Repair systems with exchangeable items and the longest queue mechanism

We consider a repair facility consisting of one repairman and two arrival streams of failed items, from bases 1 and 2. The arrival processes are independent Poisson processes, and the repair times are independent and identically exponentially distributed. The item types are exchangeable, and a failed item from base 1 could just as well be returned to base 2, and vice versa. The rule according to which backorders are satisfied by repaired items is the longest queue rule: at the completion of a service (repair), the repaired item is delivered to the base that has the largest number of failed items. We point out a direct relation between our model and the classical longer queue model. We obtain simple expressions for several probabilities of interest, and show how all two-dimensional queue length probabilities may be obtained. Finally, we derive the sojourn time distributions

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al

Sorl1 as an Alzheimer's disease predisposition gene?

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively disabling impairments in memory, cognition, and non-cognitive behavioural symptoms. Sporadic AD is multifactorial and genetically complex. While several monogenic mutations cause early-onset AD and gene alleles have been suggested as AD susceptibility factors, the only extensively validated susceptibility gene for late-onset AD is the apolipoprotein E (APOE) epsilon4 allele. Alleles of the APOE gene do not account for all of the genetic load calculated to be responsible for AD predisposition. Recently, polymorphisms across the neuronal sortilin-related receptor (SORL1) gene were shown to be significantly associated with AD in several cohorts. Here we present the results of our large case-control whole-genome scan at over 500,000 polymorphisms which presents weak evidence for association and potentially narrows the association interval

The prognostic and predictive power of redox rotein expression for anthracycline-based chemotherapy response in locally advanced breast cancer

Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre treatment needle core biopsy and postanthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) p, h and a, catalase and manganese superoxide dismutase. GST p (P¼0.05) and catalase (P¼0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P¼0.017) and thioredoxin reductase (P¼0.022) were independent prognostic factors for distant metastasis free survival and TxNIP for overall survival (P¼0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P¼0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments

Chew-Bites, Jaw Movement Allocation and Bite Rate in Grazing Cattle as Identified by Acoustic Monitoring

Bite rate derives from the time budget of the biting and chewing processes of intake, which are both performed by jaw movements. A new type of jaw movement was revealed by acoustic monitoring in cattle - the chew-bite -which chews herbage already in the mouth and harvests fresh herbage with the same jaw movement (Laca et al., 1992). Chew-biting should enable the animal to reduce the total number of jaw movements performed per bite without reducing the number of chews per bite. We examined the variation among individuals in the allocation of jaw movements between the three types, and its relation to bite rate

The Importance of Patch Size in Estimating Steady-State Bite Rate in Grazing Cattle

Since the pioneering work of Black and Kenney (1984), various intake studies have been conducted at the spatial scale of a single feeding station ( patch ) to elucidate the processes that determine instantaneous intake rate (e.g. Laca et al., 1994). While these are well-suited for patch depletion studies, it is less clear how well they represent non-patchy and relatively homogeneous environments (Ungar & Griffiths, 2002). Clearly, grazing should be restricted to the upper grazing horizon (i.e. layer of bites), but sample duration may be insufficient to characterize steady-state behaviour, especially when grazing commences on an empty mouth. We examined the impact of feeding station size on bite rate and jaw movement allocation between bites and chews

Drinking during social isolation: investigating associations between stress, inhibitory control, boredom, drinking motives, and alcohol use

Background: We aimed to assess whether stress, boredom, drinking motives, and/or inhibitory control were related to alcohol use during a period of social isolation. Method: Analyses were carried out on questionnaire data (N = 337) collected during the first wave of the COVID-19 pandemic (7 April–3 May 2020). We first assessed changes in drinking behavior, stress and boredom. We then regressed drinking behavior on drinking motives, inhibitory control, stress, and boredom. We also investigated interactions between change in stress/boredom and inhibitory control. Results: A minority of respondents reported increased alcohol use (units = 23.52%, drinking days = 20.73%, heavy days = 7.06%), alcohol-related problems (9.67%), and stress (36.63%). Meanwhile, most respondents reported increased boredom (67.42%). Similarly, boredom significantly increased (B = 21.22, p < .001), on average, while alcohol-related problems decreased (B = −1.43 p < .001). Regarding drinking motives, decreased alcohol-related problems were associated with social drinking motives (B = −0.09, p = .005). Surprisingly, risk-taking was associated with decreased alcohol-related problems (B = −0.02, p = .008) and neither stress nor boredom independently predicted changes in alcohol use. Finally, several significant interactions suggested that those who were more impulsive and less bored were more likely to report increased alcohol use and vice versa. Conclusions: These data provide a nuanced overview of changes in drinking-related behavior during the COVID-19-induced period of social isolation. While most people reduced their drinking, there was evidence of complex interactions between impulsivity and boredom that may be explored in future studies

Unanswered ethical and scientific questions for trials of invasive interventions for coronary disease: The case of single vessel disease

Trials in the 1990s demonstrated that medical therapy is as effective as invasive therapies for treating single-vessel coronary disease. Yet more recent studies enrolling patients with this condition have focused on evaluating only invasive approaches, namely, stenting versus coronary artery bypass surgery. Several ethical and scientific questions remain unanswered regarding the conduct of these later trials. Were they justified? Why wasn't a medical therapy arm included? Were subjects informed about the availability of medical therapy as an equivalent option? Was optimized medical therapy given prior to randomization? The absence of clear answers to these questions raises the possibility of serious bias in favor of invasive interventions. Considering that medical therapy is underutilized in patients with coronary disease, efforts should focus more on increasing utilization of medical therapy and proper selection of noninvasive interventions

Reno-protective effects of renin–angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis

AIMS/HYPOTHESIS: This meta-analysis aimed to compare the renal outcomes between ACE inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and other antihypertensive drugs or placebo in type 2 diabetes. METHODS: Publications were identified from Medline and Embase up to July 2011. Only randomised controlled trials comparing ACEI/ARB monotherapy with other active drugs or placebo were eligible. The outcome of end-stage renal disease, doubling of serum creatinine, microvascular complications, microalbuminuria, macroalbuminuria and albuminuria regression were extracted. Risk ratios were pooled using a random-effects model if heterogeneity was present; a fixed-effects model was used in the absence of heterogeneity. RESULTS: Of 673 studies identified, 28 were eligible (n = 13-4,912). In direct meta-analysis, ACEI/ARB had significantly lower risk of serum creatinine doubling (pooled RR = 0.66 [95% CI 0.52, 0.83]), macroalbuminuria (pooled RR = 0.70 [95% CI 0.50, 1.00]) and albuminuria regression (pooled RR 1.16 [95% CI 1.00, 1.39]) than other antihypertensive drugs, mainly calcium channel blockers (CCBs). Although the risks of end-stage renal disease and microalbuminuria were lower in the ACEI/ARB group (pooled RR 0.82 [95% CI 0.64, 1.05] and 0.84 [95% CI 0.61, 1.15], respectively), the differences were not statistically significant. The ACEI/ARB benefit over placebo was significant for all outcomes except microalbuminuria. A network meta-analysis detected significant treatment effects across all outcomes for both active drugs and placebo comparisons. CONCLUSIONS/INTERPRETATION: Our review suggests a consistent reno-protective effect of ACEI/ARB over other antihypertensive drugs, mainly CCBs, and placebo in type 2 diabetes. The lack of any differences in BP decrease between ACEI/ARB and active comparators suggest this benefit is not due simply to the antihypertensive effect