staff, and 11 (85%) family carers who were eligible to participate consented. Eight-four percent of staff attended ≥3 sessions, and we achieved 93% follow-up. We were able to complete quantitative interviews. Staff and family carers reported the intervention and delivery were acceptable and helpful. CONCLUSIONS: The intervention was feasible and acceptable indicating a larger trial for effectiveness may be warranted

Remobilisation features and structural control on ore grade distribution at the Konkola stratiform Cu-Co ore deposit, Zambia

The Konkola deposit is a high grade stratiform Cu–Co ore deposit in the Central African Copperbelt in Zambia. Economic mineralisation is confined to the Ore Shale formation, part of the Neoproterozoic metasedimentary rocks of the Katanga Supergroup. Petrographic study reveals that the copper–cobalt ore minerals are disseminated within the host rock, sometimes concentrated along bedding planes, often associated with dolomitic bands or clustered in cemented lenses and in layer-parallel and irregular veins. The hypogene sulphide mineralogy consists predominantly of chalcopyrite, bornite and chalcocite. Based upon relationships with metamorphic biotite, vein sulphides and most of the sulphides in cemented lenses were precipitated during or after biotite zone greenschist facies metamorphism. New δ34S values of sulphides from the Konkola deposit are presented. The sulphur isotope values range from −8.7‰ to +1.4‰ V-CDT for chalcopyrite from all mineralising phases and from −4.4‰ to +2.0‰ V-CDT for secondary chalcocite. Similarities in δ34S for sulphides from different vein generations, earlier sulphides and secondary chalcocite can be explained by (re)mobilisation of S from earlier formed sulphide phases, an interpretation strongly supported by the petrographic evidence. Deep supergene enrichment and leaching occurs up to a km in depth, predominantly in the form of secondary chalcocite, goethite and malachite and is often associated with zones of high permeability. Detailed distribution maps of total copper and total cobalt contents of the Ore Shale formation show a close relationship between structural features and higher copper and lower cobalt contents, relative to other areas of the mine. Structural features include the Kirilabombwe anticline and fault zones along the axial plane and two fault zones in the southern limb of the anticline. Cobalt and copper behave differently in relation to these structural features. These structures are interpreted to have played a significant role in (re)mobilisation and concentration of the metals, in agreement with observations made elsewhere in the Zambian Copperbelt