julilili42/papers huggingface dataset:
Amyloid pathology but notAPOEε4 status is permissive for tau-related hippocampal dysfunction
2021-10-21

Abstract We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A−) of amyloid pathology was defined by CSF amyloid-β42 (Aβ42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A− individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (&amp;gt;700 pg/ml) and phospho-tau (&amp;gt;100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aβ42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A− groups. After classifying this matched sample for phospho-tau pathology (T−/T+), individuals with A+/T+ were significantly more memory-impaired than A−/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer’s disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer’s disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.
DoE Optimization Empowers the Automated Preparation of Enantiomerically Pure [18F]Talazoparib and its In Vivo Evaluation as a PARP Radiotracer
2021-10-21

Given the clinical potential of poly(ADP-ribose) polymerases (PARP) imaging for the detection and stratification of various cancers, the development of novel PARP imaging probes with improved pharmacological profiles over established PARP imaging agents is warranted. Here, we present a novel <sup>18</sup>F-labeled PARP radiotracer based on the clinically superior PARP inhibitor talazoparib. An automated radiosynthesis of [<sup>18</sup>F]talazoparib (RCY: 13 ± 3.4%; <i>n</i> = 4) was achieved using a "design of experiments" (DoE) optimized copper-mediated radiofluorination reaction. The chiral product was isolated from the reaction mixture using 2D reversed-phase/chiral radio-HPLC (>99% ee). (8<i>S</i>,9<i>R</i>)-[<sup>18</sup>F]Talazoparib demonstrated PARP binding in HCC1937 cells <i>in vitro</i> and showed an excellent tumor-to-blood ratio in xenograft-bearing mice (10.2 ± 1.5). Additionally, a favorable pharmacological profile in terms of excretion, metabolism, and target engagement was observed. This synthesis of [<sup>18</sup>F]talazoparib exemplifies how DoE can enable the radiosyntheses of synthetically challenging radiolabeled compounds of high interest to the imaging community.
Silent versus reading out loud modes: An eye-tracking study
2021-10-21

The main purpose of this study is to compare the silent and loud reading ability of typical and dyslexic readers, using eye-tracking technology to monitor the reading process. The participants (156 students of normal intelligence) were first divided into three groups based on their school grade, and each subgroup was then further separated into typical readers and students diagnosed with dyslexia. The students read the same text twice, one time silently and one time out loud. Various eye-tracking parameters were calculated for both types of reading. In general, the performance of the typical students was better for both modes of reading - regardless of age. In the older age groups, typical readers performed better at silent reading. The dyslexic readers in all age groups performed better at reading out loud. However, this was less prominent in secondary and upper secondary dyslexics, reflecting a slow shift towards silent reading mode as they age. Our results confirm that the eye-tracking parameters of dyslexics improve with age in both silent and loud reading, and their reading preference shifts slowly towards silent reading. Typical readers, before 4th grade do not show a clear reading mode preference, however, after that age they develop a clear preference for silent reading.
Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study
2021-10-21

Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu2+ ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO4, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 μM) and then cells were irradiated with a single dose of 0–8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study.
Top-down resolution of visual ambiguity – knowledge from the future or footprints from the past?
2021-10-21

Current theories about visual perception assume that our perceptual system weights the a priori incomplete, noisy and ambiguous sensory information with previous, memorized perceptual experiences in order to construct stable and reliable percepts. These theories are supported by numerous experimental findings. Theories about precognition have an opposite point of view. They assume that information from the future can have influence on perception, thoughts, and behavior. Several experimental studies provide evidence for precognition effects, other studies found no such effects. One problem may be that the vast majority of precognition paradigms did not systematically control for potential effects from the perceptual history. In the present study, we presented ambiguous Necker cube stimuli and disambiguated cube variants and systematically tested in two separate experiments whether perception of a currently observed ambiguous Necker cube stimulus can be influenced by a disambiguated cube variant, presented in the immediate perceptual past (perceptual history effects) and/or in the immediate perceptual future (precognition effects). We found perceptual history effects, which partly depended on the length of the perceptual history trace but were independent of the perceptual future. Results from some individual participants suggest on the first glance a precognition pattern, but results from our second experiment make a perceptual history explanation more probable. On the group level, no precognition effects were statistically indicated. The perceptual history effects found in the present study are in confirmation with related studies from the literature. The precognition analysis revealed some interesting individual patterns, which however did not allow for general conclusions. Overall, the present study demonstrates that any future experiment about sensory or extrasensory perception urgently needs to control for potential perceptual history effects and that temporal aspects of stimulus presentation are of high relevance.
Angiokeratoma corporis diffusum with severe acroparesthesia, an endothelial abnormality, and inconspicuous genetic findings
2021-10-21

Abstract Angiokeratoma corporis diffusum (ACD) was long thought to be a specific dermal sign of Fabry disease (FD, X‐linked alpha‐galactosidase A [GLA] deficiency). However, other lysosomal storage diseases (LSDs) have also been identified as triggers of ACD. Generalized vasculopathy is an important pathogenetic factor in FD and may also lead to the acroparesthesia (AP) often predominant in FD. We report on an 85‐year‐old woman with ACD present since her youth and associated with severe AP. Ultrastructure of the dermal lesion showed no lysosomal involvement, but the absence of the basement membrane of the endothelial cells of the capillary vessels was noteworthy. Repeated analyses of the GLA gene revealed no evidence of FD. Whole‐exome sequencing was negative for FD and other LSDs, and allowed us to also study FD‐related intronic regions of the GLA gene. This is the first report of a patient with FD‐like ACD with an endothelial abnormality, otherwise unexplained vasculopathy and severe AP, which are not due to FD or another LSD. Based on family history, another genetic, yet unidentified, defect may cause the disease in this patient. In unexplained ACD, extended genetic analysis is required to exclude particular pathogenic variants of the GLA gene and other genes.
How does early symptom change predict subsequent course of depressive symptoms during psychotherapy?
2021-10-21

Objectives Previous studies reported about the influence of early changes on treatment response. However, the question of whether early changes can predict the subsequent course of depressive symptoms during treatment with psychotherapy has not yet been clearly answered. We aimed to investigate whether symptom course in the first weeks at the level of individual session can predict the further symptom progression on a session to session level during psychotherapy treatment in patients with Major Depression (MD). Design Monocentric randomized controlled trial with psychotherapeutic treatment either with cognitive‐behavioural therapy (CBT) or hypnotherapy (HT). The longitudinal course of weekly depressive symptoms during the six months treatment period was examined. Methods In this RCT with 152 randomized patients suffering from current mild‐to‐moderate MD, depressive symptoms were assessed on a weekly basis during the 20 sessions’ treatment with individual psychotherapy. We only included patients for which sufficient data for our analysis were available. Three different linear and quadratic mixed model analyses with random effects for each patient were tested: Early change was defined as the individual percentage symptom change during the first two, three, four and five weeks. Symptoms from session four, five, six and seven onward were predicted using different models, with early change added to the model in a final step. Calculating all models separately for CBT and HT lead to comparable results. Result A slow symptom decrease after session four, five, six, seven onward to the end of the treatment was found. However, adding early change to the model, had no effect on the further symptom course in all models. Conclusion Symptom changes at early stages of psychotherapy should not be considered as being predictive for further symptom course. Practitioner points The individual early symptom change in a treatment with psychotherapy in the first two, three, four, or five weeks of treatment does not predict the subsequent symptom course from session four, five, six, or seven onward at a session to session level. Symptom changes at early stages of psychotherapy should not be considered as being predictive for further symptom course. We found a symptom reduction ranging from 3% to 16% in the first two, three, four, or five weeks. Treatment response between the first and last therapy session was found in 54.5%, the number of remitted patients (with PHQ‐9 scores &lt; 5) was 44.7%. A small symptom improvement of between 0.21 and 0.42 points in the PHQ‐9 scores per week in later stages of psychotherapy is likely in all patients (with and without early symptom improvement).
Molybdenum Bioavailability and Asymbiotic Nitrogen Fixation in Soils are Raised by Iron (Oxyhydr)oxide-Mediated Free Radical Production
2021-10-22

Nitrogen (N) fixation in soils is closely linked to microbially mediated molybdenum (Mo) cycling. Therefore, elucidating the mechanisms and factors that affect Mo bioavailability is crucial for understanding N fixation. Here, we demonstrate that long-term (26 years) manure fertilization increased microbial diversity and content of short-range ordered iron (oxyhydr)oxides that raised Mo bioavailability (by 2.8 times) and storage (by ∼30%) and increased the abundance of <i>nif</i>H genes (by ∼14%) and nitrogenase activity (by ∼60%). Nanosized iron (oxyhydr)oxides (ferrihydrite, goethite, and hematite nanoparticles) play a dual role in soil Mo cycling: (i) in concert with microorganisms, they raise Mo bioavailability by catalyzing hydroxyl radical (HO<sup>•</sup>) production via the Fenton reactions and (ii) they increase Mo retention by association with the nanosized iron (oxyhydr)oxides. In summary, long-term manure fertilization raised the stock and bioavailability of Mo (and probably also of other micronutrients) by increasing iron (oxyhydr)oxide reactivity and intensified asymbiotic N fixation through an increased abundance of <i>nif</i>H genes and nitrogenase activity. This work provides a strategy for increasing biological N fixation in agricultural ecosystems.
Reproducibility and discrimination of different indices of insulin sensitivity and insulin secretion
2021-10-22

Aims Insulin sensitivity and insulin secretion can be estimated by multiple indices from fasting blood samples or blood samples obtained during oral glucose tolerance tests. The test-retest reliability of these indices in repeated measurements within the same individuals can strongly vary. Methods We analyzed data of persons without diabetes who underwent two repeated OGTTs. For each measurement pair, we calculated multiple commonly used indices for the assessment of insulin secretion and insulin sensitivity. We then evaluated the coefficient of variation (standard deviation/mean) and discriminant ratio for each index. Results 89 persons underwent two OGTTs with a median interval of 86 days (IQR 64–249). Among indices of insulin sensitivity derived from fasting blood samples, the revised quantitative insulin sensitivity check index had the smallest coefficient of variation (2.8 ± 2.1%) whereas the C-peptide based homeostasis model assessment 2 had the highest discriminant ratio (1.97 (1.65–2.39)). As for insulin sensitivity indices that are based on OGTT, the oral glucose insulin sensitivity index had the smallest coefficient of variation (6.5 ± 5.1%). The highest discriminant ratio was found for the non-esterified fatty acids-based insulin sensitivity index (NEFA-ISI, 2.70 (2.30–3.22)). For the assessment of insulin secretion from fasting variables, the lowest mean coefficient of variation was found for C-peptide based homeostasis model assessment 2 beta with 10.8 ± 8% and the highest discriminant ratio for the C-peptide / Glucose-Ratio (2.18 (1.84–2.63)). Among indices assessing insulin secretion from an OGTT, the lowest coefficient of variation was found for the ratio of the areas under the C-peptide and glucose curves from 0 to 120 minutes with 11.3 ± 9.7%. Conclusion The data reveal large differences in the reproducibility and the discrimination capability of different indices that assess insulin sensitivity or insulin secretion. Our findings can aid the selection of an appropriate index in clinical studies.
Bacterial membrane vesicles shape Staphylococcus aureus skin colonization and induction of innate immune responses
2021-10-22

Abstract Staphylococcus aureus colonization is abundant on the skin of atopic dermatitis (AD) patients where it contributes to skin inflammation. S . aureus produces virulence factors that distinguish it from commensal skin bacteria such as S . epidermidis and S . lugdunensis . However, it has remained unclear, which of these virulence factors have the strongest impact on AD. Membrane vesicles (MVs) are released by pathogenic bacteria and might play an essential role in the long‐distance delivery of bacterial effectors such as virulence factors. We show that MVs are also released by skin commensals in a similar quantity and membrane lipid amount as those from pathogenic S . aureus . Interestingly, MVs from skin commensals can protect against S . aureus skin colonization by conditioning human skin for enhanced defence. In contrast, MVs released by S . aureus are able to induce CXCL8 and TNF‐α in primary human keratinocytes, recruit neutrophils and induce neutrophil extracellular traps, which enhance S . aureus skin colonization. CXCL8 induction is TLR2‐ and NFkB‐dependent and the induction level correlates with the membrane lipid and protein A content of the MVs. Interestingly, MVs of S . aureus strains from the lesional skin of AD patients show an enhanced membrane lipid and protein A content compared to the strains from the non‐lesional sites and have an enhanced proinflammatory potential. Our data underline the complex interplay in host‐ and bacterial derived factors in S . aureus skin colonization and the important role of bacterial derived MVs and their membrane lipid and protein A content in skin inflammatory disorders.
Optimization of Rain Gauge Networks for Arid Regions Based on Remote Sensing Data
2021-10-22

Water depletion is a growing problem in the world’s arid and semi-arid areas, where groundwater is the primary source of fresh water. Accurate climatic data must be obtained to protect municipal water budgets. Unfortunately, the majority of these arid regions have a sparsely distributed number of rain gauges, which reduces the reliability of the spatio-temporal fields generated. The current research proposes a series of measures to address the problem of data scarcity, in particular regarding in-situ measurements of precipitation. Once the issue of improving the network of ground precipitation measurements is settled, this may pave the way for much-needed hydrological research on topics such as the spatiotemporal distribution of precipitation, flash flood prevention, and soil erosion reduction. In this study, a k-means cluster analysis is used to determine new locations for the rain gauge network at the Eastern side of the Gulf of Suez in Sinai. The clustering procedure adopted is based on integrating a digital elevation model obtained from The Shuttle Radar Topography Mission (SRTM 90 × 90 m) and Integrated Multi-Satellite Retrievals for GPM (IMERG) for four rainy events. This procedure enabled the determination of the potential centroids for three different cluster sizes (3, 6, and 9). Subsequently, each number was tested using the Empirical Cumulative Distribution Function (ECDF) in an effort to determine the optimal one. However, all the tested centroids exhibited gaps in covering the whole range of elevations and precipitation of the test site. The nine centroids with the five existing rain gauges were used as a basis to calculate the error kriging. This procedure enabled decreasing the error by increasing the number of the proposed gauges. The resulting points were tested again by ECDF and this confirmed the optimum of thirty-one suggested additional gauges in covering the whole range of elevations and precipitation records at the study site.
Too Blind to See the Elephant? Why Neuroscientists Ought to Be Interested in Tinnitus
2021-10-22

Abstract A curative therapy for tinnitus currently does not exist. One may actually exist but cannot currently be causally linked to tinnitus due to the lack of consistency of concepts about the neural correlate of tinnitus. Depending on predictions, these concepts would require either a suppression or enhancement of brain activity or an increase in inhibition or disinhibition. Although procedures with a potential to silence tinnitus may exist, the lack of rationale for their curative success hampers an optimization of therapeutic protocols. We discuss here six candidate contributors to tinnitus that have been suggested by a variety of scientific experts in the field and that were addressed in a virtual panel discussion at the ARO round table in February 2021. In this discussion, several potential tinnitus contributors were considered: (i) inhibitory circuits, (ii) attention, (iii) stress, (iv) unidentified sub-entities, (v) maladaptive information transmission, and (vi) minor cochlear deafferentation. Finally, (vii) some potential therapeutic approaches were discussed. The results of this discussion is reflected here in view of potential blind spots that may still remain and that have been ignored in most tinnitus literature. We strongly suggest to consider the high impact of connecting the controversial findings to unravel the whole complexity of the tinnitus phenomenon; an essential prerequisite for establishing suitable therapeutic approaches.