The constrained-monad problem

In Haskell, there are many data types that would form monads were it not for the presence of type-class constraints on the operations onthat data type. This is a frustrating problem in practice, because there is a considerable amount of support and infrastructure for monads that these data types cannot use. Using several examples,we show that a monadic computation can be restructured into a normal form such that the standard monad class can be used. The technique is not specific to monads, and we show how it can also be applied to other structures, such as applicative functors. One significant use case for this technique is domain-specific languages,where it is often desirable to compile a deep embedding of a computation to some other language, which requires restricting the types that can appear in that computation

The HERMIT in the machine: a plugin for the interactive transformation of GHC core language programs

The importance of reasoning about and refactoring programs is a central tenet of functional programming. Yet our compilers and development toolchains only provide rudimentary support for these tasks. This paper introduces a programmatic and compiler-centric interface that facilitates refactoring and equational reasoning. To develop our ideas, we have implemented HERMIT, a toolkit enabling informal but systematic transformation of Haskell programs from inside the Glasgow Haskell Compiler’s optimization pipeline. With HERMIT, users can experiment with optimizations and equational reasoning, while the tedious heavy lifting of performing the actual transformations is done for them. HERMIT provides a transformation API that can be used to build higher-level rewrite tools. One use-case is prototyping new optimizations as clients of this API before being committed to the GHC toolchain. We describe a HERMIT application - a read-eval-print shell for performing transformations using HERMIT. We also demonstrate using this shell to prototype an optimization on a specific example, and report our initial experiences and remaining challenges

Local Ca2+ Entry Via Orai1 Regulates Plasma Membrane Recruitment of TRPC1 and Controls Cytosolic Ca2+ Signals Required for Specific Cell Functions

Store-operated Ca2+ entry (SOCE) has been associated with two types of channels: CRAC channels that require Orai1 and STIM1 and SOC channels that involve TRPC1, Orai1, and STIM1. While TRPC1 significantly contributes to SOCE and SOC channel activity, abrogation of Orai1 function eliminates SOCE and activation of TRPC1. The critical role of Orai1 in activation of TRPC1-SOC channels following Ca2+ store depletion has not yet been established. Herein we report that TRPC1 and Orai1 are components of distinct channels. We show that TRPC1/Orai1/STIM1-dependent ISOC, activated in response to Ca2+ store depletion, is composed of TRPC1/STIM1-mediated non-selective cation current and Orai1/STIM1-mediated ICRAC; the latter is detected when TRPC1 function is suppressed by expression of shTRPC1 or a STIM1 mutant that lacks TRPC1 gating, STIM1(684EE685). In addition to gating TRPC1 and Orai1, STIM1 mediates the recruitment and association of the channels within ER/PM junctional domains, a critical step in TRPC1 activation. Importantly, we show that Ca2+ entry via Orai1 triggers plasma membrane insertion of TRPC1, which is prevented by blocking SOCE with 1 µM Gd3+, removal of extracellular Ca2+, knockdown of Orai1, or expression of dominant negative mutant Orai1 lacking a functional pore, Orai1-E106Q. In cells expressing another pore mutant of Orai1, Orai1-E106D, TRPC1 trafficking is supported in Ca2+-containing, but not Ca2+-free, medium. Consistent with this, ICRAC is activated in cells pretreated with thapsigargin in Ca2+-free medium while ISOC is activated in cells pretreated in Ca2+-containing medium. Significantly, TRPC1 function is required for sustained KCa activity and contributes to NFκB activation while Orai1 is sufficient for NFAT activation. Together, these findings reveal an as-yet unidentified function for Orai1 that explains the critical requirement of the channel in the activation of TRPC1 following Ca2+ store depletion. We suggest that coordinated regulation of the surface expression of TRPC1 by Orai1 and gating by STIM1 provides a mechanism for rapidly modulating and maintaining SOCE-generated Ca2+ signals. By recruiting ion channels and other signaling pathways, Orai1 and STIM1 concertedly impact a variety of critical cell functions that are initiated by SOCE

DATA PROCESSING OF SECONDARY ION MASS SPECTROMETRY: ANALYSIS OF ATMOSPHERIC AEROSOL SAMPLES FROM 2020

The results of secondary ion mass spectrometry of aerosol samples, collected in 2020 at the Institute of Industrial Ecology, are discussed. The data processing tool is introduced to identify mass peaks and corresponding chemical compounds.Исследование выполнено при финансовой поддержке РФФИ в рамках научного проекта № 19-05-50138

Определение валидности шкалы дыхательных нарушений у пациентов с острым поражением нервной системы

The aim of study: to investigate validity of respiratory insufficiency scale (RIS) in patients with acute lesions of nervous system.Material and methods. The prospective observational study included neurocritical care patients (n=179), admitted to the resuscitation and intensive care unit with independent breathing and RIS score 1 and higher. Patients were assessed according to RIS every 12 hours during the the period of RICU stay until the beginning of artificial lung ventilation or transfer to a specialized department. The RIS score did not influence the physician's decision upon intubation. The treatment was performed in accordance with national and international recommendations.Depending on the tracheal intubation and ALV, patients were divided into 3 groups. Group I (n=65): 0% tracheal intubation and ALV; Group II (n =54): 42,6% cases of intubation and ALV; Group III (n=60): 100% patients requiring intubation and ALV.The statistical analysis was performed using Shapiro—Wilk test, Mann-Whitney test, Kruskal—Wallis test, Chi-squared test. The ROC analysis was carried out to determine the sensitivity and specificity of the RIS scale.Results. Patients with RIS score 1 — 2 did not require intubation and ALV. Patients with RIS 5 or more required urgent intubation and ALV. In patients with RIS score 3—4 the need for intubation and ALV was unpredictable. If RIS score 4 was sustainig during several hours, or if increased from 3 to 4, a patient required intubation and initiation of ALV.Conclusion. RIS helps objectify indications for intubation and ALV in patients with acute neural lesions.Цель исследования. Исследовать валидность шкалы дыхательных нарушений (ШДН) у пациентов с острым повреждением нервной системы.Материал и методы. В проспективное обсервационное исследование включили нейрореанимационных пациентов (n=179), поступавших в отделение реанимации и интенсивной терапии (ОРИТ) c сохраненным самостоятельным дыханием с оценкой по ШДН, равной 1 и более балла. Пациентов оценивали по ШДН каждые 12 ч до момента интубации трахеи или до перевода из ОРИТ в профильное отделение. Оценка пациента по ШДН не влияла на принятие решения лечащим врачом об интубации трахеи. Ведение пациентов осуществляли в соответствии с национальными и международными рекомендациями. Пациентов разделили на 3 группы в зависимости от степени необходимости произвести интубацию трахеи и искусственную вентиляцию легких (ИВЛ). В группе I (n=65) — 0% интубации трахеи и ИВЛ; в группе II (n=54) — 42,6% интубации трахеи и ИВЛ; в группе III (n=60) — 100% интубации трахеи и ИВЛ. Статистический анализ проводили с применением методик Шапиро–Уилка, тестов Манна–Уитни, Крускала–Уоллиса, критерия согласия Пирсона Хи-квадрат (χ2). ROC-анализ был проведен для определения чувствительности и специфичности ШДН-шкалы.Результаты. При оценке по ШДН, равной 1–2 балла, пациенты не нуждаются в интубации трахеи и ИВЛ, при сумме 5 и более баллов необходима незамедлительная интубация трахеи и ИВЛ, при сумме 3– 4 балла необходимость в ИВЛ непредсказуема. При сохраняющейся в течение нескольких часов оценке по ШДН, равной 4 баллам, или при ее увеличении с 3 баллов до 4 необходимы интубация трахеи и начало ИВЛ.Заключение. У пациентов с острым поражением нервной системы применение оценки дыхательных нарушений по ШДН позволяет объективизировать показания для интубации трахеи и начала ИВЛ

Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses

Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-κB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype

Hasochism The Pleasure and Pain of Dependently Typed Haskell Programming

Haskell’s type system has outgrown its Hindley-Milner roots to the extent that it now stretches to the basics of dependently typed programming. In this paper, we collate and classify techniques for programming with dependent types in Haskell, and contribute some new ones. In particular, through extended examples—merge-sort and rectangular tilings—we show how to exploit Haskell’s constraint solver as a theorem prover, delivering code which, as Agda programmers, we envy. We explore the compromises involved in simulating variations on the theme of the dependent function space in an attempt to help programmers put dependent types to work, and to inform the evolving language design both of Haskell and of dependently typed languages more broadly. 1