bluuebunny/crossref_metadata_2025 huggingface dataset:
A TGFβ–miR-182–BRCA1 axis controls the mammary differentiation hierarchy
Authors: Martinez-Ruiz Haydeliz , Illa-Bochaca Irineu , Omene Coral , Hanniford Douglas , Liu Qi , Hernando Eva , Barcellos-Hoff Mary Helen
Published: December 2016

TGFβ promotes luminal differentiation of mammary stem cells by suppressing a
BRCA1
-targeting microRNA.
Emerging roles for organelles in cellular regulation
Authors: Gough Nancy R.
Published: December 2016

Organelles not only regulate cell behavior and function but are themselves regulated by internal and external signals.
Reducing nerve-damaging reactive metabolites
Authors: VanHook Annalisa M.
Published: December 2016

Nematode studies reveal the pathway that promotes detoxification of reactive α-dicarbonyls and drugs that can enhance this pathway.
Identification of a Novel Lincomycin Resistance Mutation Associated with Activation of Antibiotic Production in Streptomyces coelicolor A3(2)
Authors: Wang Guojun , Izawa Masumi , Yang Xiaoge , Xu Dongbo , Tanaka Yukinori , Ochi Kozo
Published: December 2016

Comparative genome sequencing analysis of a lincomycin-resistant strain of
Streptomyces coelicolor
A3(2) and the wild-type strain identified a novel mutation conferring a high level of lincomycin resistance. Surprisingly, the new mutation was an in-frame DNA deletion in the genes
SCO4597
and
SCO4598
, resulting in formation of the hybrid gene
linR. SCO4597
and
SCO4598
encode two histidine kinases, which together with
SCO4596
, encoding a response regulator, constitute a unique two-component system. Sequence analysis indicated that these three genes and their arrangement patterns are ubiquitous among all
Streptomyces
genomes sequenced to date, suggesting these genes play important regulatory roles. Gene replacement showed that this mutation was responsible for the high level of lincomycin resistance, the overproduction of the antibiotic actinorhodin, and the enhanced morphological differentiation of this strain. Moreover, heterologous expression of the hybrid gene
linR
in
Escherichia coli
conferred resistance to lincomycin in this organism. Introduction of the hybrid gene
linR
in various
Streptomyces
strains by gene engineering technology may widely activate and/or enhance antibiotic production.
Effects of Increasing the Affinity of CarD for RNA Polymerase on Mycobacterium tuberculosis Growth, rRNA Transcription, and Virulence
Authors: Garner Ashley L. , Rammohan Jayan , Huynh Jeremy P. , Onder Lucas M. , Chen James , Bae Brian , Jensen Drake , Weiss Leslie A. , Manzano Ana Ruiz , Darst Seth A. , Campbell Elizabeth A. , Nickels Bryce E. , Galburt Eric A. , Stallings Christina L.
Published: December 2016

CarD is an essential RNA polymerase (RNAP) interacting protein in
Mycobacterium tuberculosis
that stimulates formation of RNAP-promoter open complexes. CarD plays a complex role in
M. tuberculosis
growth and virulence that is not fully understood. Therefore, to gain further insight into the role of CarD in
M. tuberculosis
growth and virulence, we determined the effect of increasing the affinity of CarD for RNAP. Using site-directed mutagenesis guided by crystal structures of CarD bound to RNAP, we identified amino acid substitutions that increase the affinity of CarD for RNAP. Using these substitutions, we show that increasing the affinity of CarD for RNAP increases the stability of the CarD protein in
M. tuberculosis
. In addition, we show that increasing the affinity of CarD for RNAP increases the growth rate in
M. tuberculosis
without affecting 16S rRNA levels. We further show that increasing the affinity of CarD for RNAP reduces
M. tuberculosis
virulence in a mouse model of infection despite the improved growth rate
in vitro
. Our findings suggest that the CarD-RNAP interaction protects CarD from proteolytic degradation in
M. tuberculosis
, establish that growth rate and rRNA levels can be uncoupled in
M. tuberculosis
and demonstrate that the strength of the CarD-RNAP interaction has been finely tuned to optimize virulence.

IMPORTANCE
Mycobacterium tuberculosis
, the causative agent of tuberculosis, remains a major global health problem. In order to develop new strategies to battle this pathogen, we must gain a better understanding of the molecular processes involved in its survival and pathogenesis. We have previously identified CarD as an essential transcriptional regulator in mycobacteria. In this study, we detail the effects of increasing the affinity of CarD for RNAP on transcriptional regulation, CarD protein stability, and virulence. These studies expand our understanding of the global transcription regulator CarD, provide insight into how CarD activity is regulated, and broaden our understanding of prokaryotic transcription.
Role of Ribonucleotide Reductase in Bacillus subtilis Stress-Associated Mutagenesis
Authors: Castro-Cerritos Karla Viridiana , Yasbin Ronald E. , Robleto Eduardo A. , Pedraza-Reyes Mario
Published: December 2016

The Gram-positive microorganism
Bacillus subtilis
relies on a single class Ib ribonucleotide reductase (RNR) to generate 2′-deoxyribonucleotides (dNDPs) for DNA replication and repair. In this work, we investigated the influence of RNR levels on
B. subtilis
stationary-phase-associated mutagenesis (SPM). Since RNR is essential in this bacterium, we engineered a conditional mutant of strain
B. subtilis
YB955 (
hisC952 metB5 leu427
) in which expression of the
nrdEF
operon was modulated by isopropyl-β-
d
-thiogalactopyranoside (IPTG). Moreover, genetic inactivation of
ytcG
, predicted to encode a repressor (NrdR) of
nrdEF
in this strain, dramatically increased the expression levels of a transcriptional
nrdE-lacZ
fusion. The frequencies of mutations conferring amino acid prototrophy in three genes were measured in cultures under conditions that repressed or induced RNR-encoding genes. The results revealed that RNR was necessary for SPM and overexpression of
nrdEF
promoted growth-dependent mutagenesis and SPM. We also found that
nrdEF
expression was induced by H
2
O
2
and such induction was dependent on the master regulator PerR. These observations strongly suggest that the metabolic conditions operating in starved
B. subtilis
cells increase the levels of RNR, which have a direct impact on SPM.

IMPORTANCE
Results presented in this study support the concept that the adverse metabolic conditions prevailing in nutritionally stressed bacteria activate an oxidative stress response that disturbs ribonucleotide reductase (RNR) levels. Such an alteration of RNR levels promotes mutagenic events that allow
Bacillus subtilis
to escape from growth-limited conditions.
Effectiveness of foot orthoses and shock-absorbing insoles for the prevention of injury: a systematic review and meta-analysis
Authors: Bonanno Daniel R , Landorf Karl B , Munteanu Shannon E , Murley George S , Menz Hylton B
Published: December 2016

Objective

To investigate the evidence relating to the effectiveness of foot orthoses and shock-absorbing insoles for the prevention of musculoskeletal injury.

Design

Systematic review and meta-analysis.

Eligibility criteria for selecting studies

Clinical trials evaluating the effectiveness of foot orthoses and shock-absorbing insoles for the prevention of injury.

Data sources

Cochrane Library, CINAHL, EMBASE, MEDLINE and SPORTDiscus from their inception up to the first week of June 2016.

Results

11 trials that had evaluated foot orthoses and 7 trials that had evaluated shock-absorbing insoles were included. The median Physiotherapy Evidence Database (PEDro) score for trials that had evaluated foot orthoses and shock-absorbing insoles was 5 (range 3–8/10) and 3 (range 1–7/10), respectively. Meta-analysis found that foot orthoses were effective for preventing overall injuries (risk ratio (RR) 0.72, 95% CI 0.55 to 0.94) and stress fractures (RR 0.59, 95% CI 0.45 to 0.76), but not soft-tissue injuries (RR 0.79, 95% CI 0.55 to 1.14). In contrast, shock-absorbing insoles were not effective for preventing overall injuries (RR 0.92, 95% CI 0.73 to 1.16), stress fractures (RR 1.15, 95% CI 0.57 to 2.32) or soft-tissue injuries (RR 0.92, 95% CI 0.74 to 1.15).

Conclusions

Foot orthoses were found to be effective for preventing overall injuries and stress fractures but not soft-tissue injuries, while shock-absorbing insoles were not found to be effective for preventing any injury. However, further well-designed trials will assist the accuracy and precision of the estimates of risk reduction as the quality of the included trials varied greatly.
Caffeine consumption during pregnancy and ADHD at the age of 11 years: a birth cohort study
Authors: Del-Ponte Bianca , Santos Iná S , Tovo-Rodrigues Luciana , Anselmi Luciana , Munhoz Tiago N , Matijasevich Alicia
Published: December 2016

Objective

Studies evaluating caffeine intake during pregnancy and long-term outcomes, such as the child's neurobehaviour, are still scarce and their results are inconsistent. The objective of the present study was to evaluate the association between maternal consumption of caffeine during pregnancy and attention deficit hyperactivity disorder (ADHD) at the age of 11 years.

Methodology

All children born in the city of Pelotas, Brazil, during the year 2004, were selected for a cohort study. The mothers were interviewed at birth to obtain information on coffee and yerba mate consumption during pregnancy, among other matters. At the age of 11 years, presence of ADHD was evaluated using the Development and Well-Being Assessment (DAWBA) questionnaire, applied to the mothers. The prevalence of ADHD was calculated, with 95% CIs. The association between caffeine consumption and ADHD was tested by means of logistic regression.

Results

3485 children were included in the analyses. The prevalence of ADHD was 4.1% (95% CI 3.4% to 4.7%): 5.8% (95% CI 4.7% to 6.9%) among boys and 2.3% (95% CI 1.5% to 3.0%) among girls. The prevalence of caffeine consumption during the entire pregnancy and in the first, second and third trimesters was 88.7% (87.7% to 89.7%), 86.5% (85.4% to 87.5%), 83.0% (81.8% to 84.2%) and 92.3% (91.4% to 93.1%), respectively. Caffeine consumption during the entire pregnancy and the first, second and third trimesters were not associated with ADHD in the crude or adjusted analysis.

Conclusions

The present study did not show any association between maternal caffeine consumption during pregnancy and ADHD at the age of 11 years.
Quality of prescribing of antipsychotic medication for people with intellectual disability under the care of UK mental health services: a cross-sectional audit of clinical practice
Authors: Paton Carol , Bhatti Sumera , Purandare Kiran , Roy Ashok , Barnes TRE
Published: December 2016

Objectives

To determine the prevalence and quality of antipsychotic prescribing for people with intellectual disability (ID).

Design

A clinical audit of prescribing practice in the context of a quality improvement programme. Practice standards for audit were derived from relevant, evidence-based guidelines, including NICE. Data were mainly collected from the clinical records, but to determine the clinical rationale for using antipsychotic medication in individual cases, prescribers could also be directly questioned.

Settings

54 mental health services in the UK, which were predominantly NHS Trusts.

Participants

Information on prescribing was collected for 5654 people with ID.

Results

Almost two-thirds (64%) of the total sample was prescribed antipsychotic medication, of whom almost half (49%) had a schizophrenia spectrum or affective disorder diagnosis, while a further third (36%) exhibited behaviours recognised by NICE as potentially legitimate targets for such treatment such as violence, aggression or self-injury. With respect to screening for potential side effects within the past year, 41% had a documented measure of body weight (range across participating services 18–100%), 32% blood pressure (0–100%) and 37% blood glucose and blood lipids (0–100%).

Conclusions

These data from mental health services across the UK suggest that antipsychotic medications are not widely used outside of licensed and/or evidence-based indications in people with ID. However, screening for side effects in those patients on continuing antipsychotic medication was inconsistent across the participating services and the possibility that a small number of these services failed to meet basic standards of care cannot be excluded.
Managing complex respiratory patients in the community: an evaluation of a pilot integrated respiratory care service
Authors: Gillett K , Lippiett K , Astles C , Longstaff J , Orlando R , Lin S X , Powell A , Roberts C , Chauhan A J , Thomas M , Wilkinson T M
Published: December 2016

Introduction

In the UK, there is significant variation in respiratory care and outcomes. An integrated approach to the management of high-risk respiratory patients, incorporating specialist and primary care teams' expertise, is the basis for new integrated respiratory services designed to reduce this variation; however, this model needs evaluating.

Methods

To evaluate an integrated service managing high-risk respiratory patients, electronic searches for patients with asthma and chronic obstructive pulmonary disease at risk of poor outcomes were performed in two general practitioner (GP) practices in a local service-development initiative. Patients were reviewed at joint clinics by primary and secondary care professionals. GPs also nominated patients for inclusion. Reviews were delivered to best standards of care including assessments of diagnosis, control, spirometry, self-management, education, medication, inhaler technique and smoking cessation support. Follow-up of routine clinical data collected at 9-months postclinic were compared with seasonally matched 9-months prior to integrated review.

Results

82 patients were identified, 55 attended. 13 (23.6%) had their primary diagnosis changed. In comparison with the seasonally adjusted baseline period, in the 9-month follow-up there was an increase in inhaled corticosteroid prescriptions of 23.3%, a reduction in short-acting β2-agonist prescription of 33.3%, a reduction in acute respiratory exacerbations of 67.6%, in unscheduled GP surgery visits of 53.3% and acute respiratory hospital admissions reduced from 3 to 0. Only 4 patients (7.3%) required referral to secondary care. Health economic evaluation showed respiratory-related costs per patient reduced by £231.86.

Conclusions

Patients with respiratory disease in this region at risk of suboptimal outcomes identified proactively and managed by an integrated team improved outcomes without the need for hospital referral.
Clinical relevance of pharmacist intervention in an emergency department
Authors: Pérez-Moreno Maria Antonia , Rodríguez-Camacho Juan Manuel , Calderón-Hernanz Beatriz , Comas-Díaz Bernardino , Tarradas-Torras Jordi
Published: December 2016

Objectives

To evaluate the clinical relevance of pharmacist intervention on patient care in emergencies, to determine the severity of detected errors. Second, to analyse the most frequent types of interventions and type of drugs involved and to evaluate the clinical pharmacist's activity.

Methods

A 6-month observational prospective study of pharmacist intervention in the Emergency Department (ED) at a 400-bed hospital in Spain was performed to record interventions carried out by the clinical pharmacists. We determined whether the intervention occurred in the process of medication reconciliation or another activity, and whether the drug involved belonged to the High-Alert Medications Institute for Safe Medication Practices (ISMP) list. To evaluate the severity of the errors detected and clinical relevance of the pharmacist intervention, a modified assessment scale of Overhage and Lukes was used. Relationship between clinical relevance of pharmacist intervention and the severity of medication errors was assessed using ORs and Spearman's correlation coefficient.

Results

During the observation period, pharmacists reviewed the pharmacotherapy history and medication orders of 2984 patients. A total of 991 interventions were recorded in 557 patients; 67.2% of the errors were detected during medication reconciliation. Medication errors were considered severe in 57.2% of cases and 64.9% of pharmacist intervention were considered relevant. About 10.9% of the drugs involved are in the High-Alert Medications ISMP list. The severity of the medication error and the clinical significance of the pharmacist intervention were correlated (Spearman's ρ=0.728/p<0.001).

Conclusions

In this single centre study, the clinical pharmacists identified and intervened on a high number of severe medication errors. This suggests that emergency services will benefit from pharmacist-provided drug therapy services.
Vascular angular remodeling by kissing-Y stenting in wide necked intracranial bifurcation aneurysms
Authors: Melber Katharina , Meila Dan , Draheim Philipp , Grieb Dominik , Greling Björn , Schlunz-Hendann Martin , Brassel Friedhelm
Published: December 2016

Introduction

Single stent deployment leads to a change in vascular geometry in wide necked bifurcation aneurysms. In some complex cases, the use of the single stent technique might not be sufficient or may not be feasible. The kissing-Y stenting technique appears to be an alternative endovascular treatment option. The aim of this study was to evaluate the effects of the kissing-Y stenting technique on vascular angular remodeling.

Methods

21 patients with wide necked intracranial bifurcation aneurysms at different sites (10 anterior communicating artery, 6 middle cerebral artery, 3 basilar artery, 1 vertebral artery/posterior inferior cerebellar artery, 1 internal carotid artery/posterior communicating artery) were treated with 44 closed cell stents (follow-up 2012–2016) using the kissing-Y stenting technique. We analyzed vascular angle geometry between the mother and both affected daughter vessels by digital subtraction angiography, before and after stent deployment, using standard working projections.

Results

Endovascular treatment of wide necked intracranial aneurysms using the kissing-Y stenting technique significantly decreased the angle between the bifurcation branches from 130.4±9.5° to 91.5±9.1° (p<0.0001).

Conclusions

Kissing-Y stenting in wide necked bifurcation aneurysms leads to vascular angular remodeling of both affected branches. The resulting straightening of the bifurcation angle may prevent aneurysmal recurrence.
Understanding the holographic principle via RG flow
Authors: Mukhopadhyay Ayan
Published: December 2016

This is a review of some recent works which demonstrate how the classical equations of gravity in AdS themselves hold the key to understand their holographic origin in the form of a strongly coupled large N QFT whose algebra of local operators can be generated by a few (single-trace) elements. I discuss how this can be realized by reformulating Einstein’s equations in AdS in the form of a nonperturbative RG flow that further leads to a new approach toward constructing strongly interacting QFTs. In particular, the RG flow can self-determine the UV data that are otherwise obtained by solving classical gravity equations and demanding that the solutions do not have naked singularities. For a concrete demonstration, I focus on the hydrodynamic limit in which case this RG flow connects the AdS/CFT correspondence with the membrane paradigm, and also reproduces the known values of the dual QFT transport coefficients.
New physics in neutral D → V V modes
Authors: Biswas Aritra , Mandal Sanjoy
Published: December 2016

We show that it is possible to construct observables to test the existence of new physics in a model independent way for the [Formula: see text] modes using a time-dependent analysis of the neutral [Formula: see text] meson. We show that it is possible to identify whether the NP is due to decay, mixing or a combination of both. We also provide numerical estimates for the polarization amplitudes for the [Formula: see text] mode and show that our analysis is consistent with the present data.
Analysis of DIS structure functions of the nucleon within truncated Mellin moments approach
Authors: Kotlorz Dorota , Kotlorz Andrzej
Published: December 2016

We present generalized evolution equations and factorization in terms of the truncated Mellin moments (TMM) of the parton distributions and structure functions. We illustrate the x and Q2 dependence of TMM in the polarized case. Using the TMM approach we compare the integrals of g1 with HERMES and COMPASS data from the limited x-ranges.
Weyl representation of the canonical commutation relations algebras in a Krein space
Authors: Mnatsakanova M. N. , Salinsky S. G. , Vernov Yu. S.
Published: December 2016

In this paper, the existence of the Weyl representation for the canonical commutation relations algebras was proved in a Krein space.
Isogeometric nonlinear shell elements for thin laminated composites based on analytical thickness integration
Authors: Roohbakhshan Farshad , Sauer Roger A.
Published: December 2016

This paper presents two different formulations for the modeling of thin laminated composite shells, which do not need any numerical integration through the shell thickness. The two proposed formulations are suitable for thin rotation-free shells based on Kirchhoff–Love kinematics. The composite shell is modeled in the framework of equivalent single layer (ESL) theory and the kinematics are adopted from classical laminated plate theory. The two formulations allow for any desired nonlinear isotropic or anisotropic material model as well as arbitrary large strains and deformations. The presented shell models can be used to analyze any arrangement and material behavior of the laminate layers. The FE solution is based on isogeometric analysis (IGA). Quadratic NURBS-based elements are used to ensure the smoothness required for the analysis of thin shells. The robustness and accuracy of the formulation is demonstrated by various numerical examples.
An Efficient Representation Format for Fuzzy Intervals Based on Symmetric Membership Functions
Authors: Marin Manuel , Defour David , Milano Federico
Published: December 2016

This article addresses the execution cost of arithmetic operations with a focus on fuzzy arithmetic. Thanks to an appropriate representation format for fuzzy intervals, we show that it is possible to halve the number of operations and divide by 2 to 8 the memory requirements compared to conventional solutions. In addition, we demonstrate the benefit of some hardware features encountered in today’s accelerators (GPU) such as static rounding, memory usage, instruction-level parallelism (ILP), and thread-level parallelism (TLP). We then describe a library of fuzzy arithmetic operations written in CUDA and C++. The library is evaluated against traditional approaches using compute-bound and memory-bound benchmarks on Nvidia GPUs, with an observed performance gain of 2 to 20.
Automatically disproving fair termination of higher-order functional programs
Authors: Watanabe Keiichi , Sato Ryosuke , Tsukada Takeshi , Kobayashi Naoki
Published: December 2016

We propose an automated method for
disproving
fair termination of higher-order functional programs, which is complementary to Murase et al.’s recent method for
proving
fair termination. A program is said to be
fair terminating
if it has no infinite execution trace that satisfies a given fairness constraint. Fair termination is an important property because program verification problems for arbitrary ω-regular temporal properties can be transformed to those of fair termination. Our method reduces the problem of disproving fair termination to higher-order model checking by using predicate abstraction and CEGAR. Given a program, we convert it to an abstract program that generates an approximation of the (possibly infinite) execution traces of the original program, so that the original program has a fair infinite execution trace if the tree generated by the abstract program satisfies a certain property. The method is a non-trivial extension of Kuwahara et al.’s method for disproving plain termination.
Farms, pipes, streams and reforestation: reasoning about structured parallel processes using types and hylomorphisms
Authors: Castro David , Hammond Kevin , Sarkar Susmit
Published: December 2016

The increasing importance of parallelism has motivated the creation of better abstractions for writing parallel software, including structured parallelism using nested algorithmic skeletons. Such approaches provide high-level abstractions that avoid common problems, such as race conditions, and often allow strong cost models to be defined. However, choosing a combination of algorithmic skeletons that yields good parallel speedups for a program on some specific parallel architecture remains a difficult task. In order to achieve this, it is necessary to simultaneously reason both about the costs of different parallel structures and about the semantic equivalences between them. This paper presents a new type-based mechanism that enables strong static reasoning about these properties. We exploit well-known properties of a very general recursion pattern, hylomorphisms, and give a denotational semantics for structured parallel processes in terms of these hylomorphisms. Using our approach, it is possible to determine formally whether it is possible to introduce a desired parallel structure into a program without altering its functional behaviour, and also to choose a version of that parallel structure that minimises some given cost model.
Talking bananas: structural recursion for session types
Authors: Lindley Sam , Morris J. Garrett
Published: December 2016

Session types provide static guarantees that concurrent programs respect communication protocols. We give a novel account of recursive session types in the context of GV, a small concurrent extension of the linear λ-calculus. We extend GV with recursive types and catamorphisms, following the initial algebra semantics of recursion, and show that doing so naturally gives rise to recursive session types. We show that this principled approach to recursion resolves long-standing problems in the treatment of duality for recursive session types.

We characterize the expressiveness of GV concurrency by giving a CPS translation to (non-concurrent) λ-calculus and proving that reduction in GV is simulated by full reduction in λ-calculus. This shows that GV remains terminating in the presence of positive recursive types, and that such arguments extend to other extensions of GV, such as polymorphism or non-linear types, by appeal to normalization results for sequential λ-calculi. We also show that GV remains deadlock free and deterministic in the presence of recursive types.

Finally, we extend CP, a session-typed process calculus based on linear logic, with recursive types, and show that doing so preserves the connection between reduction in GV and cut elimination in CP.
Queueing and glueing for optimal partitioning (functional pearl)
Authors: Mu Shin-Cheng , Chiang Yu-Hsi , Lyu Yu-Han
Published: December 2016

The queueing-glueing algorithm is the nickname we give to an algorithmic pattern that provides amortised linear time solutions to a number of optimal list partition problems that have a peculiar property: at various moments we know that two of three candidate solutions could be optimal. The algorithm works by keeping a queue of lists, glueing them from one end, while chopping from the other end, hence the name. We give a formal derivation of the algorithm, and demonstrate it with several non-trivial examples.
A new verified compiler backend for CakeML
Authors: Tan Yong Kiam , Myreen Magnus O. , Kumar Ramana , Fox Anthony , Owens Scott , Norrish Michael
Published: December 2016

We have developed and mechanically verified a new compiler backend for CakeML. Our new compiler features a sequence of intermediate languages that allows it to incrementally compile away high-level features and enables verification at the right levels of semantic detail. In this way, it resembles mainstream (unverified) compilers for strict functional languages. The compiler supports efficient curried multi-argument functions, configurable data representations, exceptions that unwind the call stack, register allocation, and more. The compiler targets several architectures: x86-64, ARMv6, ARMv8, MIPS-64, and RISC-V.

In this paper, we present the overall structure of the compiler, including its 12 intermediate languages, and explain how everything fits together. We focus particularly on the interaction between the verification of the register allocator and the garbage collector, and memory representations. The entire development has been carried out within the HOL4 theorem prover.
The best of both worlds: linear functional programming without compromise
Authors: Morris J. Garrett
Published: December 2016

We present a linear functional calculus with both the safety guarantees expressible with linear types and the rich language of combinators and composition provided by functional programming. Unlike previous combinations of linear typing and functional programming, we compromise neither the linear side (for example, our linear values are first-class citizens of the language) nor the functional side (for example, we do not require duplicate definitions of compositions for linear and unrestricted functions). To do so, we must generalize abstraction and application to encompass both linear and unrestricted functions. We capture the typing of the generalized constructs with a novel use of qualified types. Our system maintains the metatheoretic properties of the theory of qualified types, including principal types and decidable type inference. Finally, we give a formal basis for our claims of expressiveness, by showing that evaluation respects linearity, and that our language is a conservative extension of existing functional calculi.
Experience report: growing and shrinking polygons for random testing of computational geometry algorithms
Authors: Sergey Ilya
Published: December 2016

This paper documents our experience of adapting and using the QuickCheck-style approach for extensive randomised property-based testing of computational geometry algorithms.

The need in rigorous evaluation of computational geometry procedures has naturally arisen in our quest of organising a medium-size programming contest for second year university students—an experiment we conducted as an attempt to introduce them to computational geometry. The main effort in organising the event was implementation of a solid infrastructure for testing and ranking solutions. For this, we employed functional programming techniques. The choice of the language and the paradigm made it possible for us to engineer, from scratch and in a very short period of time, a series of robust geometric primitives and algorithms, as well as implement a scalable framework for their randomised testing.

We describe the main insights, enabling efficient random testing of geometric procedures, and report on our experience of using the testing framework, which helped us to detect and fix a number of issues not just in our programming artefacts, but also in the published algorithms we had implemented.
Set-theoretic types for polymorphic variants
Authors: Castagna Giuseppe , Petrucciani Tommaso , Nguyễn Kim
Published: December 2016

Polymorphic variants are a useful feature of the OCaml language whose current definition and implementation rely on kinding constraints to simulate a subtyping relation via unification. This yields an awkward formalization and results in a type system whose behaviour is in some cases unintuitive and/or unduly restrictive.

In this work, we present an alternative formalization of polymorphic variants, based on set-theoretic types and subtyping, that yields a cleaner and more streamlined system. Our formalization is more expressive than the current one (it types more programs while preserving type safety), it can internalize some meta-theoretic properties, and it removes some pathological cases of the current implementation resulting in a more intuitive and, thus, predictable type system. More generally, this work shows how to add full-fledged union types to functional languages of the ML family that usually rely on the Hindley-Milner type system. As an aside, our system also improves the theory of semantic subtyping, notably by proving completeness for the type reconstruction algorithm.
Indexed codata types
Authors: Thibodeau David , Cave Andrew , Pientka Brigitte
Published: December 2016

Indexed data types allow us to specify and verify many interesting invariants about finite data in a general purpose programming language. In this paper we investigate the dual idea: indexed codata types, which allow us to describe data-dependencies about infinite data structures. Unlike finite data which is defined by constructors, we define infinite data by observations. Dual to pattern matching on indexed data which may refine the type indices, we define copattern matching on indexed codata where type indices guard observations we can make.

Our key technical contributions are three-fold: first, we extend Levy's call-by-push value language with support for indexed (co)data and deep (co)pattern matching; second, we provide a clean foundation for dependent (co)pattern matching using equality constraints; third, we describe a small-step semantics using a continuation-based abstract machine, define coverage for indexed (co)patterns, and prove type safety. This is an important step towards building a foundation where (co)data type definitions and dependent types can coexist.
Oh Lord, please don't let contracts be misunderstood (functional pearl)
Authors: Dimoulas Christos , New Max S. , Findler Robert Bruce , Felleisen Matthias
Published: December 2016

Contracts feel misunderstood, especially those with a higher-order soul. While software engineers appreciate contracts as tools for articulating the interface between components, functional programmers desperately search for their types and meaning, completely forgetting about their pragmatics.

This gem presents a novel analysis of contract systems. Applied to the higher-order kind, this analysis reveals their large and clearly unappreciated software engineering potential. Three sample applications illustrate where this kind of exploration may lead.
Sequent calculus as a compiler intermediate language
Authors: Downen Paul , Maurer Luke , Ariola Zena M. , Peyton Jones Simon
Published: December 2016

The λ-calculus is popular as an intermediate language for practical compilers. But in the world of logic it has a lesser-known twin, born at the same time, called the
sequent calculus
. Perhaps that would make for a good intermediate language, too? To explore this question we designed Sequent Core, a practically-oriented core calculus based on the sequent calculus, and used it to re-implement a substantial chunk of the Glasgow Haskell Compiler.
Hierarchical memory management for parallel programs
Authors: Raghunathan Ram , Muller Stefan K. , Acar Umut A. , Blelloch Guy
Published: December 2016

An important feature of functional programs is that they are parallel by default. Implementing an efficient parallel functional language, however, is a major challenge, in part because the high rate of allocation and freeing associated with functional programs requires an efficient and scalable memory manager.

In this paper, we present a technique for parallel memory management for strict functional languages with nested parallelism. At the highest level of abstraction, the approach consists of a technique to organize memory as a hierarchy of heaps, and an algorithm for performing automatic memory reclamation by taking advantage of a disentanglement property of parallel functional programs. More specifically, the idea is to assign to each parallel task its own heap in memory and organize the heaps in a hierarchy/tree that mirrors the hierarchy of tasks.

We present a nested-parallel calculus that specifies hierarchical heaps and prove in this calculus a disentanglement property, which prohibits a task from accessing objects allocated by another task that might execute in parallel. Leveraging the disentanglement property, we present a garbage collection technique that can operate on any subtree in the memory hierarchy concurrently as other tasks (and/or other collections) proceed in parallel. We prove the safety of this collector by formalizing it in the context of our parallel calculus. In addition, we describe how the proposed techniques can be implemented on modern shared-memory machines and present a prototype implementation as an extension to MLton, a high-performance compiler for the Standard ML language. Finally, we evaluate the performance of this implementation on a number of parallel benchmarks.
Allocation characterizes polyvariance: a unified methodology for polyvariant control-flow analysis
Authors: Gilray Thomas , Adams Michael D. , Might Matthew
Published: December 2016

The polyvariance of a static analysis is the degree to which it structurally differentiates approximations of program values. Polyvariant techniques come in a number of different flavors that represent alternative heuristics for managing the trade-off an analysis strikes between precision and complexity. For example, call sensitivity supposes that values will tend to correlate with recent call sites, object sensitivity supposes that values will correlate with the allocation points of related objects, the Cartesian product algorithm supposes correlations between the values of arguments to the same function, and so forth.

In this paper, we describe a unified methodology for implementing and understanding polyvariance in a higher-order setting (i.e., for control-flow analyses). We do this by extending the method of abstracting abstract machines (AAM), a systematic approach to producing an abstract interpretation of abstract-machine semantics. AAM eliminates recursion within a language’s semantics by passing around an explicit store, and thus places importance on the strategy an analysis uses for allocating abstract addresses within the abstract heap or store. We build on AAM by showing that the design space of possible abstract allocators exactly and uniquely corresponds to the design space of polyvariant strategies. This allows us to both unify and generalize polyvariance as tunings of a single function. Changes to the behavior of this function easily recapitulate classic styles of analysis and produce novel variations, combinations of techniques, and fundamentally new techniques.
Refinement through restraint: bringing down the cost of verification
Authors: O'Connor Liam , Chen Zilin , Rizkallah Christine , Amani Sidney , Lim Japheth , Murray Toby , Nagashima Yutaka , Sewell Thomas , Klein Gerwin
Published: December 2016

We present a framework aimed at significantly reducing the cost of verifying certain classes of systems software, such as file systems. Our framework allows for equational reasoning about systems code written in our new language, Cogent. Cogent is a restricted, polymorphic, higher-order, and purely functional language with linear types and without the need for a trusted runtime or garbage collector. Linear types allow us to assign two semantics to the language: one imperative, suitable for efficient C code generation; and one functional, suitable for equational reasoning and verification. As Cogent is a restricted language, it is designed to easily interoperate with existing C functions and to connect to existing C verification frameworks. Our framework is based on certifying compilation: For a well-typed Cogent program, our compiler produces C code, a high-level shallow embedding of its semantics in Isabelle/HOL, and a proof that the C code correctly refines this embedding. Thus one can reason about the full semantics of real-world systems code productively and equationally, while retaining the interoperability and leanness of C. The compiler certificate is a series of language-level proofs and per-program translation validation phases, combined into one coherent top-level theorem in Isabelle/HOL.
A lambda-calculus foundation for universal probabilistic programming
Authors: Borgström Johannes , Dal Lago Ugo , Gordon Andrew D. , Szymczak Marcin
Published: December 2016

We develop the operational semantics of an untyped probabilistic λ-calculus with continuous distributions, and both hard and soft constraints,as a foundation for universal probabilistic programming languages such as Church, Anglican, and Venture. Our first contribution is to adapt the classic operational semantics of λ-calculus to a continuous setting via creating a measure space on terms and defining step-indexed approximations. We prove equivalence of big-step and small-step formulations of this
distribution-based semantics
. To move closer to inference techniques, we also define the
sampling-based semantics
of a term as a function from a trace of random samples to a value. We show that the distribution induced by integration over the space of traces equals the distribution-based semantics. Our second contribution is to formalize the implementation technique of trace
Markov chain Monte Carlo
(MCMC) for our calculus and to show its correctness. A key step is defining sufficient conditions for the distribution induced by trace MCMC to converge to the distribution-based semantics. To the best of our knowledge, this is the first rigorous correctness proof for trace MCMC for a higher-order functional language, or for a language with soft constraints.
Higher-order ghost state
Authors: Jung Ralf , Krebbers Robbert , Birkedal Lars , Dreyer Derek
Published: December 2016

The development of concurrent separation logic (CSL) has sparked a long line of work on modular verification of sophisticated concurrent programs. Two of the most important features supported by several existing extensions to CSL are higher-order quantification and custom ghost state. However, none of the logics that support both of these features reap the full potential of their combination. In particular, none of them provide general support for a feature we dub "higher-order ghost state": the ability to store arbitrary higher-order separation-logic predicates in ghost variables.

In this paper, we propose higher-order ghost state as a interesting and useful extension to CSL, which we formalize in the framework of Jung et al.'s recently developed Iris logic. To justify its soundness, we develop a novel algebraic structure called CMRAs ("cameras"), which can be thought of as "step-indexed partial commutative monoids". Finally, we show that Iris proofs utilizing higher-order ghost state can be effectively formalized in Coq, and discuss the challenges we faced in formalizing them.
Dag-calculus: a calculus for parallel computation
Authors: Acar Umut A. , Charguéraud Arthur , Rainey Mike , Sieczkowski Filip
Published: December 2016

Increasing availability of multicore systems has led to greater focus on the design and implementation of languages for writing parallel programs. Such languages support various abstractions for parallelism, such as fork-join, async-finish, futures. While they may seem similar, these abstractions lead to different semantics, language design and implementation decisions, and can significantly impact the performance of end-user applications.

In this paper, we consider the question of whether it would be possible to unify various paradigms of parallel computing. To this end, we propose a calculus, called
dag calculus
, that can encode fork-join, async-finish, and futures, and possibly others. We describe dag calculus and its semantics, establish translations from the aforementioned paradigms into dag calculus. These translations establish that dag calculus is sufficiently powerful for encoding programs written in prevailing paradigms of parallelism. We present concurrent algorithms and data structures for realizing dag calculus on multicore hardware and prove that the proposed techniques are consistent with the semantics. Finally, we present an implementation of the calculus and evaluate it empirically by comparing its performance to highly optimized code from prior work. The results show that the calculus is expressive and that it competes well with, and sometimes outperforms, the state of the art.
Datafun: a functional Datalog
Authors: Arntzenius Michael , Krishnaswami Neelakantan R.
Published: December 2016

Datalog may be considered either an unusually powerful query language or a carefully limited logic programming language. Datalog is declarative, expressive, and optimizable, and has been applied successfully in a wide variety of problem domains. However, most use-cases require extending Datalog in an application-specific manner. In this paper we define Datafun, an analogue of Datalog supporting higher-order functional programming. The key idea is to track monotonicity with types.
A functional programmer's guide to homotopy type theory
Authors: Licata Dan
Published: December 2016

Dependent type theories are functional programming languages with types rich enough to do computer-checked mathematics and software verification. Homotopy type theory is a recent area of work that connects dependent type theory to the mathematical disciplines of homotopy theory and higher-dimensional category theory. From a programming point of view, these connections have revealed that all types in dependent type theory support a certain generic program that had not previously been exploited. Specifically, each type can be equipped with computationally relevant witnesses of equality of elements of that type, and all types support a generic program that transports elements along these equalities. One mechanism for equipping types with non-trivial witnesses of equality is Voevodsky’s univalence axiom, which implies that equality of types themselves is witnessed by type isomorphism. Another is higher inductive types, an extended datatype schema that allows identifications between different datatype constructors. While these new mechanisms were originally formulated as axiomatic extensions of type theory, recent work has investigated their computational meaning, leading to the development of new programming languages that better support them. In this talk, I will illustrate what univalence and higher inductive types mean in programming terms. I will also discuss how studying some related semantic settings can reveal additional structure on types; for example, moving from groupoids (categories where all maps are invertible) to general categories yields an account of coercions instead of equalities. Overall, I hope to convey some of the beauty and richness of these connections between disciplines, which we are just beginning to understand.