Implications of non-feasible transformations among icosahedral hh orbitals

The symmetric group $S_6$ that permutes the six five-fold axes of an icosahedron is introduced to go beyond the simple rotations that constitute the icosahedral group $I$. Owing to the correspondence $h\leftrightarrow d$, the calculation of the Coulomb energies for the icosahedral configurations $h^N$ based on the sequence $O(5) \supset S_6 \supset S_5 \supset I$ can be brought to bear on Racah's classic theory for the atomic d shell based on $SO(5) \supset SO_L(3) \supset I$. Among the elements of $S_6$ is the kaleidoscope operator ${\cal K}$ that rotates the weight space of SO(5) by $\pi/2$. Its use explains some puzzling degeneracies in d^3 involving the spectroscopic terms ^2P, ^2F, ^2G and ^2H.Comment: Tentatively scheduled to appear in Physical Preview Letters Apr 5, 99. Revtex, 1 ps figur

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

Dynamical Jahn-Teller Effect and Berry Phase in Positively Charged Fullerene I. Basic Considerations

We study the Jahn-Teller effect of positive fullerene ions $^2$C$_{60}^{+}$ and $^1$C$_{60}^{2+}$. The aim is to discover if this case, in analogy with the negative ion, possesses a Berry phase or not, and what are the consequences on dynamical Jahn-Teller quantization. Working in the linear and spherical approximation, we find no Berry phase in $^1$C$_{60}^{2+}$, and presence/absence of Berry phase for coupling of one $L=2$ hole to an $L=4$/$L=2$ vibration. We study in particular the special equal-coupling case ($g_2=g_4$), which is reduced to the motion of a particle on a 5-dimensional sphere. In the icosahedral molecule, the final outcome assesses the presence/absence of a Berry phase of $\pi$ for the $h_u$ hole coupled to $G_g$/$H_h$ vibrations. Some qualitative consequences on ground-state symmetry, low-lying excitations, and electron emission from C$_{60}$ are spelled out.Comment: 31 pages (RevTeX), 3 Postscript figures (uuencoded

Pupillary light reflex metrics as an objective biomarker for sport-related concussion in elite field hockey

Background Concussion diagnosis is based on subjective assessment of several nonspecifc clinical signs and symptoms with no objective test to aid in diagnosis. The pupillary system, in particular the pupil light refexes (PLR) has attracted plausible consideration in this area, given its complex neural circuitry and autonomic function.Aim To assess the reliability and validity of using the NeurOptics PLR-3000 pupilometer to measure PLR, and to determine normative data for female athletes.Methods A cross sectional cohort study of 33 senior elite female feld hockey athletes (aged 19–34 years) were recruited. Three valid pupillometry readings were acquired, per eye. Measurements of nine PLR metrics were obtained. Reliability was determined using intraclass coefcients, standard error of measurement (SEM), and minimum detectable change (MDC). Between group diferences (concussion history vs. controls) were analysed using non-parametric tests.Results NeurOptics PLR-3000 showed good to excellent reliability for eight PLR metrics derived from the pupilometer [latency, average constriction velocity (ACV), peak constriction velocity (PCV), average dilation velocity (ADV), T75%max. pupil diameter, min. pupil diameter and percent constriction]. There was no statistical diference between any of the PLR metrics in athletes who had a history of concussion and those that had no history of concussion. The two athletes with a recent history of concussion (<3 months) showed trends towards slowed latency, ACV, PCV and ADV when compared to controls.Conclusion This research does not support previous research that the PLR-3000 is an accurate instrument for distinguishing between those with and without a history of concussion. However, the ICC values for intratester reliability were good to excellent for most PLR metrics, with data comparing favourably to normative values previously reported from other populations. Some PLR metrics may distinguish between distinct group of female athletes (recent history of concussion), but this is a small sample size and exploratory in nature. Larger studies are required to confrm its validity and responsiveness

Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity

Tau is a microtubule-associated protein that is highly soluble and natively unfolded. Its dysfunction is involved in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD), where it aggregates within neurons. Deciphering the physiological and pathogenic roles of human Tau (hTau) is crucial to further understand the mechanisms leading to its dysfunction in vivo. We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo

The PEARL score predicts 90-day readmission or death after hospitalisation for acute exacerbation of COPD.

BACKGROUND: One in three patients hospitalised due to acute exacerbation of COPD (AECOPD) is readmitted within 90 days. No tool has been developed specifically in this population to predict readmission or death. Clinicians are unable to identify patients at particular risk, yet resources to prevent readmission are allocated based on clinical judgement. METHODS: In participating hospitals, consecutive admissions of patients with AECOPD were identified by screening wards and reviewing coding records. A tool to predict 90-day readmission or death without readmission was developed in two hospitals (the derivation cohort) and validated in: (a) the same hospitals at a later timeframe (internal validation cohort) and (b) four further UK hospitals (external validation cohort). Performance was compared with ADO, BODEX, CODEX, DOSE and LACE scores. RESULTS: Of 2417 patients, 936 were readmitted or died within 90 days of discharge. The five independent variables in the final model were: Previous admissions, eMRCD score, Age, Right-sided heart failure and Left-sided heart failure (PEARL). The PEARL score was consistently discriminative and accurate with a c-statistic of 0.73, 0.68 and 0.70 in the derivation, internal validation and external validation cohorts. Higher PEARL scores were associated with a shorter time to readmission. CONCLUSIONS: The PEARL score is a simple tool that can effectively stratify patients' risk of 90-day readmission or death, which could help guide readmission avoidance strategies within the clinical and research setting. It is superior to other scores that have been used in this population. TRIAL REGISTRATION NUMBER: UKCRN ID 14214

Exome-Wide Association Study of Endometrial Cancer in a Multiethnic Population

Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome-wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC

Differential Regulation of GABABReceptor Trafficking by Different Modes ofN-methyl-d-aspartate (NMDA) Receptor Signaling

Inhibitory GABAB receptors (GABABRs) can down-regulate most excitatory synapses in the CNS by reducing postsynaptic excitability. Functional GABABRs are heterodimers of GABAB1 and GABAB2 subunits and here we show that the trafficking and surface expression of GABABRs is differentially regulated by synaptic or pathophysiological activation of NMDA receptors (NMDARs). Activation of synaptic NMDARs using a chemLTP protocol increases GABABR recycling and surface expression. In contrast, excitotoxic global activation of synaptic and extrasynaptic NMDARs by bath application of NMDA causes the loss of surface GABABRs. Intriguingly, exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) increases GABAB1 but decreases GABAB2 surface expression. The increase in surface GABAB1 involves enhanced recycling and is blocked by the NMDAR antagonist AP5. The decrease in surface GABAB2 is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is critical in GABABR trafficking and function and that the individual subunits can be separately controlled to regulate neuronal responsiveness and survival