julilili42/papers huggingface dataset:
Evaluation of Printability of Pva-Based Tablets from Powder and Assessment of Critical Rheological Parameters
2024-03-26

Fused deposition modeling (FDM) is a rather new technology in the production of personalized dosage forms. Melting and printing of polymer&amp;ndash;active pharmaceutical ingredient (API) &amp;ndash; mixtures can be used to produce oral dosage forms with different dosage as well as release behavior. This process is utilized to increase the bioavailability of pharmaceutically relevant active ingredients that are poorly soluble in physiological medium by transforming them into solid amorphous dispersions (ASD). Release from such ASDs is expected to be faster and higher compared to the raw materials and thus enhance bioavailability. Printing directly from powder while forming ASDs was realized. Different techniques to change release patterns as well as a non-destructive way for determination of API distribution were shown. By measuring the melt viscosities of mixtures printed a rheological model for the printer used is proposed.
Analysing the Cyanobacterial PipX Interaction Network Using NanoBiT Complementation in <em>Synechococcus elongatus</em> PCC7942
2024-03-26

The conserved cyanobacterial protein PipX is part of a complex interaction network with regulators involved in essential processes that include metabolic homeostasis or ribosome assembly. Because PipX interactions depend on the relative levels of their different partners and of the effector molecules binding to them, in vivo studies are required to understand the physiological significance and contribution of environmental factors to regulation of PipX complexes. Here we have used the NanoBiT complementation system to analyse regulation of complex formation in Synechococcus elongatus between PipX and each of its two best characterized partners, PII and NtcA. Our results confirm previous in vitro analysis on regulation of PipX-PII and PipX-NtcA complexes by 2-oxoglutarate and on regulation of PipX-PII by the ATP/ADP ratio, showing the disruption of PipX-NtcA complexes by increased levels of ADP-bound PII in Synechococcus elongatus. The demonstration of a positive role of PII on PipX-NtcA complexes under the initial response to nitrogen starvation or the impact of a PipX point mutation on the activity of PipX-PII and PipX-NtcA reporters are further indications of the sensitivity of the system. This study reveals additional regulatory complexities in the PipX interaction network, opening the way to future research in cyanobacteria.
Evaluating Malaria Rapid Diagnostic Tests and Microscopy for Detecting Plasmodium Infection and Status of Plasmodium falciparum Histidine-Rich Protein 2/3 Gene Deletions in Southeastern Nigeria
2024-03-26

ABSTRACT. Delays in malaria diagnosis increase treatment failures and deaths. In endemic regions, standard diagnostic methods are microscopy and malaria rapid diagnostic tests (mRDTs) detecting Plasmodium falciparum histidine-rich protein 2/3 (PFHRP2/PFHRP3), but gene deletions can allow certain parasites to remain undetected. We enlisted a cohort comprising 207 symptomatic individuals, encompassing both children and adults, at a hospital in Nnewi, Nigeria. The prevalence of parasites was determined using a highly sensitive, species-specific quantitative polymerase chain reaction (SS-qPCR). Within a subset of 132 participants, we assessed the sensitivity and specificity of microscopy and HRP2-mRDTs in comparison to SS-qPCR for the detection of P. falciparum . We also investigated the prevalence of pfhrp2 / pfhrp 3 gene deletions. Greater sensitivity was achieved with mRDTs (95%) compared with microscopy (77%). Also, mRDTs exhibited greater specificity (68%) than microscopy (44%). The positive predictive value of mRDTs (89%) surpassed that of microscopy (80%), suggesting a greater probability of accurately indicating the presence of infection. The negative predictive value of mRDTs (82%) was far greater than microscopy (39%). Of the 165 P. falciparum –positive samples screened for pfhrp2 / pfhrp3 gene deletions, one gene deletion was detected in one sample. Regarding infection prevalence, 84% were positive for Plasmodium spp. (by reverse transcription [RT]-qPCR), with P. falciparum responsible for the majority (97%) of positive cases. Thus, exclusive reliance on microscopy in endemic areas may impede control efforts resulting from false negatives, underscoring the necessity for enhanced training and advocating for high-throughput molecular testing such as RT-qPCR or qPCR at referral centers to address limitations.
Cerebrovascular reactivity impairment in genetic frontotemporal dementia
2024-03-26

Abstract INTRODUCTION Cerebrovascular reactivity (CVR) is an indicator of cerebrovascular health and its signature in hereditary frontotemporal dementia (FTD) remains unknown. We investigated CVR in genetic FTD and its relationship to cognition. METHODS CVR differences were assessed between 284 pre-symptomatic and 124 symptomatic mutation carriers, and 265 non-carriers, using resting-state fluctuation amplitudes (RSFA) on component-based and voxel-level RSFA maps. Associations and interactions between RSFA, age, genetic status, and cognition were examined using generalised linear models. RESULTS Compared to non-carriers, mutation carriers exhibited greater RSFA reductions, predominantly in frontal cortex. These reductions increased with age. The RSFA in these regions correlated with cognitive function in symptomatic and, to a lesser extent, pre- symptomatic individuals, independent of disease stage. DISCUSSION CVR impairment in genetic FTD predominantly affects frontal cortical areas, and its preservation may yield cognitive benefits for at-risk individuals. Cerebrovascular health may be a potential target for biomarker identification and disease-modifying efforts.
Transforming spontaneous premature neonatal EEG to unpaired spontaneous fetal MEG using a CycleGan learning approach
2024-03-26

Abstract A large body of electroencephalography (EEG) studies has characterized the spontaneous neural activity of premature neonates at different gestational ages. However, evaluation of normal and pathological fetal brain development is still a challenge due to the complexity of the extraction and analysis of fetal neural activity. Fetal magnetoencephalography (fMEG) is currently the only available technique to record fetal neural activity with a time resolution equivalent to that of EEG. However, the signatures and characteristics of fetal spontaneous neural activity are still largely unknown. Benefiting from progress in machine learning and artificial intelligence, we aimed to transfer premature EEG to fMEG, to characterize the manifestation of spontaneous activity using the knowledge obtained from premature EEG. In this study, 30 high-resolution EEG recordings from premature newborns and 44 fMEG recordings, both from 34 to 37 weeks of gestation (wGA) were used to develop a transfer function to predict the spontaneous neural activity of the fetus. After preprocessing, bursts of spontaneous activity were detected using the non-linear energy operator over both EEG and fMEG signals. Next, we proposed a CycleGAN-based model to transform the premature EEG to fMEG and vice versa and evaluated its performance with both time and frequency measurements on both forward and inverse conversions. In the time domain, the values were similar for the mean square error (&lt; 5%) and correlation (0.91 ± 0.05 and 0.89 ± 0.08) for the EEG to fMEG and fMEG to EEG transformations between the original data and that generated by CycleGAN. However, considering the frequency content, the CycleGAN-based model modulated the frequency content of EEG to MEG transformed signals relative to the original signals by increasing the power, on average, in all frequency bands, except for the slow delta frequency band. Our developed model showed promising potential to generate a priori signatures of fMEG manifestations related to spontaneous neural activity. Collectively, this study represents the first steps toward identifying neurobiomarkers of fetal brain development.
Role of Weight Loss Induced Prediabetes Remission in the Prevention of Type 2 Diabetes – Time to Improve Diabetes Prevention
2024-03-26

Abstract Aims/hypothesis For individuals with prediabetes, the current American Diabetes Association (ADA) guidelines recommend a body weight loss &gt;7% to prevent the development of type 2 diabetes (T2D) without any glycemic target goals. However, we have recently shown that weight loss induced prediabetes remission reduces relative T2D risk by 73% within the following two years. Therefore, we investigated relative T2D risk reduction in people with weight loss vs those with weight loss and prediabetes remission in an independent cohort: the randomized controlled Diabetes Prevention Program (DPP). Methods Individuals who lost &gt;7% of their body weight over the first year were included in this analysis. Of these, 416 were assigned to intensive lifestyle intervention and 64 received placebo. Remission of prediabetes was defined by normalization of fasting and 2h glucose during an oral glucose tolerance test and a normalized HbA1c according to ADA criteria. Non-remission was given when at least one of these criteria was not met. We computed Kaplan-Meier curves and compared them using log-rank tests and future T2D risk was assessed by computing the relative risk between groups. Results In DPP, 480 individuals achieved a weight loss of &gt;7% and of these 114 additionally achieved prediabetes remission. Over the period of 6 years, those who achieved weight loss and remission had a 66% lower relative risk to develop T2D compared to those who only met the 7% weight loss goal [RR=0.34, 95% CI (0.15, 0.76)]. Similarly, weight loss responders had a lower relative future T2D risk compared to weight loss non-responders [RR=0.28, 95% CI (0.13, 0.64)]. Importantly, there was only a single T2D case in weight loss responders for up to 4 years after the intervention. Conclusions/interpretation The combination of achieving weight loss goals and prediabetes remission is most effective in reducing future T2D risk. Thus, beside weight loss goals, interventions in individuals with prediabetes should be continued until prediabetes remission is achieved and this ought to be adapted in current clinical praxis guidelines.
Asciminib Maintains Antibody-Dependent Cellular Cytotoxicity against Leukemic Blasts
2024-03-26

B cell acute lymphoblastic leukemia (B-ALL) is characterized by an accumulation of malignant precursor cells. Treatment consists of multiagent chemotherapy followed by allogeneic stem cell transplantation in high-risk patients. In addition, patients bearing the BCR-ABL1 fusion gene receive concomitant tyrosine kinase inhibitor (TKI) therapy. On the other hand, monoclonal antibody therapy is increasingly used in both clinical trials and real-world settings. The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839). The efficacy of monoclonal antibodies is based, at least in part, on their ability to induce antibody-dependent cellular cytotoxicity (ADCC). Combination treatments, e.g., chemotherapy and TKI, should therefore be screened for potential interference with ADCC. Here, we report on in vitro data using BCR-ABL1 positive and negative B-ALL cell lines treated with rituximab and TKI. NK cell activation, proliferation, degranulation, cytokine release and tumor cell lysis were analyzed. In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.
Different components of cognitive-behavioral therapy affect specific cognitive mechanisms
2024-03-27

Psychological therapies are among the most effective treatments for common mental health problems—however, we still know relatively little about how exactly they improve symptoms. Here, we demonstrate the power of combining theory with computational methods to parse effects of different components of cognitive-behavioral therapies onto underlying mechanisms. Specifically, we present data from a series of randomized-controlled experiments testing the effects of brief components of behavioral and cognitive therapies on different cognitive processes, using well-validated behavioral measures and associated computational models. A goal setting intervention, based on behavioral activation therapy activities, reliably and selectively reduced sensitivity to effort when deciding how to act to gain reward. By contrast, a cognitive restructuring intervention, based on cognitive therapy materials, reliably and selectively reduced the tendency to attribute negative everyday events to self-related causes. The effects of each intervention were specific to these respective measures. Our approach provides a basis for beginning to understand how different elements of common psychotherapy programs may work.
To Be Long or To Be Wide: How Data Format Influences Convergence and Estimation Accuracy in Multilevel Structural Equation Modeling
2024-03-27

A two-level data set can be structured in either long format (LF) or wide format (WF), and both have corresponding SEM approaches for estimating multilevel models. Intuitively, one might expect these approaches to perform similarly. However, the two data formats yield data matrices with different numbers of columns and rows, and their cols:rows is related to the magnitude of eigenvalue bias in sample covariance matrices. Previous studies have shown similar performance for both approaches, but they were limited to settings where cols≪rows in both data formats. We conducted a Monte Carlo study to investigate whether varying cols:rows result in differing performances. Specifically, we examined the p:N (cols:rows) effect on convergence and estimation accuracy in multilevel settings. Our findings suggest that (1) the LF approach is more likely to achieve convergence, but for the models that converged in both, (2) the LF and WF approach yield similar estimation accuracy, which is related to (3) differential cols:rows effects in both approaches, and (4) smaller ICC values lead to less accurate between-group parameter estimates.
Cracking the NLRP3 code: Pioneering precision medicine for inflammation
2024-03-27

Precisely diagnosing and effectively treating cryopyrin-associated periodic syndrome (CAPS), an inflammatory condition linked to gain-of-function NLRP3 inflammasome mutations, poses challenges. A novel classification approach may help inform therapeutic decisions and offer valuable insights into broader inflammatory conditions (Cosson et al. J. Exp. Med. 2024. https://doi.org/10.1084/jem.20231200).
Dorsal Root Ganglion Stimulation Relieves Chronic Neuropathic Pain Along With a Decrease in Cortical γ Power
2024-03-27

A lateralized decrease in broadband γ power may be considered further evidence supporting a reduction in the hyperexcitability of the nociceptive system in response to DRGS therapy. In the future, γ-band power could serve as a biomarker for assessing the efficacy of DRGS during the seven-day test phase preceding the implantation of the DRGS system.
Vitamin D3 deficiency and osteopenia in spastic paraplegia type 5 indicate impaired bone homeostasis
2024-03-27

Abstract Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessively inherited movement disorder characterized by progressive spastic gait disturbance and afferent ataxia. SPG5 is caused by bi-allelic loss of function mutations in CYP7B1 resulting in accumulation of the oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol in serum and cerebrospinal fluid of SPG5 patients. An effect of 27- hydroxycholesterol via the estrogen and liver X receptors was previously shown on bone homeostasis. This study analyzed bone homeostasis and osteopenia in 14 SPG5 patients as a non-motor feature leading to a potential increased risk for bone fractures. T-Scores in CT bone density measurements were reduced, indicating osteopenia in SPG5 patients. Further, we analyzed various metabolites of bone homeostasis by ELISA in serum samples of these patients. We identified a lack of vitamin D 3 metabolites (Calcidiol and Calcitriol), an increase in Sclerostin as a bone formation/mineralization inhibiting factor, and a decrease in cross-linked N-telopeptide of type I collagen (NTX), a marker indicating reduced bone resorption. As statin treatment has been found to lower oxysterol levels, we evaluated its effect in samples of the STOP-SPG5 trial and found atorvastatin to normalize the increased sclerostin levels. In summary, our study identified osteopenia as a non-motor feature in SPG5 and suggests the need for vitamin D 3 substitution in SPG5 patients. Sclerostin may be considered a therapeutic target and biomarker in upcoming therapeutical trials in SPG5.
Equality of magnetization and edge current for interacting lattice fermions at positive temperature
2024-03-27

We prove that the magnetization is equal to the edge current in the thermodynamic limit for a large class of models of lattice fermions with finite-range interactions satisfying local indistinguishability of the Gibbs state, a condition known to hold for sufficiently high temperatures. Our result implies that edge currents in such systems are determined by bulk properties and are therefore stable against large perturbations near the boundaries. Moreover, the equality persists also after taking the derivative with respect to the chemical potential. We show that this form of bulk-edge correspondence is essentially a consequence of homogeneity in the bulk and locality of the Gibbs state. An important intermediate result is a new version of Bloch's theorem for two-dimensional systems, stating that persistent currents vanish in the bulk.
Metabolic dysfunction-associated steatotic liver disease can be alleviated by activating NO/cGMP signaling
2024-03-27

<p class="first" dir="auto" id="d1332678e174">Metabolic dysfunction-associated steatotic liver disease encompasses a spectrum of chronic liver diseases ranging from steatosis to metabolic dysfunction-associated steatohepatitis (MASH). Hepatic stellate cells (HSCs), the pericytes of the liver, have been associated with the pathogenesis of MASH. In diseased livers, HSCs transdifferentiate into αSMA+ myofibroblasts. In this activated stage, they produce excess collagen as well as proinflammatory and profibrogenic cytokines. HSCs are known to express proteins of the NO/cGMP pathway. We hypothesized that modulation of this pathway may alter HSC transdifferentiation and thereby the progression of MASH. As a model for MASH, we used ApoE-deficient mice fed a Western diet. In comparison to wild-type mice receiving a normal diet, these animals showed characteristics of MASH, such as steatosis, fibrosis, and inflammation. Both quiescent HSCs and activated αSMA+ myofibroblasts expressed NO-sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase type I (cGKI), indicating the existence of a functional NO/cGMP pathway in healthy as well as MASH livers. This was further supported by the real-time detection of NO-induced cGMP signals in HSCs isolated from mice expressing a FRET-based cGMP sensor. Moreover, we show that pharmacological treatment with a NO-GC activator elevates cGMP in HSCs and attenuates the pathological phenotype of MASH <i>invivo</i>. In drug-treated mice, we found a reduced amount of fat bubbles and fibrosis, decreased liver enzyme levels, and decreased expression of markers for activated myofibroblasts. In conclusion, we report the NO/cGMP/cGKI signaling pathway as a marker of HSCs and NO-GC activators as potential drugs for the treatment of MASH.
Mechanosensitive cGMP signaling in platelets and thrombus formation
2024-03-27

<p class="first" dir="auto" id="d1370922e187">Thrombotic events remain one of the main causes of death worldwide. Although several antithrombotic therapies are available, most of them bear the risk of bleeding. Nitric oxide (NO) is an important endogenous inhibitor of platelet aggregation. Recent work indicated that NO drives the generation of cGMP in platelets via the NO-sensitive guanylyl cyclase (NO-GC) in a flow/shear-sensitive manner, also referred to as mechanosensitive cGMP signaling (mechano-cGMP). In the present work, the cGMP pathway was induced in murine and human platelets via the application of the NO donor DEA/NO and/or the clinically used NO-GC stimulator riociguat. Compared to control conditions, this treatment resulted in a significant reduction of thrombus formation and a faster dissolution of preformed thrombi ex vivo. Furthermore, using a laser-induced thrombosis model in arteries of the mouse cremaster muscle, we found a faster thrombus dissolution and stabilization after treatment with riociguat in vivo. To investigate the molecular mechanism behind flow-regulated cGMP signals in platelets, we used co-immunoprecipitation followed by mass spectrometry, as well as high-resolution fluorescence microscopy. We identified a cGMP signaling complex at the human platelet membrane consisting of NO-GC, cGMP-dependent protein kinase I, and several integrins. Blocking integrin αIIbβ3 led to an attenuation of mechano-cGMP as measured by real-time imaging of cGMP signals in platelet thrombi ex vivo. Our findings suggest that integrins play a key role in mechanosensitive cGMP signaling and that pharmacological targeting of mechano-cGMP in platelets with riociguat may be a valuable strategy to limit thrombosis while avoiding life-threatening bleeding side effects.
cGKI supports Schaffer-collateral LTP and facilitates hippocampus- dependent memory formation
2024-03-27

<p class="first" dir="auto" id="d6650192e126">Synaptic plasticity, a crucial determinant of learning and memory consolidation, is determined by dynamic modulation of synaptic transmission efficiency. Previous studies highlighted the involvement of 3',5'-cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (cGKI) in synaptic plasticity and cognitive functions; its postsynaptic role, however, remains insufficiently characterized and requires further elucidation. We explore cGKI's contribution to activity-dependent hippocampal synaptic transmission and hippocampus-dependent memory formation using CA1 pyramidal neuron-specific knockout mice (CA1-cGKI-KO) and litter-matched controls (CA1-cGKI-CTRL). <p dir="auto" id="d6650192e128">Hippocampal CA1-specific cGKI depletion was confirmed by Western blot and immunofluorescence. In accordance with a significant function of cGKI in spatial memory formation, CA1-cGKI-KO were incapable to develop goal-directed target localization strategies in the Morris Water Maze coupled with deficits in memory acquisition. These learning impairments were consistent with significantly hampered electrically-induced CA3 to CA1 Schaffer-collateral long-term potentiation (LTP) in CA1-cGKI-KO brain slices. This finding was completed by reduced phosphorylation of the AMPAR subunit GluA1 at S845 in slices from CA1-cGKI-cKO compared to CA1-cGKI-CTRL after chemically induced LTP (cLTP). Additional application of the cGMP-elevating pharmacological agents cinaciguat and vardenafil during cLTP augmented GluA1 S845 phosphorylation exclusively in CA1-cGKI-CTRL, but not CA1-cGKI-cKO. Furthermore, cLTP increased the neuronal Ca <sup>2+</sup>-oscillation frequency recorded using FURA-2AM in primary hippocampal neurons. This effect was amplified by cinaciguat, vardenafil and 8-Br-cGMP. <p dir="auto" id="d6650192e133">Based on these findings, we suggest that cGKI regulates hippocampal synaptic plasticity by controlling oscillatory Ca <sup>2+</sup> influx during LTP. This suggests cGMP/cGKI has the potential to serve as a pharmacological target for the treatment of cognitive impairment.