Next generation direct dark matter detection experiments are favorable facilities to probe neutrino properties and light mediators beyond the Standard Model. We explore the implications of the recent ...data reported by LUX-ZEPLIN (LZ) and XENONnT collaborations on electromagnetic neutrino interactions and neutrino generalized interactions (NGIs). We show that XENONnT places the most stringent upper limits on the effective and transition neutrino magnetic moment (of the order of few ×10−12μB) as well as stringent constraints to neutrino millicharge (of the order of ∼10−13e)–competitive to LZ–and improved by about one order of magnitude in comparison to existing constraints coming from Borexino and TEXONO. We furthermore explore the XENONnT and LZ sensitivities to simplified models with light NGIs and find improved constraints in comparison to those extracted from Borexino-Phase II data.
Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy ...Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
We introduce a measure called width, quantifying the amount of nondetermin-ism in automata. Width generalises the notion of good-for-games (GFG) automata, that correspond to NFAs of width 1, and ...where an accepting run can be built on-the-fly on any accepted input. We describe an incremental determinisation construction on NFAs, which can be more efficient than the full powerset determinisation, depending on the width of the input NFA. This construction can be generalised to infinite words, and is particularly well-suited to coBüchi automata. For coBüchi automata, this procedure can be used to compute either a deterministic automaton or a GFG one, and it is algorithmically more efficient in the last case. We show this fact by proving that checking whether a coBüchi automaton is determinisable by pruning is NP-complete. On finite or infinite words, we show that computing the width of an automaton is EXPTIME-complete. This implies EXPTIME-completeness for multipebble simulation games on NFAs.
Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human ...disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K
channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K
conductance, referred to as syndromic neurodevelopmental K
channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic ...crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11‐13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged‐red/cytochrome c oxidase‐negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum‐Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.
Broadcast networks allow one to model networks of identical nodes communicating through message broadcasts. Their parameterized verification aims at proving a property holds for any number of nodes, ...under any communication topology, and on all possible executions. We focus on the coverability problem which dually asks whether there exists an execution that visits a configuration exhibiting some given state of the broadcast protocol. Coverability is known to be undecidable for static networks, i.e. when the number of nodes and communication topology is fixed along executions. In contrast, it is decidable in PTIME when the communication topology may change arbitrarily along executions, that is for reconfigurable networks. Surprisingly, no lower nor upper bounds on the minimal number of nodes, or the minimal length of covering execution in reconfigurable networks, appear in the literature. In this paper we show tight bounds for cutoff and length, which happen to be linear and quadratic, respectively, in the number of states of the protocol. We also introduce an intermediary model with static communication topology and non-deterministic message losses upon sending. We show that the same tight bounds apply to lossy networks, although, reconfigurable executions may be linearly more succinct than lossy executions. Finally, we show NP-completeness for the natural optimisation problem associated with the cutoff.
We introduce two-player games which build words over infinite alphabets, and we study the problem of checking the existence of winning strategies. These games are played by two players, who take ...turns in choosing valuations for variables ranging over an infinite data domain, thus generating multi-attributed data words. The winner of the game is specified by formulas in the Logic of Repeating Values, which can reason about repetitions of data values in infinite data words. We prove that it is undecidable to check if one of the players has a winning strategy, even in very restrictive settings. However, we prove that if one of the players is restricted to choose valuations ranging over the Boolean domain, the games are effectively equivalent to single-sided games on vector addition systems with states (in which one of the players can change control states but cannot change counter values), known to be decidable and effectively equivalent to energy games. Previous works have shown that the satisfiability problem for various variants of the logic of repeating values is equivalent to the reachability and coverability problems in vector addition systems. Our results raise this connection to the level of games, augmenting further the associations between logics on data words and counter systems.
Transgender endocrinology Majumdar, Anirban; Sanyal, Debmalya; Sukumar, Suja ...
Indian journal of endocrinology and metabolism,
03/2020, Volume:
24, Issue:
2
Journal Article
Peer reviewed
Open access
The curriculum for endocrinology training does not include adequate focus on transgender health, while that for internal medicine makes no mention of this important subject. ...few physicians and ...endocrinologists possess the skills necessary for transgender care. Optimal trans-healthcare delivery will be possible only if we move away from the one-size-fits-all concept to a more individualized person-centered care, learn patient–provider communication skills, and practice informed, shared decision-making. 6 These ideas have been paraphrased as the four core competencies of professional responsibility, caregiver/care-receiver relationship, interdisciplinary practice, and content knowledge, by the World Professional Association for Transgender Health (WPATH).
PDF
