Variational cross-validation of slow dynamical modes in molecular kinetics

Markov state models (MSMs) are a widely used method for approximating the eigenspectrum of the molecular dynamics propagator, yielding insight into the long-timescale statistical kinetics and slow dynamical modes of biomolecular systems. However, the lack of a unified theoretical framework for choosing between alternative models has hampered progress, especially for non-experts applying these methods to novel biological systems. Here, we consider cross-validation with a new objective function for estimators of these slow dynamical modes, a generalized matrix Rayleigh quotient (GMRQ), which measures the ability of a rank-$m$ projection operator to capture the slow subspace of the system. It is shown that a variational theorem bounds the GMRQ from above by the sum of the first $m$ eigenvalues of the system's propagator, but that this bound can be violated when the requisite matrix elements are estimated subject to statistical uncertainty. This overfitting can be detected and avoided through cross-validation. These result make it possible to construct Markov state models for protein dynamics in a way that appropriately captures the tradeoff between systematic and statistical errors

Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) is defined by extreme sensitivity to sunlight, resulting in sunburn, pigment changes in the skin and a greatly elevated incidence of skin cancers. It is a rare autosomal recessive disorder and has been found in all continents and racial groups. Estimated incidences vary from 1 in 20, 000 in Japan to 1 in 250, 000 in the USA, and approximately 2.3 per million live births in Western Europe. The first features are either extreme sensitivity to sunlight, triggering severe sunburn, or, in patients who do not show this sun-sensitivity, abnormal lentiginosis (freckle-like pigmentation due to increased numbers of melanocytes) on sun-exposed areas. This is followed by areas of increased or decreased pigmentation, skin aging and multiple skin cancers, if the individuals are not protected from sunlight. A minority of patients show progressive neurological abnormalities. There are eight XP complementation groups, corresponding to eight genes, which, if defective, can result in XP. The products of these genes are involved in the repair of ultraviolet (UV)- induced damage in DNA. Seven of the gene products (XPA through G) are required to remove UV damage from the DNA. The eighth (XPV or DNA polymerase h) is required to replicate DNA containing unrepaired damage. There is wide variability in clinical features both between and within XP groups. Diagnosis is made clinically by the presence, from birth, of an acute and prolonged sunburn response at all exposed sites, unusually early lentiginosis in sun-exposed areas or onset of skin cancers at a young age. The clinical diagnosis is confirmed by cellular tests for defective DNA repair. These features distinguish XP from other photodermatoses such as solar urticaria and polymorphic light eruption, Cockayne Syndrome (no pigmentation changes, different repair defect) and other lentiginoses such as Peutz-Jeghers syndrome, Leopard syndrome and Carney complex (pigmentation not sunassociated), which are inherited in an autosomal dominant fashion. Antenatal diagnosis can be performed by measuring DNA repair or by mutation analysis in CVS cells or in amniocytes. Although there is no cure for XP, the skin effects can be minimised by rigorous protection from sunlight and early removal of pre-cancerous lesions. In the absence of neurological problems and with lifetime protection against sunlight, the prognosis is good. In patients with neurological problems, these are progressive, leading to disabilities and a shortened lifespan

CARBONIC SPRINGS AS DISTAL MANIFESTATIONS OF THE JEMEZ GEOTHERMAL SYSTEM, SAN YSIDRO, NEW MEXICO, HIGHLIGHTING THE IMPORTANCE OF FAULT PATHWAYS AND HYDROCHEMICAL MIXING.

Input of deeply sourced (endogenic) waters can contribute significant quantities of salinity to groundwater, degrading water quality, with faults acting as conduits for subsurface fluid flow. Understanding the source, movement, and chemistry of groundwater is becoming ever more significant with changing climate and weather patterns. Systematic sampling was carried out on three groups of carbonic warm and hot springs in New Mexico, USA: 1) Tierra Amarilla springs (~ 20ºC), near San Ysidro south of Nacimiento Mountains, 2) Penasco springs (~ 20 ºC) along the Nacimiento fault west of the Nacimiento basement mountain block, and 3) Soda Dam, Jemez, and Indian hot springs (40-60 ºC) in San Diego Canyon along the Jemez River. Application of multiple hydrochemical tracers (including major/minor elemental chemistry and stable isotopes) was applied to quantitatively evaluate possible flow paths and mixing. The goal is to test three hypotheses for source and transport of waters to these carbonic springs: San Juan basin origin, meteoric flow from the Nacimiento high topography, and/or influence from the Valles Caldera geothermal system of the Jemez Mountains. Numerous geochemical plots show that all three carbonic spring groups are very different than meteoric and sedimentary aquifer waters. The springs are warm (20oC) to hot (60oC) and all deposit travertine, pH ranges from 5.38 – 6.94; conductivities range from 3300 - 20000µS and PCO2 ranges from -0.94 to 0.93. San Ysidro springs look similar in major anions and cations to Penasco springs (both along the Nacimiento fault) and each shows a different range of the same mixing trend. Soda Dam appears to anchor these mixing trends, but itself is part of a broader mixing trend with a Valles Caldera geothermal water end member. The main tracers that define mixing trends are: 1) major cations and anions (Piper diagram), 2) stable isotopes, 3) conservative tracers (Li, B, Br, Cl), 4) temperature, and 5) helium isotope ratios. In all of these tracers, the Tierra Amarilla and Penasco springs overlap with each other strongly and fall on well-defined mixing trends anchored by geothermal fluids of the Valles system. Stable isotope composition in the San Ysidro and Penasco springs ranges from δ13C= -8.71 to 2.698 and δ18O = -11.45 to -8.15 overlap with Soda Dam hot springs values fall on a mixing line with Valles Caldera geothermal waters. High lithium (0.1 to 10.4 ppm), boron (0.2 to 12.5 ppm), and bromine values all show the San Ysidro carbonic springs to have hydrochemical influence from the Jemez hydrothermal system (e.g. values are similar to Soda Dam and Jemez springs). Similarly, helium gas data show elevated 3He/4He values consistent with contributions from the Jemez volcanic system. However, in the San Ysidro and Penasco spring groups, plots of high Li and B versus chloride suggest that geothermal waters have acquired Cl from other sources, including salt and gypsum of the Paleozoic and Mesozoic rock aquifers. Thus we interpret these carbonic springs to be distal manifestations of fluid circulation along faults (e.g. the Soda Dam and Nacimiento faults) with a mixture of Jemez geothermal waters and waters sourced from either/both San Juan Basin aquifers and meteoric sources. Semi-confined fault conduits, especially of the Soda Dam/ Jemez and Nacimiento fault zones, provide connectivity between carbonic spring systems and help explain geochemical similarities and mixing trends between Valles Caldera, Soda Dam, and Jemez geothermal waters with more distal San Ysidro and Penasco carbonic spring waters. Penasco springs are interpreted to reflect a component of outflow from the geothermal system that crosses the Nacimiento Mountain basement block along NE- trending faults

Language Standardisation in Modern Irish::Complaints sustaining discourse?

Language standardisation is the process by which a particular form of languagebecomes the conventional norm – particularly in the domains of officialdom(e.g. in government). It involves conscious intervention, often by the state ora language specific authority, to plan which type of language will function insociety. This usually involves the development of language uniformity, often atthe expense of dialectal diversity. In most cases, it also involves the developmentof modern terminology, and the production of dictionaries and grammars tostabilise the standard language as a definite frame of reference for correctnessand accuracy. This paper discusses that process in the context of the Irishlanguage.Disparities, complaints and disagreements regarding the correctness andlegitimacy of standardised language conventions are investigated. In particular,attention is drawn to the period (1958-2016) during which the Irish governmentpublished three versions of their official guidance document for writing in Irish:firstly in 1958, followed by later iterations in 2012 and 2016. The paper showsthat Irish language scholars played an important role in sustaining discourseregarding language standardisation; despite the vacuum of over fifty yearsbetween these editions