Evidence for Irruptive Fluctuation in Axis Deer of Hawai‘i

Axis deer on the Hawaiian Islands of Maui, Lāna‘i, and Moloka‘i simultaneously experienced one of the most dramatic population crashes on record in 2020-2021, which coincided with extended drought conditions and prompted an emergency declaration for these islands. This phenomenon has been anecdotally documented during previous drought events in 2011-2012, but never formally studied. Newspaper articles document abundant deer becoming a nuisance to agriculture and natural resources, and then experiencing high mortality during droughts. This phenomenon fits Caughley’s (1970) operational definition of eruptive (sic) fluctuation “…as an increase in numbers over at least two generations, followed by a marked decline.” We examined available deer population and rainfall records over the time period of interest. Deer may have increased rapidly during favorable years with high survival and recruitment. During moderate drought, young of the year may experience high mortality, with little recruitment to populations. During severe drought, adults may experience noticeably high mortality. When populations are suppressed by large numbers of removals, fluctuations in mortality may be modulated. Abandonment of large-scale intensive agriculture in recent decades may complicate interpretation but understanding these population processes may lead to better management strategies for axis deer in Hawai‘i

Parameterized Compilation Lower Bounds for Restricted CNF-formulas

We show unconditional parameterized lower bounds in the area of knowledge compilation, more specifically on the size of circuits in decomposable negation normal form (DNNF) that encode CNF-formulas restricted by several graph width measures. In particular, we show that - there are CNF formulas of size $n$ and modular incidence treewidth $k$ whose smallest DNNF-encoding has size $n^{\Omega(k)}$, and - there are CNF formulas of size $n$ and incidence neighborhood diversity $k$ whose smallest DNNF-encoding has size $n^{\Omega(\sqrt{k})}$. These results complement recent upper bounds for compiling CNF into DNNF and strengthen---quantitatively and qualitatively---known conditional low\-er bounds for cliquewidth. Moreover, they show that, unlike for many graph problems, the parameters considered here behave significantly differently from treewidth

Bit-Vector Model Counting using Statistical Estimation

Approximate model counting for bit-vector SMT formulas (generalizing \#SAT) has many applications such as probabilistic inference and quantitative information-flow security, but it is computationally difficult. Adding random parity constraints (XOR streamlining) and then checking satisfiability is an effective approximation technique, but it requires a prior hypothesis about the model count to produce useful results. We propose an approach inspired by statistical estimation to continually refine a probabilistic estimate of the model count for a formula, so that each XOR-streamlined query yields as much information as possible. We implement this approach, with an approximate probability model, as a wrapper around an off-the-shelf SMT solver or SAT solver. Experimental results show that the implementation is faster than the most similar previous approaches which used simpler refinement strategies. The technique also lets us model count formulas over floating-point constraints, which we demonstrate with an application to a vulnerability in differential privacy mechanisms

The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn’s disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects

Eukaryotic initiation factor 4E-binding protein as an oncogene in breast cancer

Abstract Background Eukaryotic Initiation Factor 4E-Binding Protein (EIF4EBP1, 4EBP1) is overexpressed in many human cancers including breast cancer, yet the role of 4EBP1 in breast cancer remains understudied. Despite the known role of 4EBP1 as a negative regulator of cap-dependent protein translation, 4EBP1 is predicted to be an essential driving oncogene in many cancer cell lines in vitro, and can act as a driver of cancer cell proliferation. EIF4EBP1 is located within the 8p11-p12 genomic locus, which is frequently amplified in breast cancer and is known to predict poor prognosis and resistance to endocrine therapy. Methods Here we evaluated the effect of 4EBP1 targeting using shRNA knock-down of expression of 4EBP1, as well as response to the mTORC targeted drug everolimus in cell lines representing different breast cancer subtypes, including breast cancer cells with the 8p11-p12 amplicon, to better define a context and mechanism for oncogenic 4EBP1. Results Using a genome-scale shRNA screen on the SUM panel of breast cancer cell lines, we found 4EBP1 to be a strong hit in the 8p11 amplified SUM-44 cells, which have amplification and overexpression of 4EBP1. We then found that knock-down of 4EBP1 resulted in dramatic reductions in cell proliferation in 8p11 amplified breast cancer cells as well as in other luminal breast cancer cell lines, but had little or no effect on the proliferation of immortalized but non-tumorigenic human mammary epithelial cells. Kaplan-Meier analysis of EIF4EBP1 expression in breast cancer patients demonstrated that overexpression of this gene was associated with reduced relapse free patient survival across all breast tumor subtypes. Conclusions These results are consistent with an oncogenic role of 4EBP1 in luminal breast cancer and suggests a role for this protein in cell proliferation distinct from its more well-known role as a regulator of cap-dependent translation.https://deepblue.lib.umich.edu/bitstream/2027.42/149184/1/12885_2019_Article_5667.pd

Single Nucleotide Polymorphisms That Increase Expression of the Guanosine Triphosphatase RAC1 Are Associated With Ulcerative Colitis

BACKGROUND & AIMS: RAC1 is a GTPase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases (IBD) are associated with dysregulation of immune defenses. We studied the role of RAC1 in IBD using human genetic and functional studies and animal models of colitis. METHODS: We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms (SNPs) in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 mRNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulphate sodium (DSS). RESULTS: We observed a genetic association between RAC1 with ulcerative colitis (UC) in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the SNPs rs10951982 (Pcombined UC = 3.3 × 10–8, odds ratio [OR]=1.43 [1.26–1.63]) and rs4720672 (Pcombined UC=4.7 × 10–6, OR=1.36 [1.19–1.58]). Patients with IBD who had the rs10951982 risk allele had increased expression of RAC1, compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected them against DSS-induced colitis. CONCLUSION: Studies of human tissue samples and knockout mice demonstrated a role for the GTPase RAC1 in the development of UC; increased expression of RAC1 was associated with susceptibility to colitis

Online social networking and psychological experiences:the perceptions of young people with mental health difficulties

Objectives This study explores the interaction between online social networking experiences and wellbeing in 12 young people accessing mental health services. Methods Data from semi-structured interviews was analysed using Grounded Theory methodology. Results “Threats and judgement” and “connection and support” were experienced by adolescents, facilitated by having continuous access to a vast social network. These experiences influenced adolescents' psychological wellbeing, mediated by their responses to threat and judgement and maintaining “safe sharing” with their network. Social network use was conceived as a gamble of balancing its potentially positive and negative impact in a culture in which social network use appears to be unavoidable. Conclusions The findings indicate the importance of routine assessment and formulation of social networking use in understanding adolescents' psychological distress. Furthermore, a range of opportunities exist for clinicians to utilise the anonymity and peer support that social networks offer to broaden the range of mental health services offered to young people

Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease

Contains fulltext : 96924.pdf (publisher's version ) (Open Access)BACKGROUND: We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD. METHODS: mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls. RESULTS: mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD. CONCLUSIONS: FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients