Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential reliance of CTD-nuclear envelope phosphatase 1 on its regulatory subunit in ER lipid synthesis and storage

The endoplasmic reticulum (ER) is the site for the synthesis of the major membrane and storage lipids. Lipin 1 produces diacylglycerol, the lipid intermediate critical for the synthesis of both membrane and storage lipids in the ER. CTD-Nuclear Envelope Phosphatase 1 (CTDNEP1) regulates lipin 1 to restrict ER membrane synthesis, but its role in lipid storage in mammalian cells is unknown. Here, we show that the ubiquitin-proteasome degradation pathway controls the levels of ER/nuclear envelope-associated CTDNEP1 to regulate ER membrane synthesis through lipin 1. The N-terminus of CTDNEP1 is an amphipathic helix that targets to the ER, nuclear envelope and lipid droplets. We identify key residues at the binding interface of CTDNEP1 with its regulatory subunit NEP1R1 and show that they facilitate complex formation in vivo and in vitro. We demonstrate a role for NEP1R1 in temporarily shielding CTDNEP1 from proteasomal degradation to regulate lipin 1 and restrict ER size. Unexpectedly, we found that NEP1R1 is not required for CTDNEP1’s role in restricting lipid droplet biogenesis. Thus, the reliance of CTDNEP1 function on its regulatory subunit differs during ER membrane synthesis and lipid storage. Together, our work provides a framework into understanding how the ER regulates lipid synthesis and storage under fluctuating conditions.
Gentle label-free nonlinear optical imaging relaxes linear-absorption-mediated triplet

Sample health is critical for live-cell fluorescence microscopy and has promoted light-sheet microscopy that restricts its ultraviolet-visible excitation to one plane inside a three-dimensional sample. It is thus intriguing that laser-scanning nonlinear optical microscopy, which similarly restricts its near-infrared excitation, has not broadly enabled gentle label-free molecular imaging. We hypothesize that intense near-infrared excitation induces phototoxicity via linear absorption of intrinsic biomolecules with subsequent triplet buildup, rather than the commonly assumed mechanism of nonlinear absorption. Using a reproducible phototoxicity assay based on the time-lapse elevation of auto-fluorescence (hyper-fluorescence) from a homogeneous tissue model (chicken breast), we provide strong evidence supporting this hypothesis. Our study justifies a simple imaging technique, e.g., rapidly scanned sub-80-fs excitation with full triplet-relaxation, to mitigate this ubiquitous linear-absorption-mediated phototoxicity independent of sample types. The corresponding label-free imaging can track freely moving C. elegans in real-time at an irradiance up to one-half of water optical breakdown.
Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alström Syndrome

Background Alström Syndrome (AS), a multi-system disease caused by mutations in the ALMS1 gene, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and hepatosteatosis. How loss of ALMS1 causes this phenotype is poorly understood, but prior studies have circumstancially implicated impaired adipose tissue expandability. We set out to test this by comparing the metabolic effects of selective Alms1 knockout in mesenchymal cells including preadipocytes to those of global Alms1 knockout. Methods Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα-Cre driver was used to abrogate Alms1 function selectively in mesenchymal stem cells (MSCs) and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfrα+ Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues. Results Global Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfrα-cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfrα expression. Conclusions Mesenchymal deletion of Alms1 recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. AS should be regarded as a forme fruste of lipodystrophy. Therapies should prioritise targeting positive energy balance.
Exploring the genetic architecture of ecophysiological traits in microbial ecology using statistical analysis of the properties of protein sequences: application to the glycogen accumulating organism (GAO) phenotype

Nearly 50 years ago, King and Wilson introduced a key distinction between two types of genetic variation–named structural and regulatory variation–for exploring the molecular basis for phenotypic traits. Structural variation is genetic variation that will influence gene product structure via changes in coding sequence, whereas regulatory variation will influence the control of gene product expression. Here we repurpose these concepts to study the molecular basis of eco-physiological traits observed in microbial ecology, focusing on a specialized glycogen accumulating phenotype, known to be exhibited by a phylogenetically diverse group of microbes. We analyse the statistical properties of the protein sequence of the 1,4–α–glucan branching enzyme (glgB), a key enzyme responsible for formation of glycogen from linear glucans. We show that the glgB proteins in a subgroup of these organisms show unusual statistical properties of protein sequence length, sequence similarity and patterning of functional domains, compared to organisms that do not exhibit this phenotype. These findings suggest a role for structural genetic variation in determining this phenotype in some species. Our analysis holds implications for dissecting the genetic/genomic architecture of complex traits exhibited by microbial communities and also provides a complementary framework to presence–absence level analyses that are ubiquitous in microbial ecology.
THE EFFECTS OF DIFFERENT ASPECTS OF TOURISM SERVICES ON TRAVELERS' QUALITY OF LIFE: MODEL VALIDATION, REFINEMENT, AND EXTENSION

Numerous satisfaction studies have been conducted in both tourism and marketing which have examined various aspects of travelers and/or consumers. Quality of life satisfaction studies look beyond the types of satisfaction experiences that endure for only a short time to those that “spill over” into individuals’ life domains thus enhancing their overall life satisfaction. Many research studies in the discipline of marketing have revealed that the overall quality of life of consumers may be affected by the marketing efforts of organizations for all of the marketing mix elements. Although it logically follows that the marketing endeavors of tourism organizations would likely have the same impact on their consumers (i.e., travelers), little research has been done to date to determine the validity of this premise. The purpose of this study is to examine the effects of leisure tourism on the traveler’s quality of life. A model and measurement instrument which help to explain the role of satisfaction with leisure tourism services and experiences in satisfaction with leisure life and overall life were designed for use in this study. The model was based on the hierarchy of life satisfaction model and speculated that overall life satisfaction is derived from satisfaction with the major life domains (e.g., leisure life). Lasting satisfaction or dissatisfaction experienced within the leisure life domain spills up vertically to the most superordinate domain (life in general), thus affecting the overall life satisfaction or dissatisfaction of the traveler. Both the model and the measurement instrument were validated, refined, and extended in this study. A survey of 815 consumers of travel/tourism services who reside in Southwest Virginia was conducted. Structural Equation Modeling (i.e., LISREL) analysis was performed to test the goodness of fit of the model. The results indicated a good model fit. That is, no revisions to the hypothesized model were needed, thus confirming the belief leisure travel does contribute to travelers’ overall quality of life satisfaction. Additional analyses were conducted to test the moderating effects of personality type, length of stay, and type of trip on select relationships in the model. Differences of effects for some of the relationships in the model were identified for length of stay and type of trip, but not for the traveler’s personality type. Among the key findings of this work are the establishment of those factors which contribute to the overall life satisfaction of travelers, the validation of a measurement instrument which could be used periodically by industry experts to gauge the “health” of the industry in its contribution to the overall life satisfaction of tourism consumers, and the revelation that the length of stay moderates several of the relationships in the model, thus suggesting differences in the way the various identified components influence the overall life satisfaction of short-term versus long-term visitors.
Non-verbal skills in auditory word processing: Implications for typical and dyslexic readers

Dyslexia is characterized by poor phonological skills and atypical neural responses to text and speech stimuli, while non-verbal intelligence remains unaffected. However, the impact of non-verbal intelligence on language-evoked neural responses in dyslexia is underexplored. This study examines non-verbal intelligence’s effects on neural responses to auditory words in typical and dyslexic readers. Participants completed IQ tests, reading and phonological assessments, and underwent magnetoencephalography recordings while listening to words. Event-related brain field responses at different stages of auditory word processing (100ms, 200ms, 400ms) were analyzed in relation to non-verbal IQ scores and reading performance. Higher non-verbal IQ in typical readers yielded earlier right hemisphere perceptual responses (100ms). Dyslexic readers showed no IQ-related latency effects but those with lower non-verbal IQ displayed amplified left hemisphere response amplitudes at 100ms. These findings confirm the link between non-verbal cognitive abilities and early auditory word processing in adults, highlighting distinct effects in dyslexia and controls.
Reprocessing of a global GPS network

[1] During the 10 years since the official start of the International GNSS Service (IGS) in 1994 considerable improvements in the processing strategies and modeling of global GPS solutions were achieved. Owing to changes at the individual IGS Analysis Centers during these years the resulting time series of global geodetic parameters are very inhomogeneous and inconsistent. A geophysical interpretation of these long series and the realization of a high-accuracy global reference frame are therefore difficult and questionable. In view of these deficiencies, the Technical Universities of Munich and Dresden decided to perform a reprocessing of a global GPS network over the last decade in a joint effort. First results of the reprocessing of 11 years of data show significant improvements in the quality and homogeneity of the estimated parameters and will allow for new geodynamic and geophysical interpretations. In the early years an improvement of the coordinate repeatability by a factor of more than 2 could be achieved. The formal errors of subdaily Earth rotation parameters could be reduced by 30%. Advanced modeling approaches like a mapping function based on numerical weather models, consideration of second- and third-order ionospheric corrections and absolute antenna phase center corrections for receivers and satellites were tested to achieve further improvements.
EEG spectral attractors identify a geometric core of resting brain activity

Spectral analysis of electroencephalographic (EEG) data simplifies the characterization of periodic band parameters but can obscure underlying dynamics. By contrast, reconstruction of neural activity in state-space preserves geometric complexity in the form of a multidimensional, global attractor. Here we combine these perspectives, inferring complexity and shared dynamics from eigen-time-delay embedding of periodic and aperiodic spectral parameters to yield unique dynamical attractors for each EEG parameter. We find that resting-state alpha and aperiodic attractors show low geometric complexity and shared dynamics with all other frequency bands, what we refer to as geometric cross-parameter coupling. Further, the geometric signatures of alpha and aperiodic attractors dominate spectral dynamics, identifying a geometric core of brain activity. Non-core attractors demonstrate higher complexity but retain traces of this low-dimensional signal, supporting a hypothesis that frequency specific information differentiates out of an integrative, dynamic core. Older adults show lower geometric complexity but greater geometric coupling, resulting from dedifferentiation of gamma band activity. The form and content of resting-state thoughts were further associated with the complexity of core dynamics. Thus, the hallmarks of resting-state EEG in the frequency domain, the alpha peak and the aperiodic backbone, reflect a dynamic, geometric core of resting-state brain activity. This evidence for a geometric core in EEG complements evidence for a regionally defined dynamic core from fMRI-based neuroimaging, further supporting the utility of geometric approaches to the analysis of neural data.
AR4 climate model performance in simulating snow water equivalent over Catskill Mountain watersheds, New York, USA

In this study, we evaluate the ability of GCMs participating in the Intergovernmental Panel for Climate Change's (IPCC) Fourth Assessment Report (AR4) to simulate variability in the snow water equivalent (SWE) in New York City Water Supply watersheds located northwest of NYC in the Catskill Mountains. SWE is estimated using an empirical temperature‐based degree day model. Inputs to this model are either measured with historical meteorological (1961–2000) data or a GCM model output for the same historical period. The evaluation of the GCMs is based on a skill score developed using probability distribution functions derived from the time series of simulated snowpack. From the skill scores (SS) calculated, the GCMs are ranked based on their ability to simulate the snowpack. These results have implications for selecting a subset of GCM simulations for climate change impact assessments in New York City's water supply.
Graptolite ontogeny and the size of the graptolite zooid

Abstract Two methods of estimating the size of the graptolite zooid are described and discussed. It is possible to size a zooid by reference to cortical bandages or with reference to modem Rhabdopleura and its tubes. These two methods give very different results, with the first suggesting small zooids relative to thecal size and the second suggesting zooids that filled their thecae completely. Comparison is made with the evidence available from rare cases of preserved zooids. When all these observations are considered in the light of the ontogeny of modem pterobranchs, an ontogenetic sequence for the graptolite zooid can be inferred which helps to reconcile the two methods of estimating zooid size. This sequence postulates that most skeletal building occurred early in the life of the zooid, before it developed the capacity to feed or to reproduce, and it implies that only the first of three stages in the zooid's life is recorded in the skeleton. The later stages occurred without normally leaving any trace on the preservable remains of the colony. Finally, there is discussion of the effects which different zooid sizes would have had on some aspects of the functional morphology of a theca and on the hydrodynamic behaviour of the rhabdosome as a whole.
Heavy Nodes in a Small Neighborhood: Algorithms and Applications

We introduce a weighted and unconstrained variant of the well-known minimum k union problem: Given a bipartite graph G ( U, V, E ) with weights for all nodes in V , ﬁnd a set S ⊆ V such that the ratio between the total weight of the nodes in S and the number of their distinct incident nodes in U is maximized. Our problem, which we term Heavy Nodes in a Small Neighborhood ( HNSN ), ﬁnds applications in marketing, team formation, and money laundering detection. For example, in the latter application, S represents bank account holders who obtain illicit money from some peers of a criminal and route it through their accounts to a target account belonging to the criminal. We prove that HNSN can be solved exactly in polynomial time via linear programming. As the size of G can be very large in practice, we also develop a near linear-time greedy heuristic. In addition, we formalize a money laundering scenario involving multiple target accounts and show how our algorithms can be extended to deal with it. Our experiments on real and synthetic datasets show that our algorithms ﬁnd optimal or near-optimal solutions, outperforming a natural baseline, and that they can detect money laundering much more effectively and eﬃciently than a state-of-the-art method.
Journal of Cellular Neuroscience and Oxidative Stress

and of , vitamins, antioxidant enzymes, metabolism of nitric oxide, oxidative stress, biophysics, biochemistry and physiology of free oxygen Abstract Prevalence of glioblastomas is high within the adult brain tumors and the proliferation of the glioblastomas was induced by excessive Ca 2+ influx. Ca 2+ permeable TRPV1 channel is gated by capsaicin and reactive oxygen species (ROS), although its activity was decreased in neurons by AMG and antioxidants. Clostridium botulinum neurotoxin A (BotxA) acted antioxidant action in several cells and its treatment modulated TRPV1 in neurons. Hence, treatment of BotxA may modulate glioblastoma cell proliferation and death via inhibition of TRPV1 in the DBTRG glioblastoma in vitro cell line model. The DBTRG cells were divided into three groups as control, BotxA (5 IU for 24 hours) and BotxA+TRPV1 channel blocker (AMG and 1 µ M for 30 min). Intracellular Ca 2+ response to TRPV1 activation was increased in the cells from capsaicin, although it was reduced by the BotxA and AMG. BotxA treatment decreased cell proliferation, although its treatment increased cell death (propidium iodide/Hoechst rate). In addition, BotxA decreased mitochondrial membrane depolarization levels, cytosolic and mitochondrial ROS generation in the cells. Their levels were further decreased in the BotxA+AMG group by the AMG treatment. The antiproliferative and neurotoxic effects of BotxA were shown to be exerted via modulation of oxidative stress and TRPV1 activation. BotxA could be used as an effective agent in the treatment of glioblastoma proliferation. cells by capsaicin (CPS), although it is inhibited by AMG and BotxA. Hence, glioblastoma cell proliferation, MitoROS and ROS were modulated via inhibition of TRPV1 by BotxA and AMG.
Trade and Informality in the Presence of Labor Market Frictions

We build an equilibrium model of a small open economy with labor market frictions and imperfectly enforced regulations. Heterogeneous firms sort into the formal or informal sector. We estimate the model using data from Brazil, and use counterfactual simulations to understand how trade affects economic outcomes in the presence of informality. We show that: (1) Trade openness unambiguously decreases informality in the tradable sector, but has ambiguous effects on aggregate informality. (2) The productivity gains from trade are understated when the informal sector is omitted. (3) Trade openness results in large welfare gains even when informality is repressed. (4) Repressing informality increases productivity, but at the expense of employment and welfare. (5) The effects of trade on wage inequality are reversed when the informal sector is incorporated in the analysis. (6) The informal sector works as an “unemployment,” but not a “welfare buffer” in the event of negative economic shocks. JEL codes: F14, F16, J46, O17 ∗Dix-Carneiro: rafael.dix. carneiro@duke.edu; Goldberg: penny.goldberg@yale.edu; Meghir: c.meghir@yale.edu; Ulyssea: g.ulyssea@ucl.ac. uk. This project was supported by award SES-1629124 from the National Science Foundation and by the Early Career Research Grant 15-150-04 from the W.E. Upjohn Institute for Employment Research. We would like to thank Nina Pavcnik, Jean-Marc Robin, and Jim Tybout, as well as numerous seminar and conference participants, for helpful comments and discussions.
The 2003 North American electrical blackout: An accidental experiment in atmospheric chemistry

The August 2003 North American electrical blackout provided a unique opportunity to quantify directly the contribution of power plants to regional haze and O3. Airborne observations over central Pennsylvania on August 15, 2003, ∼24 h into the blackout, revealed large reductions in SO2 (>90%), O3 (∼50%), and light scattered by particles (∼70%) relative to measurements outside the blackout region and over the same location when power plants were operating normally. CO and light absorbing particles were unaffected. Low level O3 decreased by ∼38 ppbv and the visual range increased by >40 km. This clean air benefit was realized over much of the eastern U.S. Reported SO2 and NOx emissions from upwind power plants were down to 34 and 20% of normal, respectively. The improvement in air quality provides evidence that transported emissions from power plants hundreds of km upwind play a dominant role in regional haze and O3 production.
Proof of a conjecture of Kudla and Rallis on quotients of degenerate principal series

In this paper we prove a conjecture of Kudla and Rallis. Let $\chi$ be a unitary character, $s\in \mathbb{C}$ and $W$ a symplectic vector space over a non-archimedean field with symmetry group $G(W)$. Denote by $I(\chi,s)$ the degenerate principal series representation of $G(W\oplus W)$. Pulling back $I(\chi,s)$ along the natural embedding $G(W)\times G(W)\hookrightarrow G(W\oplus W)$ gives a representation $I_{W,W}(\chi,s)$ of $G(W)\times G(W)$. Let $\pi$ be an irreducible smooth complex representation of $G(W)$. We then prove \[\dim _\mathbb{C}\mathrm{Hom}_{G(W)\times G(W)}(I_{W,W}(\chi,s),\pi\otimes \pi^\lor)=1. \] We also give analogous statements for $W$ orthogonal or unitary. This gives in particular a new proof of the conservation relation of the local Theta correspondence for symplectic-orthogonal and unitary dual pairs.
Simulation Based Composite Likelihood

Inference for high-dimensional hidden Markov models is challenging due to the exponential-in-dimension computational cost of the forward algorithm. To address this issue, we introduce an innovative composite likelihood approach called"Simulation Based Composite Likelihood"(SimBa-CL). With SimBa-CL, we approximate the likelihood by the product of its marginals, which we estimate using Monte Carlo sampling. In a similar vein to approximate Bayesian computation (ABC), SimBa-CL requires multiple simulations from the model, but, in contrast to ABC, it provides a likelihood approximation that guides the optimization of the parameters. Leveraging automatic differentiation libraries, it is simple to calculate gradients and Hessians to not only speed-up optimization, but also to build approximate confidence sets. We conclude with an extensive experimental section, where we empirically validate our theoretical results, conduct a comparative analysis with SMC, and apply SimBa-CL to real-world Aphtovirus data.