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Several modern programming systems, including GHC Haskell, Agda, Idris, and Hazel, support typed holes . Assigning static and, to varying degree, dynamic meaning to programs with holes allows program editors and other tools to offer meaningful feedback and assistance throughout editing, i.e. in a live manner. Prior work, however, has considered only holes appearing in expressions and types. This paper considers, from type theoretic and logical first principles, the problem of typed pattern holes. We confront two main difficulties, (1) statically reasoning about exhaustiveness and irredundancy when patterns are not fully known, and (2) live evaluation of expressions containing both pattern and expression holes. In both cases, this requires reasoning conservatively about all possible hole fillings. We develop a typed lambda calculus, Peanut, where reasoning about exhaustiveness and redundancy is mapped to the problem of deriving first order entailments. We equip Peanut with an operational semantics in the style of Hazelnut Live that allows us to evaluate around holes in both expressions and patterns. We mechanize the metatheory of Peanut in Agda and formalize a procedure capable of deciding the necessary entailments. Finally, we scale up and implement these mechanisms within Hazel, a programming environment for a dialect of Elm that automatically inserts holes during editing to provide static and dynamic feedback to the programmer in a maximally live manner, i.e. for every possible editor state. Hazel is the first maximally live environment for a general-purpose functional language.

Background: Although men of African ancestry (AA) have the highest mortality rate from prostate cancer (PCa), relatively little is known about the germline variants that are associated with PCa risk in AA men. The goal of this study is to systematically evaluate rare, recurrent nonsynonymous variants across the exome for their association with PCa in AA men. Methods: Whole exome sequencing (WES) of germline DNA in two AA PCa patient cohorts of Johns Hopkins Hospital (N=960) and Wayne State University (N=747) was performed. All nonsynonymous variants presented in both case cohorts, with a carrier rate between 0.3% and 1%, were identified. Their carrier rates were compared with rates from 8,128 African/African American (AFR) control subjects from The Genome Aggregation Database (gnomAD) using Fisher’s exact test. Significant variants, defined as false discovery rate (FDR) adjusted p-value £0.05, were further evaluated in AA PCa cases (N=132) and controls (N=1,184) from the UK Biobank (UKB). Results: Two variants reached a pre-specified statistical significance level. The first was p.R14Q in GPRC5C (found in 0.47% of PCa cases and 0.01% of population controls); odds ratio (OR) for PCa was 37.46 (95%CI 4.68-299.72), pexact=7.01E-06, FDR adjusted p-value=0.05. The second was p.R511Q in IGF1R (found in 0.53% of PCa cases and 0.01% of population controls); OR for PCa was 21.54 (95%CI 4.65-99.76), pexact=5.51E-06, FDR adjusted p-value=0.05. The mean percentage of African ancestry was similar between variant carriers and non-carriers of each variant, p>0.05. In the UKB AA men, GPRC5C R14Q was 0.76% and 0.08% in cases and controls, respectively, OR for PCa was 9.00 (95%CI 0.56-145.23), pexact =0.19. However, IGF1R R511Q was not found in cases or controls. Conclusions: This WES study identified two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Confirmation in additional large populations of AA PCa cases and controls is required.

Deep brain stimulation (DBS) is an established intervention for use in pediatric movement disorders, especially dystonia. Although multiple publications have provided guidelines for deep brain stimulation patient selection and programming in adults, there are no evidence-based or consensus statements published for pediatrics. The result is lack of standardized care and underutilization of this effective treatment. To this end, we assembled a focus group of 13 pediatric movement disorder specialists and 1 neurosurgeon experienced in pediatric deep brain stimulation to review recent literature and current practices and propose a standardized approach to candidate selection, implantation target site selection, and programming algorithms. For pediatric dystonia, we provide algorithms for (1) programming for initial session and follow-up sessions, and (2) troubleshooting side effects encountered during programming. We discuss common side effects, how they present, and recommendations for management. This topical review serves as a resource for movement disorders specialists interested in using deep brain stimulation for pediatric dystonia.

Advanced and aggressive prostate cancer (PCa) depends on glutamine for survival and proliferation. We have previously shown that inhibition of glutaminase 1, which catalyzes the rate-limiting step of glutamine catabolism, achieves significant therapeutic effect; however, therapy resistance is inevitable. Here we report that while the glutamine carbon is critical to PCa survival, a parallel pathway of glutamine nitrogen catabolism that actively contributes to pyrimidine assembly is equally important for PCa cells. Importantly, we demonstrate a reciprocal feedback mechanism between glutamine carbon and nitrogen pathways which leads to therapy resistance when one of the two pathways is inhibited. Combination treatment to inhibit both pathways simultaneously yields better clinical outcome for advanced PCa patients.

Genetic studies of prostate cancer susceptibility have predominantly focused on non-Hispanic White men, despite the observation that Black men are more likely to develop prostate cancer and die from the disease. Therefore, we sought to identify genetic variants in Black patients diagnosed with early-onset prostate cancer.Whole-exome sequencing of germline DNA from a population-based cohort of Black men diagnosed with prostate cancer at age 62 years or younger was performed. Analysis was focused on a panel of DNA damage repair (DDR) genes andAmong 743 Black prostate cancer patients, we identified 26 unique pathogenic (P) or likely pathogenic (LP) variants in 14 genes (includingVariants in DDR genes and

Several studies have shown that microsatellite changes can be profiled in urine for the detection of bladder cancer. Use of microsatellite analysis (MSA) for bladder cancer detection requires a comprehensive analysis of up to 15 to 20 markers, which were based on amplification and interpretations of many individual MSA markers and can be technically challenging. Here, in a way to develop fast, more efficient, standardized and less costly MSA for detection of bladder cancer, we have developed 3 multiplex PCR based MSA assay, all of which were analyzed by genetic analyzer. First, we have selected 16 MSA markers based on 9 selected publications. Based on samples from Johns Hopkins University (JHU Sample, first set sample), we have attempted to develop MSA assay based on doublet, 2 tube based multiplex PCR combined with singlet, 1 tube based single plex PCR. While this assay was initially successful, we have encountered a reproducibility issue and we then developed MSA based on triplet, 3 tube based multiplex PCR (Triplet MSA assay). From second set samples (6 cancer patients’ and 14 normal individuals’ sample), our Triplet Assay with 15 MSA markers correctly predicted all of 6/6 cancer samples to be cancerous sample and 14/14 samples from normal individuals as normal samples. This result suggests that our Triplet MSA Assay combined with genetic analyzer is a potentially time and cost-effective genetic assay for bladder cancer detection and can be used potentially as a dependable assay in patient care.

Text editing is powerful, but some types of expressions are more naturally represented and manipulated graphically. Examples include expressions that compute colors, music, animations, tabular data, plots, diagrams, and other domain-specific data structures. This paper introduces live literals, or livelits, which allow clients to fill holes of types like these by directly manipulating a user-defined GUI embedded persistently into code. Uniquely, livelits are compositional: a livelit GUI can itself embed spliced expressions, which are typed, lexically scoped, and can in turn embed other livelits. Livelits are also uniquely live: a livelit can provide continuous feedback about the run-time implications of the client’s choices even when splices mention bound variables, because the system continuously gathers closures associated with the hole that the livelit is filling. We integrate livelits into Hazel, a live hole-driven programming environment, and describe case studies that exercise these novel capabilities. We then define a simply typed livelit calculus, which specifies how livelits operate as live graphical macros. The metatheory of macro expansion has been mechanized in Agda.

Studies of the human skin microbiome suggest that Propionibacterium acnes strains may contribute differently to skin health and disease. However, the immune phenotype and functions of T helper type 17 (Th17) cells induced by healthy (PH) versus acne (PA) skin-associated P. acnes strains are currently unknown. We stimulated peripheral blood mononuclear cells from healthy donors and observed that PA strains induce higher IL-17 levels than PH strains. We next generated PH and PA strain-specific Th17 clones and show that P. acnes strains induce Th17 cells of varied phenotype and function that are stable in the presence of IL-2 and IL-23. Although PH- and PA-specific clones expressed similar levels of LL-37 and DEFB4, only PH-specific clones secreted molecules sufficient to kill P. acnes. Furthermore, electron microscopic studies showed that supernatants derived from activated PH and not PA-specific clones exhibited robust bactericidal activity against P. acnes, and complete breaches in the bacterial cell envelope were observed. This antimicrobial activity was independent of IL-26, because both natural IL-26 released by Th17 clones and rhIL-26 lacked antimicrobial potency against P. acnes. Overall, our data suggest that P. acnes strains may differentially modulate the CD4+ T-cell responses, leading to the generation of Th17 cells that may contribute to either homeostasis or acne pathogenesis.

This article considers the environmental legacy of Soviet central planning, that began in the late-1920s, and also longer-term human intervention, in the ‘natural’ world of rural Southern Ukraine. It is based on a journey across the steppe, what the author learned from people, especially scientists, he met, and research in written sources. The first section considers ‘nature transformed’. Since the conquest by the Russian Empire in the 18th century, the steppe grassland has been transformed from pasture for livestock into arable land farmed by settlers of European origin. The second section, ‘nature protected’, discusses the Askania Nova biosphere reserve, where an area of grassland has been protected since the late-19th century. The reserve also contains an artificial woodland park and a collection of grazing animals from all over the world. The third section, ‘nature destroyed’, is about the Oleshkivs’ki sands, on the left bank of the estuary of the Dnipro river opposite the city of Kherson. In ancient times, a forest grew on the sands. From the 18th century, European settlers cleared much of the forest for grazing, leading to erosion. Trees have since been replanted surrounding a curious landscape of sand dunes, which have become a habitat for rare plant species. The sands were also used a bombing range for Warsaw Pact air forces during the Cold War, but part if now protected as a nature reserve.

Previous versions: Mylavarapu, Rao. 2009. “UF/IFAS Extension Soil Testing Laboratory (ESTL) Analytical Procedures and Training Manual”. EDIS 2009 (2), 14. https://doi.org/10.32473/edis-ss312-2009. Mylavarapu, Rao, and Elizabeth Kennelley. 1. “UF/IFAS Extension Soil Testing Laboratory (ESTL) Analytical Procedures and Training Manual”. EDIS 2002 (5). https://doi.org/10.32473/edis-ss312-2002.

Summary Background We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents the results of the study after a median follow-up of 9·7 years (IQR 7·8–12·7). Methods In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year follow-up analysis was not prespecified in the trial's protocol and thus was not adjusted for multiple, sequential testing. This trial is registered with ClinicalTrials.gov, number NCT00072293. Findings Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after randomisation. Disease-free survival at 10 years was 76·8% (95% CI 72·5–81·0) in the no axillary dissection group, compared with 74·9% (70·5–79·3) in the axillary dissection group (HR 0·85, 95% CI 0·65–1·11; log-rank p=0·24; p=0·0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of 453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group). One serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to axillary dissection; the event resolved without sequelae. Interpretation The findings of the IBCSG 23-01 trial after a median follow-up of 9·7 years (IQR 7·8–12·7) corroborate those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel nodes is minimal or moderate in patients with early breast cancer. Funding International Breast Cancer Study Group.

S100A2, a member of the S100 protein family, is known to be downregulated in a number of human cancers, leading to its designation as a potential tumor suppressor gene. Here, we investigated the expression and methylation status of S100A2 in head&neck and bladder cancer. Reduced mRNA and protein expression was observed in 8 head&neck and bladder cancer cell lines. To explore the mechanism responsible for the downregulation of S100A2, we treated six cell lines with 5-aza-2′-deoxycytidine. We found S100A2 is silenced in association with aberrant promoter-region methylation and its expression is restored with 5-aza-2′-deoxycytidine treatment. Of 31 primary head&neck cancer cases and 31 bladder cancer cases, promoter methylation was detected in 90% and 80% of cases, respectively. Interestingly, only 1/9 of normal head&neck tissues and 2/6 of normal bladder tissues showed promoter methylation. S100A2 promoter methylation can be detected in urine and is more frequent in bladder cancer patients than in healthy subjects (96% vs 48% respectively). Moreover, increased methylation of S100A2 is linked to the progression of the tumor in bladder cancer (p

A beautiful theorem of Zeckendorf states that every positive integer can be uniquely decomposed as a sum of non-consecutive Fibonacci numbers $\{F_n\}$, where $F_1 = 1$, $F_2 = 2$ and $F_{n+1} = F_n + F_{n-1}$. For general recurrences $\{G_n\}$ with non-negative coefficients, there is a notion of a legal decomposition which again leads to a unique representation, and the number of summands in the representations of uniformly randomly chosen $m \in [G_n, G_{n+1})$ converges to a normal distribution as $n \to \infty$. We consider the converse question: given a notion of legal decomposition, is it possible to construct a sequence $\{a_n\}$ such that every positive integer can be decomposed as a sum of terms from the sequence? We encode a notion of legal decomposition as a function $f:\N_0\to\N_0$ and say that if $a_n$ is in an "$f$-decomposition", then the decomposition cannot contain the $f(n)$ terms immediately before $a_n$ in the sequence; special choices of $f$ yield many well known decompositions (including base-$b$, Zeckendorf and factorial). We prove that for any $f:\N_0\to\N_0$, there exists a sequence $\{a_n\}_{n=0}^\infty$ such that every positive integer has a unique $f$-decomposition using $\{a_n\}$. Further, if $f$ is periodic, then the unique increasing sequence $\{a_n\}$ that corresponds to $f$ satisfies a linear recurrence relation. Previous research only handled recurrence relations with no negative coefficients. We find a function $f$ that yields a sequence that cannot be described by such a recurrence relation. Finally, for a class of functions $f$, we prove that the number of summands in the $f$-decomposition of integers between two consecutive terms of the sequence converges to a normal distribution., Comment: Version 1.0, 18 pages, keywords: Zeckendorf decompositions, recurrence relations, Stirling numbers of the first kind, Gaussian behavior