Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel agonist for the HGF receptor MET promotes differentiation of human pluripotent stem cells into hepatocyte‐like cells

Hepatocyte growth factor (HGF) is the natural ligand of the MET receptor tyrosine kinase. This ligand–receptor couple is essential for the maturation process of hepatocytes. Previously, the rational design of a synthetic protein based on the assembly of two K1 domains from HGF led to the production of a potent and stable MET receptor agonist. In this study, we compared the effects of K1K1 with HGF during the differentiation of hepatocyte progenitors derived from human induced pluripotent stem cells (hiPSCs). In vitro, K1K1, in the range of 20 to 200 nM, successfully substituted for HGF and efficiently activated ERK downstream signaling. Analysis of the levels of hepatocyte markers showed typical liver mRNA and protein expression (HNF4α, albumin, alpha‐fetoprotein, CYP3A4) and phenotypes. Although full maturation was not achieved, the results suggest that K1K1 is an attractive candidate MET agonist suitable for replacing complex and expensive HGF treatments to induce hepatic differentiation of hiPSCs.
Reviewing the evidence surrounding preservative-free tafluprost/timolol fixed-dose combination therapy in open-angle glaucoma and ocular hypertension management: a focus on efficacy, safety, and tolerability

ABSTRACT Introduction Elevated intraocular pressure (IOP) is the most important modifiable risk factor for irreversible sight loss in open-angle glaucoma (OAG). The topical fixed-dose combination (FC) of preservative-free (PF) tafluprost (0.0015%) and timolol (0.5%) (tafluprost/timolol) is among the second-line IOP-lowering options for OAG and ocular hypertension (OHT). Areas covered PubMed searches identified publications reporting key evidence from randomized controlled trials (RCTs) and real-world studies examining the safety, tolerability, and IOP-lowering efficacy of PF tafluprost/timolol FC therapy in OAG/OHT management. Expert opinion Glaucoma patients are more likely to have ocular surface disease, and treatment should be individualized so that target response may be achieved while considering tolerability and quality of life, according to European Glaucoma Society guidelines. PF FC therapies, such as PF tafluprost/timolol FC, avoid ocular surface exposure to toxic preservative agents and reduce the required number of treatment administrations. These properties may enhance treatment tolerability and adherence, resulting in improved IOP-lowering efficacy and disease control. Treatment outcomes from RCTs and real-world studies examining PF tafluprost/timolol FC therapy support this hypothesis, with significant IOP reductions and/or improvements in tolerability parameters demonstrated, regardless of the prior topical therapy used and even when switched directly to PF tafluprost/timolol FC treatment (without washout).
High temporal resolution Nanopore sequencing dataset of SARS-CoV-2 and host cell RNAs

Abstract Background Recent studies have disclosed the genome, transcriptome, and epigenetic compositions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the effect of viral infection on gene expression of the host cells. It has been demonstrated that, besides the major canonical transcripts, the viral genome also codes for noncanonical RNA molecules. While the structural characterizations have revealed a detailed transcriptomic architecture of the virus, the kinetic studies provided poor and often misleading results on the dynamics of both the viral and host transcripts due to the low temporal resolution of the infection event and the low virus/cell ratio (multiplicity of infection [MOI] = 0.1) applied for the infection. It has never been tested whether the alteration in the host gene expressions is caused by aging of the cells or by the viral infection. Findings In this study, we used Oxford Nanopore's direct cDNA and direct RNA sequencing methods for the generation of a high-coverage, high temporal resolution transcriptomic dataset of SARS-CoV-2 and of the primate host cells, using a high infection titer (MOI = 5). Sixteen sampling time points ranging from 1 to 96 hours with a varying time resolution and 3 biological replicates were used in the experiment. In addition, for each infected sample, corresponding noninfected samples were employed. The raw reads were mapped to the viral and to the host reference genomes, resulting in 49,661,499 mapped reads (54,62 Gbs). The genome of the viral isolate was also sequenced and phylogenetically classified. Conclusions This dataset can serve as a valuable resource for profiling the SARS-CoV-2 transcriptome dynamics, the virus–host interactions, and the RNA base modifications. Comparison of expression profiles of the host gene in the virally infected and in noninfected cells at different time points allows making a distinction between the effect of the aging of cells in culture and the viral infection. These data can provide useful information for potential novel gene annotations and can also be used for studying the currently available bioinformatics pipelines.
Kinematic alignment versus mechanical alignment in total knee arthroplasty: An up-to-date meta-analysis

Purpose The purpose of this meta-analysis was to compare the efficacy and imaging parameters of kinematic alignment (KA) and mechanical alignment (MA) in total knee arthroplasty (TKA) and to evaluate whether patients undergoing KA-TKA benefited more than those undergoing MA-TKA. Methods Studies comparing the efficacy of KA-TKA and MA-TKA were included after searching and screening in the database, including PubMed, Embase, Web of Science and Cochrane Database Library. A total of 1420 patients were enrolled in the study, with 736 MA-TKA and 738 KA-TKA. The primary outcomes were postoperative knee function scores including KSS series, WOMAC, KOOS and OKS. Secondary outcomes included the operative time, the length of hospital stay, knee extension/flexion angle, and some imaging parameters. The risk of bias for included studies was assessed using the Cochrane Collaborative risk-of-bias assessment tool or the Newcastle-Ottawa Scale(NOS). Results Sixteen studies were included in this meta-analysis (11 randomized controlled studies and 5 cohort studies). Primary outcomes: Knee Society score (KSS, MD = 8.36, 95% Cl: 0.83–15.90) and combined KSS (MD = 15.24, 95% CI: 5.41–25.07) were higher in KA-TKA than in MA-TKA, and other functional scores were not statistically significant in KA-TKA and MA-TKA, including knee injury and osteoarthritis outcome score (KOOS), Oxford knee score (OKS), Knee Function score (KFS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes: KA-TKA resulted in smaller medial proximal tibial angle (MPTA) and lateral distal femoral angle (LDFA) compared to MA-TKA. For other outcome measures, KA-TKA showed similar results compared to MA-TKA, including hip-knee-ankle (HKA) angle, extension/flexion angle, tibial component slope angle, joint line orientation angle (JLOA), the operation time, the length of hospital stay and ligament release rate. Conclusions In our analysis results, patients undergoing KA-TKA benefit as much as patients undergoing MA-TKA. KA may be a viable reference in total knee replacement.
The JMJD6/HURP axis promotes cell migration via NF‐κB‐dependent centrosome repositioning and Cdc42‐mediated Golgi repositioning

Golgi apparatus (GA) and centrosome reposition toward cell leading end during directional cell migration in a coupling way, thereby determining cell polarity by transporting essential factors to the proximal plasma membrane. The study provides mechanistic insights into how GA repositioning (GR) is regulated, and how GR and centrosome repositioning (CR) are coupled. Our previous published works reveals that PRMT5 methylates HURP at R122 and the HURP m122 inhibits GR and cell migration by stabilizing GA‐associated acetyl‐tubulin and then rigidifying GA. The current study further shows that the demethylase JMJD6‐guided demethylation of HURP at R122 promotes GR and cell migration. The HURP methylation mimicking mutant 122 F blocks JMJD6‐induced GR and cell migration, suggesting JMJD6 relays GR stimulating signal to HURP. Mechanistic studies reveal that the HURP methylation deficiency mutant 122 K promotes GR through NF‐κB‐induced CR and subsequently CR‐dependent Cdc42 upregulation, where Cdc42 couples CR to GR. Taken together, HURP methylation statuses provide a unique opportunity to understand how GR is regulated, and the GA intrinsic mechanism controlling Golgi rigidity and the GA extrinsic mechanism involving NF‐κB‐CR‐Cdc42 cascade collectively dictate GR.
Post‐amputation pain: Comparing pain presentations between adults with and without increased amputated‐region sensitivity

Among adults with persistent post‐amputation pain, increased amputated‐region pain sensitivity may reflect peripheral sensitization or indicate underlying central sensitization. To determine whether underlying central sensitization may contribute to increased pain sensitivity in this population, this study compared clinical signs and symptoms associated with central sensitization between adults with post‐amputation pain who demonstrate or lack increased amputated‐region sensitivity (as compared to reference data).
The effect of bergamot (KoksalGarry) supplementation on lipid profiles: A systematic review and meta‐analysis of randomized controlled trials

This systematic review and meta‐analysis were conducted to evaluate the impact of bergamot (KoksalGarry) and its nutraceutical compounds on lipid profiles. PubMed, Web of Knowledge, Scopus, and Google Scholar searched for relevant articles. Trials investigating the effect of oral bergamot supplementation on serum levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C), and high‐density lipoprotein cholesterol (HDL‐C) in adults were included. The mean differences and standard deviations were pooled using a random‐effects model. Fourteen trials were included in this systematic review and meta‐analysis. Bergamot supplementation significantly decreased serum levels of TC (weighted mean difference (WMD): −63.60 mg/dL; 95% CI: −78.03 to −49.18; p < . 001), TG (WMD: −74.72 mg/dL; 95% CI: −83.58 to −65.87; p < .001), LDL‐C (WMD: −55.43 mg/dL; 95% CI: −67.26 to −43.60; p < .001), and increased HDL‐C (WMD: 5.78 mg/dL; 95% CI: 3.27 to 8.28; p < .001), respectively. Our systematic review of the effects of nutraceuticals containing bergamot on lipid markers showed inconsistent results. The results showed that bergamot supplementation might improve lipid profiles. The findings for nutraceutical compounds containing bergamot were inconsistent. However, the clinical efficacy of bergamot on lipid profiles needs to be further established through higher‐quality studies.
Anatomical adjustments of the tree hydraulic pathway decrease canopy conductance under long-term elevated CO2

Abstract The cause of reduced leaf-level transpiration under elevated CO2 remains largely elusive. Here, we assessed stomatal, hydraulic, and morphological adjustments in a long-term experiment on Aleppo pine (Pinus halepensis) seedlings germinated and grown for 22–40 months under elevated (eCO2; c. 860 ppm) or ambient (aCO2; c. 410 ppm) CO2. We assessed if eCO2-triggered reductions in canopy conductance (gc) alter the response to soil or atmospheric drought and are reversible or lasting due to anatomical adjustments by exposing eCO2 seedlings to decreasing [CO2]. To quantify underlying mechanisms, we analyzed leaf abscisic acid (ABA) level, stomatal and leaf morphology, xylem structure, hydraulic efficiency, and hydraulic safety. Effects of eCO2 manifested in a strong reduction in leaf-level gc (−55%) not caused by ABA and not reversible under low CO2 (c. 200 ppm). Stomatal development and size were unchanged, while stomatal density increased (+18%). An increased vein-to-epidermis distance (+65%) suggested a larger leaf resistance to water flow. This was supported by anatomical adjustments of branch xylem having smaller conduits (−8%) and lower conduit lumen fraction (−11%), which resulted in a lower specific conductivity (−19%) and leaf-specific conductivity (−34%). These adaptations to CO2 did not change stomatal sensitivity to soil or atmospheric drought, consistent with similar xylem safety thresholds. In summary, we found reductions of gc under elevated CO2 to be reflected in anatomical adjustments and decreases in hydraulic conductivity. As these water savings were largely annulled by increases in leaf biomass, we do not expect alleviation of drought stress in a high CO2 atmosphere.
The generalized Phillips' spectra and new dissipation function for wind-driven seas

A generalization of the kinetic equation is proposed for explaining observed shapes of wind wave spectra. The approach allows to fix a critical uncertainty in modeling wind wave spectra using a condition of equilibrium of nonlinear transfer and wave dissipation due to breaking. We demonstrate transition from the Kolmogorov-Zakharov spectrum $E(\omega)\sim \omega^{-4}$ to the Phillips spectrum $E(\omega)\sim \omega^{-4}$. This transition is routinely observed in field experiments. The first results of the generalized kinetic equation simulations are presented.
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia

Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia‐derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD.
Cosmic microwave background constraints on light dark matter candidates

Unveiling the nature of cosmic dark matter (DM) is an urgent issue in cosmology. Here we make use of a strategy based on the search for the imprints left on the cosmic microwave background temperature and polarization spectra by the energy deposition due to annihilations of the most promising DM candidate, a stable weakly interacting massive particle (WIMP) of mass m� = 1 − 20 GeV. A major improvement with respect to previous similar studies is a detailed treatment of the annihilation cascade and its energy deposition in the cosmic gas. This is vital as this quantity is degenerate with the annihilation cross-section hσvi. The strongest constraints are obtained from Monte Carlo Markov chain analysis of the combined WMAP7 and SPT data sets up to lmax = 3100. If annihilation occurs via the e + − e channel, a light WIMP can be excluded at the 2 σ confidence level as a viable DM candidate in the above mass range. However, if annihilation occurs via � + −� or τ + −τ channel instead we find that WIMPs with m� > 5 GeV might represent a viable cosmological DM candidate. We compare the results obtained in this work with those obtained adopting an analytical simplified model for the energy deposition process widely used in the literature, and we found that realistic energy deposition descriptions can influence the resulting constraints up to 60%.
The Characteristic Response of the Human Leukocyte Transcriptome to 60 Days of Bed Rest and to Reambulation

ABSTRACT Introduction We sought to isolate the microgravity effect of spaceflight from other space stressors by characterizing the leukocytes’ transcriptome of participants to a 60-d bed rest study; an Earth model of microgravity. Methods Twenty healthy men received a nutritional supplement or not and 10 blood samples were collected throughout three study phases: baseline data collection (BDC) (BDC-12, BDC-11), head-down tilt (HDT) bed rest (HDT1, HDT2, HDT30, HDT60), and reambulation (R1, R2, R12, R30). We measured gene expression through RNA sequencing of leukocytes, applied generalized linear models to assess differential expression followed by enrichment analysis to identify temporal changes (model 1) and to measure the impact of a nutritional supplement (model 2). Results Baseline transcriptomes included 14,624 protein-coding transcripts and showed both high intraindividual correlations (mean Kendall coefficient, 0.91 ± 0.04) and interindividual homogeneity (0.89 ± 0.03). We identified 2415 differentially expressed protein-coding transcripts grouping into six clusters (C1–C6). At phase transitions, clusters showed either a decrease-then-increase (C3 and C5) or an increase-then-decrease (C1, C2, C6) pattern. All six clusters converged toward average expression at HDT30 and HDT60. Gene ontology terms at baseline related to immune functions while in bed rest and reambulation related to sequestration of ions, immune response, cellular stress, and mineralization. The nutritional intervention had no effect. Conclusions The temporal profiles of leukocytes’ transcriptomes emphasized the dynamic nature of gene expression occurring during and after bed rest. Enriched biological processes among the differentially expressed genes included immune related and unrelated responses. The convergence toward no differential expression at days 30 and 60 of bed rest suggests a hypometabolic state. Current findings can guide future work on the complex responses and adaptation mechanisms to microgravity.
ON HELIUM MIXING IN QUASI-GLOBAL SIMULATIONS OF THE INTRACLUSTER MEDIUM

The assumption of a spatially uniform helium distribution in the intracluster medium (ICM) can lead to biases in the estimates of key cluster parameters if composition gradients are present. The helium concentration profile in galaxy clusters is unfortunately not directly observable. Current models addressing the putative sedimentation are one-dimensional and parametrize the presence of magnetic fields in a crude way, ignoring the weakly collisional, magnetized nature of the medium. When these effects are considered, a wide variety of instabilities can play an important role in the plasma dynamics. In a series of recent papers, we have developed the local, linear theory of these instabilities and addressed their nonlinear development with a modified version of Athena. Here, we extend our study by developing a quasi-global approach that we use to simulate the mixing of helium as induced by generalizations of the heat-flux-driven buoyancy instability (HBI) and the magnetothermal instability, which feed off thermal and composition gradients. In the inner region of the ICM, mixing can occur over a few gigayears, after which the average magnetic field inclination angle is ∼30°–50°, resulting in an averaged Spitzer parameter higher by about 20% than the value obtained in homogeneous simulations. In the cluster outskirts the instabilities are rather inefficient, due to the shallow gradients. This suggests that composition gradients in cluster cores might be shallower than one-dimensional models predict. More quantitative statements demand more refined models that can incorporate the physics driving the sedimentation process and simultaneously account for the weakly collisional nature of the plasma.
CO SPECTRAL LINE ENERGY DISTRIBUTIONS OF INFRARED-LUMINOUS GALAXIES AND ACTIVE GALACTIC NUCLEI

We report on new sensitive CO J = 6–5 line observations of several luminous infrared galaxies (LIRGs; LIR(8–1000 μm) ≳ 1011 L☉), 36% (8/22) of them ultraluminous infrared galaxies (ULIRGs) (LIR>1012 L☉), and two powerful local active galactic nuclei (AGNs)—the optically luminous QSO PG 1119+120 and the powerful radio galaxy 3C 293—using the James Clerk Maxwell Telescope on Mauna Kea in Hawaii. We combine these observations with existing low-J CO data and dust emission spectral energy distributions in the far-infrared–submillimeter from the literature to constrain the properties of the star-forming interstellar medium (ISM) in these systems. We then build the first local CO spectral line energy distributions (SLEDs) for the global molecular gas reservoirs that reach up to high J-levels. These CO SLEDs are neither biased by strong lensing (which affects many of those constructed for high-redshift galaxies), nor suffer from undersampling of CO-bright regions (as most current high-J CO observations of nearby extended systems do). We find: (1) a significant influence of dust optical depths on the high-J CO lines, suppressing the J = 6–5 line emission in some of the most IR-luminous LIRGs, (2) low global CO line excitation possible even in vigorously star-forming systems, (3) the first case of a shock-powered high-excitation CO SLED in the radio galaxy 3C 293 where a powerful jet–ISM interaction occurs, and (4) unusually highly excitated gas in the optically powerful QSO PG 1119+120. In Arp 220 and possibly other (U)LIRGs very faint CO J = 6–5 lines can be attributed to significant dust optical depths at short submillimeter wavelengths immersing those lines in a strong dust continuum, and also causing the C+ line luminosity deficit often observed in such extreme starbursts. Re-analysis of the CO line ratios available for submillimeter galaxies suggests that similar dust opacities also may be present in these high-redshift starbursts, with genuinely low excitation of large amounts of SF-quiescent gas being the only other possibility for their often low CO (high-J)/(low-J) line ratios. We then present a statistical method of separating these two almost degenerate possibilities, and show that high dust optical depths at submillimeter wavelengths can impede the diagnostic potential of submillimeter/IR lines (e.g., starbursts versus AGNs as gas excitation agents), which is of particular importance for the upcoming observations of the Herschel Space Observatory and the era of ALMA.
Patient and general practitioner experiences of implementing a medication review intervention in older people with multimorbidity: Process evaluation of the SPPiRE trial

The SPPiRE cluster randomized controlled trial found that a general practitioner (GP)‐delivered medication review that incorporated screening for potentially inappropriate prescriptions (PIP), a brown bag review and a patient priority assessment, resulted in a significant but small reduction in the number of medicines and no significant reduction in PIP. This process evaluation aims to explore the experiences of GPs and patients and the potential for system‐wide implementation.