Miracle-dz/UniFAR-FTUs huggingface dataset:
Blood biomarkers in ALS: challenges, applications and novel frontiers

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease among adults. With diagnosis reached relatively late into the disease process, extensive motor cell loss narrows the window for therapeutic opportunities. Clinical heterogeneity in ALS and the lack of disease‐specific biomarkers have so far led to large‐sized clinical trials with long follow‐up needed to define clinical outcomes. In advanced ALS patients, there is presently limited scope to use imaging or invasive cerebrospinal fluid (CSF) collection as a source of disease biomarkers. The development of more patient‐friendly and accessible blood biomarker assays is hampered by analytical hurdles like the matrix effect of blood components. However, blood also provides the opportunity to identify disease‐specific adaptive changes of the stoichiometry and conformation of target proteins and the endogenous immunological response to low‐abundance brain peptides, such as neurofilaments (Nf). Among those biomarkers under investigation in ALS, the change in concentration before or after diagnosis of Nf has been shown to aid prognostication and to allow the a priori stratification of ALS patients into smaller sized and clinically more homogeneous cohorts, supporting more affordable clinical trials. Here, we discuss the technical hurdles affecting reproducible and sensitive biomarker measurement in blood. We also summarize the state of the art of non‐CSF biomarkers in the study of prognosis, disease progression, and treatment response. We will then address the potential as disease‐specific biomarkers of the newly discovered cryptic peptides which are formed down‐stream of TDP‐43 loss of function, the hallmark of ALS pathobiology.
Looking through a Different Lens: Microhistory and the Workhouse Experience in Late Nineteenth-Century London

Abstract:This article uses a microhistorical approach to investigate the “workhouse experience” of a single pauper in late nineteenth-century London. Its subject is Frank Burge, a remarkably prolific (though by no means unique) correspondent who wrote several lengthy letters of complaint from the Poplar workhouse to the Local Government Board (the central poor law authority) between 1884 and 1885. It places these letters, and the official responses they stimulated, alongside other public and official documents and uses a blended methodological approach to uncover a rich narrative of hardship, struggle, and personal agency. In doing so, it argues that, in contrast to more orthodox histories of welfare, it is only through this kind of painstaking and sensitive historical reconstruction that we truly can understand the nature, and the legacy, of poverty and the “workhouse experience” on the nineteenth-century poor.
How closely do baryons follow dark matter on large scales

We investigate the large-scale clustering and gravitational interaction of baryons and dark matter (DM) over cosmic time using a set of collisionless N-body simulations. Both components, baryons and DM, are evolved from distinct primordial density and velocity power spectra as predicted by early-universe physics. We first demonstrate that such two-component simulations require an unconventional match between force and mass resolution (i.e. force softening on at least the mean particle separation scale). Otherwise, the growth on any scale is not correctly recovered because of a spurious coupling between the two species at the smallest scales. With these simulations, we then demonstrate how the primordial differences in the clustering of baryons and DM are progressively diminished over time. In particular, we explicitly show how the BAO signature is damped in the spatial distribution of baryons and imprinted in that of DM. This is a rapid process, yet it is still not fully completed at low redshifts. On large scales, the overall shape of the correlation function of baryons and DM differs by 2% at z = 9 and by 0.2% at z = 0. The differences in the amplitude of the BAO peak are approximately a factor of 5 larger: 10% at z = 9 and 1% at z = 0. These discrepancies are, however, smaller than effects expected to be introduced by galaxy formation physics in both the shape of the power spectrum and in the BAO peak, and are thus unlikely to be detected given the precision of the next generation of galaxy surveys. Hence, our results validate the standard practice of modelling the observed galaxy distribution using predictions for the total mass clustering in the Universe.
Dissipative dynamics in quasifission

Quasifission is the primary reaction mechanism that prevents the formation of superheavy elements in heavy-ion fusion experiments. Employing the time-dependent density functional theory approach, we study quasifission in the systems $^{40,48}\mathrm{Ca}+^{238}\mathrm{U}$. Results show that for $^{48}\mathrm{Ca}$ projectiles the quasifission is substantially reduced in comparison to the $^{40}\mathrm{Ca}$ case. This partly explains the success of superheavy element formation with $^{48}\mathrm{Ca}$ beams. For the first time, we also calculate the repartition of excitation energies of the two fragments in a dynamic microscopic theory. The differences between both systems are interpreted in terms of initial neutron to proton asymmetry of the colliding partners.
Structural, electronic, and optical properties of ZrO2 from ab initio calculations

Structural, electronic, and optical properties for the cubic, tetragonal, and monoclinic crystalline phases of ZrO2, as derived from ab initio full-relativistic calculations, are presented. The electronic structure calculations were carried out by means of the all-electron full-potential linear augmented plane wave method, within the framework of the density functional theory and the local density approximation. The calculated carrier effective masses are shown to be highly anisotropic. The results obtained for the real and imaginary parts of the dielectric function, the reflectivity, and the refraction index show good agreement with the available experimental results. In order to obtain the static dielectric constant of ZrO2, we added to the electronic part the optical phonon contribution, which leads to values of ϵ1(0)≃29.5,26.2,21.9, respectively, along the xx, yy, and zz directions, for the monoclinic phase, in excellent accordance with experiment. Relativistic effects, including the spin-orbit intera.
Diagram for vortex formation in quasi-two-dimensional magnetic dots

The existence of nonlinear objects of the vortex type in two-dimensional magnetic systems presents itself as one of the most promising candidates for the construction of nanodevices, useful for storing data, and for the construction of reading and writing magnetic heads. The vortex appears as the ground state of a magnetic nanodisk whose magnetic moments interact via the dipole-dipole potential {D∑[Si⋅Sj−3(Si⋅rij)×(Sj⋅rij)]/rij3} and the exchange interaction (−J∑Si⋅Sj). In this work it is investigated the conditions for the formation of vortices in nanodisks in triangular, square, and hexagonal lattices as a function of the size of the lattice and of the strength of the dipole interaction D. Our results show that there is a “transition” line separating the vortex state from a capacitorlike state. This line has a finite size scaling form depending on the size, L, of the system as Dc=D0+1/A(1+BL2). This behavior is obeyed by the three types of lattices. Inside the vortex phase it is possible to iden.
Exploring the Impact of GRE-Accepting Admissions on Law School Diversity and Selectivity

Abstract:Reducing barriers to graduate and professional education may reduce racial inequities in high-status professions. In 2020, one-quarter of law schools accepted the GRE in place of the LSAT, reflecting an effort across educational domains to revisit standardized test requirements. We use a generalized difference-in-differences design to investigate the impact of GRE-accepting admissions on diversity and selectivity in legal education. We find some evidence of decreased racial diversity after policies have been in place a couple of years, along with increases in applications and decreases in acceptance rates. Findings indicate GRE-accepting admissions alone are unlikely to expand access to high-status fields.
Bioefficacy of hydroxytyrosol-rich food supplements on preventing lipid peroxidation in healthy men

In the present study we report the efficacy of food matrices derived from olives in preventing oxidation of low-density lipoprotein cholesterol (LDL) and lipid peroxidation. To this end, 12 healthy volunteers were divided into 3 groups and cross-received a single dose of olive phenolics, mainly hydroxytyrosol (HT), provided as a liquid dietary supplement (30.6 or 61.5 mg HT), or as fortified extra virgin olive oil (12.19 mg HT + tyrosol). Blood and urine samples were collected at baseline and up to 12 hours after ingestion. Plasma oxidized LDL levels were measured by ELISA using a monoclonal antibody, while F2-isoprostanes were quantified in urine by UHPLC-MS/MS. Despite the great variability between individuals, a tendency to reduce lipoxidation reactions has been observed after olive phenolics intake in both, blood and urine. In addition, the subgroup of individuals with the highest baseline lipoxidation level showed a decrease in F2-isoprostanes (p < 0.05) after taking the food supplements, as well as a marked decrease in oxidized LDL levels (p < 0.01) after intake of the food supplement with the lowest HT dose. These promising results suggest that HT supplementation could be a useful aid in preventing lipoxidation. Additionally, people with a redox imbalance could benefit even more from supplementing with bioavailable HT.
Predicting phenotype transition probabilities via conditional algorithmic probability approximations

Unravelling the structure of genotype-phenotype (GP) maps is an important problem in biology. Recently, arguments inspired by algorithmic information theory (AIT) and Kolmogorov complexity have been invoked to uncover simplicity bias in GP maps, an exponentially decaying upper bound in phenotype probability with increasing phenotype descriptional complexity. This means that phenotypes with very many genotypes assigned via the GP map must be simple, while complex phenotypes must have few genotypes assigned. Here we use similar arguments to bound the probability P (x → y) that phenotype x, upon random genetic mutation, transitions to phenotype y. The bound is , where is the estimated conditional complexity of y given x, quantifying how much extra information is required to make y given access to x. This upper bound is related to the conditional form of algorithmic probability from AIT. We demonstrate the practical applicability of our derived bound by predicting phenotype transition probabilities (and other related quantities) in simulations of RNA and protein secondary structures. Our work contributes to a general mathematical understanding of GP maps, and may facilitate the prediction of transition probabilities directly from examining phenotype themselves, without utilising detailed knowledge of the GP map.
Genetic drift promotes and recombination hinders speciation on holey fitness landscapes

Dobzhansky and Muller proposed a general mechanism through which microevolution, the substitution of alleles within populations, can cause the evolution of reproductive isolation between populations and, therefore, macroevolution. As allopatric populations diverge, many combinations of alleles differing between them have not been tested by natural selection and may thus be incompatible. Such genetic incompatibilities often cause low fitness in hybrids between species. Furthermore, the number of incompatibilities grows with the genetic distance between diverging populations. However, what determines the rate and pattern of accumulation of incompatibilities remains unclear. We investigate this question by simulating evolution on holey fitness landscapes on which genetic incompatibilities can be identified unambiguously. We find that genetic incompatibilities accumulate more slowly among genetically robust populations and identify two determinants of the accumulation rate: recombination rate and population size. In large populations with abundant genetic variation, recombination selects for increased genetic robustness and, consequently, incompatibilities accumulate more slowly. In small populations, genetic drift interferes with this process and promotes the accumulation of genetic incompatibilities. Our results suggest a novel mechanism by which genetic drift promotes and recombination hinders speciation. Author summary As geographically isolated populations evolve, genetic incompatibilities accumulate between them. Eventually, these incompatibilities may cause the populations to become different species. What determines how quickly species are formed in this way remains unclear. We investigate this question using computer simulations and find that genetic incompatibilities accumulate more slowly among populations with individuals that are robust to genetic perturbations. We identify two factors that influence the accumulation rate via their effects on genetic robustness: the size of the populations and how much recombination takes place in them. Small populations with rare recombination accumulate incompatibilities more quickly.
DATA STUDY OF THE INDONESIA FAMILY LIFE SURVEY 5 (IFLS 5) THE RISK FACTORS OF CENTRAL OBESITY IN INDONESIAN MEN: A CROSS-SECTIONAL

Obesity is one of the leading health problems in both developed and developing countries. Central obesity can be defined as a condition where excess fat has accumulated in the abdominal area. There are several risk factors that may cause central obesity in men such as smoking habits, physical activity, and dietary habits. This study aimed to analyse the risk factors of central obesity in Indonesian men. This was an analytical observational study using a cross-sectional design. It used secondary data from the Indonesia Family Life Survey (IFLS 5) with a sample size of 4,648 respondents. The variables studied here were smoking status, type of smoker, type of cigarette, physical activity, and meat consumption frequency. Logistic regression analysis was used. The results of this study showed that the mean age of the respondents was 51 years old. There was a relationship between smoking status (p=0.000), type of smoker (p=0.002), type of cigarette (p=0.000), physical activity (p=0.000), and meat consumption frequency (p=0.024) and the incidence of central obesity. The conclusion of the study was that there was a relationship between smoking status, type of smoker, type of cigarette, physical activity, meat consumption frequency, and the incidence of central obesity, all of which were risk factors of central obesity in Indonesian men. A low level of physical activity was the most prominent risk factor associated with central obesity among Indonesian men. From this study, we suggested controlling the risk factors of central obesity by providing education on the dangers of smoking and the importance of physical activity and a balanced nutritional diet. activity, unhealthy dietary habits, and smoking habits. This study aimed to analyze the risk factors for central obesity in Indonesian men.
Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1

Stem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on CAR-T immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that the CAR-T cell mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSC caused an increase of CD4+ T cells and Treg cells but decrease of CD8+ T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death-ligand 1 (PD-L1) that contribute to the immune-suppressive function of tumor. Moreover, MSCs suppressed key components of NLRP3 inflammasome by modulating mitochondrial ROS release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the STC1 gene, which encodes the glycoprotein hormone staniocalcin-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo and STC1 played a critical role. These data revealed a novel function of MSC and staniocalcin-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from excessive immune response.
parsec: stellar tracks and isochrones with the PAdova and TRieste Stellar Evolution Code

We present the updated version of the code used to compute stellar evolutionary tracks in Padova. It is the result of a thorough revision of the major in put physics, together with the inclusion of the pre‐main sequence phase, not present in our previous releases of stellar models. Another innovative aspect is the possibility of prompt ly generating accurate opacity tables fully consistent with any selected initial chemical composition, by coupling the OPAL opacity data at high temperatures to the molecular opacities computed with our AESOPUS code (Marigo & Aringer 2009). In this work we present extended sets of stellar evolutionary models for various initial chemical compositions, while other set s with different metallicities and/or different distributions of heavy elements are being computed. For the present release of models we adopt the solar distribution of heavy elements from the recent revision by Caffau et al. (2011), corresponding to a Sun’s metallicity Z≃ 0.0152. From all computed sets of stellar tracks, we also derive isochrones in several photometric systems. The aim is to provide the community with the basic tools to model star clusters and galaxies by means of population synthesis techniques.
Irregular optogenetic stimulation waveforms can induce naturalistic patterns of hippocampal spectral activity

Introduction Brain stimulation is a fundamental and effective therapy for neurological diseases including Parkinson’s disease, essential tremor, and epilepsy. One key challenge in delivering effective brain stimulation is identifying the stimulation parameters, such as the amplitude, frequency, contact configuration, and pulse width, that induce an optimal change in symptoms, behavior, or neural activity. Most clinical and translational studies use constant-frequency pulses of stimulation, but stimulation with irregular pulse patterns or non-pulsatile waveforms might induce unique changes in neural activity that could enable better therapeutic responses. Here, we comprehensively evaluate several optogenetic stimulation waveforms, report their differing effects on hippocampal spectral activity, and compare these induced effects to activity recorded during natural behavior. Methods Sprague-Dawley rats were prepared for pan-neuronal excitatory optogenetic stimulation of the medial septum (hSyn-ChR2) and 16-channel microelectrode recording in CA1 and CA3 layers of the hippocampus. We performed grid and random sampling of the parameters comprising several stimulation waveforms, including standard pulse, nested pulse, sinusoid, double sinusoid, and Poisson pulse waveforms. Results We comprehensively report the effects of changing stimulation parameters in these parameter spaces on two key biomarkers of hippocampal function, theta (4-10 Hz) and gamma (32-50 Hz) power. Similarly, robust excitation of hippocampal gamma power was observed across all waveforms, whereas no set of stimulation parameters was sufficient to consistently increase power in the theta band beyond baseline levels of activity (despite the prominent role of the medial septum in pacing hippocampal theta oscillations). Using a manifold learning algorithm to compare high-dimensional neural activity, we show that irregular stimulation patterns produce differing effects with respect to multi-band patterns of activity and can induce activity patterns that more closely resemble activity recorded during natural behavior than conventional parameters. Conclusion Our counter-intuitive findings – that stimulation of the medial septum ubiquitously does not increase hippocampal theta power, and that different waveforms have similar effects on single power bands – contradict recent trends in brain stimulation research, necessitating greater caution and fewer mechanistic assumptions as to how a given stimulation target or waveform will modulate a neurophysiological biomarker of disease. We also reveal that irregular stimulation patterns can have biomimetic utility, promoting their exploration in medical applications where inducing a particular activity pattern can have therapeutic benefit. Last, we demonstrate a scalable data-driven analysis strategy that can make the discovery of such physiologically informed temporal stimulation patterns more empirically tractable in translational settings.
In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ failure including testicular injury and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury can likely result either from direct virus infection of resident cells or by exposure to systemic inflammatory mediators or virus antigens. We here characterized SARS-CoV-2 infection in different human testicular 2D and 3D models including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not establish a productive infection in any testicular cell types. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma depicted a significant decrease in cell viability and death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 envelope protein, but not Spike or nucleocapsid proteins led to cytopathic effects on testicular cells that was dependent on the TLR2 receptor. A similar trend was observed in the K18h-ACE2 mouse model which revealed gross pathology in the absence of virus replication in the testis. Collectively, data strongly indicates that the testicular injury is not due to direct infection of SARS-CoV-2 but more likely an indirect effect of exposure to systemic inflammation or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.
Experimental Parameters-Based Monte-Carlo Simulation of Single-Molecule Localization Microscopy of Nuclear Pore Complex to Evaluate Clustering Algorithms

Single-molecule localization microscopy (SMLM) enables the detailed visualization of nuclear pore complexes (NPC) in vitro with sub-20 nm resolution. However, it is challenging to translate the localized coordinates in SMLM images to NPC functions because different algorithms to cluster localizations as individual NPCs can be biased without ground truth for validation. We developed a Monte-Carlo simulation to generate synthetic SMLM images of NPC and used the simulated NPC images as the ground truth to evaluate the performance of six clustering algorithms. We identified HDBSCAN as the optimal clustering algorithm for NPC counting and sizing. Furthermore, we compared the clustering results between the experimental and synthetic data for NUP133, a subunit in the NPC, and found them to be in good agreement.