Miracle-dz/UniFAR-FTUs huggingface dataset:
Yesterday is history, tomorrow is a mystery: An eye-tracking investigation of the processing of past and future time reference during sentence reading.

The ability to think about nonpresent time is a crucial aspect of human cognition. Both the past and future imply a temporal displacement of an event outside the "now. " They also intrinsically differ: The past refers to inalterable events; the future to alterable events, to possible worlds. Are the past and future processed similarly or differently? In this study, we addressed this question by investigating how Spanish speakers process past/future time reference violations during sentence processing, while recording eye movements. We also investigated the role of verbs (in isolation; within sentences) and adverbs (deictic; nondeictic) during time processing. Existing accounts propose that past processing, which requires a link to discourse, is more complex than future processing, which-like the present-is locally bound. Our findings show that past and future processing differs, especially at early stages of verb processing, but this difference is not limited to the presence/absence of discourse linking. We found earlier mismatch effects for past compared to future time reference in incongruous sentences, in line with previous studies. Interestingly, it took longer to categorize the past than the future tense when verbs were presented in isolation. However, it took longer to categorize the future than the past when verbs were presented in congruous sentences, arguably because the future implies alterable worlds. Finally, temporal adverbs were found to play an important role in reinspection and reanalysis triggered by the presence of undefined time frames (nondeictic adverbs) or incongruences (mismatching verbs). (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Alpha oscillatory power decreases are associated with better memory for higher valued information

ABSTRACT Items associated with high value are often better remembered. Value may increase attention toward item in context associations. Alpha oscillations (8–13 Hz) are thought to underlie attention and their observation may reveal the role attention plays in value-based memory. In the current study, EEG is used to record brain activity while participants (n = 30) completed a source recognition memory task where items were associated with either high or low value backgrounds to determine whether greater attentional resources are deployed when encoding high value information. Participants demonstrated better memory for objects associated with high value backgrounds. Alpha oscillatory power in occipital/temporal brain regions exhibited greater desynchronization when encoding objects associated with high value that were later successfully recalled compared to those associated with low value. In addition, beta oscillatory power in midfrontal brain regions exhibited greater desynchronization during successful recall of high value objects compared to low value objects. Together these results suggest that more attentional resources are used to encode information that is associated with high value, which increases the likelihood of later successful memory recall.
Carfilzomib and dexamethasone induction with lenalidomide, clarithromycin and dexamethasone consolidation and lenalidomide maintenance for newly diagnosed multiple myeloma

Combination treatment regimens including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and a corticosteroid are standards of care for initial treatment of multiple myeloma (MM). We aimed to evaluate if a sequential treatment program using PI induction followed by IMiD based consolidation and maintenance could achieve similar outcomes with reduced toxicities. This phase 2 study was designed to assess the safety and efficacy of the Car‐BiRd regimen: carfilzomib and dexamethasone (Kd) induction until maximum response, followed by lenalidomide, clarithromycin and dexamethasone (BiRd) consolidation until next maximum response, then lenalidomide maintenance in patients with newly diagnosed MM. Seventy‐two patients, including both transplant eligible and ineligible patients, were enrolled and evaluated for response. The overall response rate to the Car‐BiRd regimen was 94% with 83% of patients achieving a ≥ VGPR and 35% achieving a CR/sCR. The rate of CR/sCR increased from 7% with Kd induction to 21% with BiRd consolidation and 35% with lenalidomide maintenance. These results did not meet the study's target endpoint of a CR rate of 55%. The median PFS using this deferred transplant approach was 37.3 months (95% CI 27.9, 52.7) and median OS was not reached with a median follow‐up of 60 months. Toxicities were primarily low grade and manageable. Hematologic toxicities were lower than those expected with a combination PI/IMiD protocol. The sequential Car‐BiRd regimen is an effective and safe approach for the upfront treatment of MM including patients unfit for transplant.
Development and characterization of prototypes for in vitro and in vivo mouse models of ibrutinib-resistant CLL.

Although ibrutinib improves the overall survival of patients with chronic lymphocytic leukemia (CLL), some patients still develop resistance, most commonly through point mutations affecting cysteine residue 481 (C481) in Bruton's tyrosine kinase (BTKC481S and BTKC481R). To enhance our understanding of the biological impact of these mutations, we established cell lines that overexpress wild-type or mutant BTK in in vitro and in vivo models that mimic ibrutinib-sensitive and -resistant CLL. MEC-1 cell lines stably overexpressing wild-type or mutant BTK were generated. All cell lines coexpressed GFP, were CD19+ and CD23+, and overexpressed BTK. Overexpression of wild-type or mutant BTK resulted in increased signaling, as evidenced by the induction of p-BTK, p-PLCγ2, and p-extracellular signal-related kinase (ERK) levels, the latter further augmented upon IgM stimulation. In all cell lines, cell cycle profiles and levels of BTK expression were similar, but the RNA sequencing and reverse-phase protein array results revealed that the molecular transcript and protein profiles were distinct. To mimic aggressive CLL, we created xenograft mouse models by transplanting the generated cell lines into Rag2-/-γc-/- mice. Spleens, livers, bone marrow, and peripheral blood were collected. All mice developed CLL-like disease with systemic involvement (engraftment efficiency, 100%). We observed splenomegaly, accumulation of leukemic cells in the spleen and liver, and macroscopically evident necrosis. CD19+ cells accumulated in the spleen, bone marrow, and peripheral blood. The overall survival duration was slightly lower in mice expressing mutant BTK. Our cell lines and murine models mimicking ibrutinib-resistant CLL will serve as powerful tools to test reversible BTK inhibitors and novel, non-BTK-targeted therapeutics.
A Validation Study of the BRIEF-2 Among Kindergarteners and First Graders At-Risk for Behavior Problems

Early identification of executive dysfunction and timely school-based intervention efforts are critical for students at risk for problematic behaviors during early elementary school. The original Behavior Rating Inventory of Executive Functioning (BRIEF) was designed to measure real-world behavioral manifestations of executive functioning, neurocognitive processes critical for school success. With the updated BRIEF-2, independent validation is needed with kindergarten and first grade students at risk for emotional and behavioral disorders. Thus, using item level analyses, we examined the factor structure of the BRIEF-2 Teacher Rating form with 1,112 students. Results indicated little evidence for the original three-index model and supported a modified two-index model, with a Cognitive Regulation Index and an overall Behavior–Emotion Regulation Index. Criterion related validity indicated positive relationships with performance-based executive functioning (Head-Toes-Knees-Shoulders) and later internalizing and externalizing behaviors. We discuss implications of findings for early identification and school-based intervention efforts, as well as future research.
Effects of Peroral Omega-3 Fatty Acid Supplementation on Cerebrospinal Fluid Biomarkers in Patients with Alzheimer's Disease: A Randomized Controlled Trial-The OmegAD Study.

BACKGROUND Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer's disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD. OBJECTIVE To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE). METHODS Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n = 18) or placebo (n = 15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ 38, Aβ 40, Aβ 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6. RESULTS There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable. CONCLUSION Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score.
Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS)

Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low‐intensity therapy, to elderly patients with newly diagnosed AML.
An Efficient and Green Synthesis of 1′Hspiro[isoindoline-1,2′-quinazoline]-3,4′(3′H)-dione Derivatives in the Presence of Nano Fe3O4–GO–SO3H

ABSTRACT In this article a simple, rapid, green and efficient method for the synthesis of various 1′Hspiro[isoindoline-1,2′-quinazoline]-3,4′(3′H)-diones in the presence of acidic magnetic graphene oxide nanosheets (Fe3O4–GO–SO3H) as catalyst is reported. Different substituted spirooxindoles have been synthesized from one-pot three component reaction of isatoic anhydride, aliphatic or aromatic primary amines and isatin in the presence of Fe3O4–GO–SO3H. This reaction allowed us to prepare some new and known derivatives of substituted spirooxindoles. The worthwhile advantages of this method are high product yields, short reaction times, the possibility of using of a magnetic, reusable and non-toxic catalyst and solvent-free conditions.
1H-MR Spectroscopy of the Early Developmental Brain, Neonatal Encephalopathies, and Neurometabolic Disorders

MRI interpretations of the pediatric brain are often challenging for general radiologists and clinicians because MR signals and morphology are continuously changing in the developing brain. Furthermore, the developing brain reacts differently to injuries, resulting in imaging characteristics that differ from those of the mature brain. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method for assessing neurological abnormalities at the microscopic level and measures in vivo brain metabolites using a clinical MR machine. In MR examinations of the pediatric brain, 1H-MRS demonstrates its powerful diagnostic capability when MRI is insufficient for diagnostic features. MRI and 1H-MRS may be complementary tools for diagnosing and monitoring diseases. However, there is currently no consensus on how to include 1H-MRS in clinical MR examinations. An overview of the clinical implementation of 1H-MRS for the assessment of early pediatric developmental brains as well as the diagnosis, prognostification, and disease monitoring of various non-neoplastic brain disorders, including neonatal encephalopathies and neurometabolic/neurodegenerative diseases, was provided herein. Qualitative and quantitative 1H-MRS is a powerful non-invasive tool for accessing various brain metabolites to confirm age appropriate peaks and detect abnormal peaks or deficient or reduced peaks, which may facilitate the identification of metabolic and neurodegenerative disorders as well as damage associated with hypoxic-ischemic encephalopathy (HIE). Moreover, 1H-MRS has potential as a biomarker for monitoring therapeutic efficacy in metabolic diseases and neonatal HIE. It also provides insights into the pathophysiologies of various disorders, which may facilitate the use of novel therapeutic approaches. Therefore, 1H-MRS needs to be included more frequently in routine clinical MR examinations of pediatric patients with neurological disorders.
Cut points and contexts

In research, policy, and practice, continuous variables are often categorized. Statisticians have generally advised against categorization for many reasons, such as loss of information and precision as well as distortion of estimated statistics. Here, a different kind of problem with categorization is considered: the idea that, for a given continuous variable, there is a unique set of cut points that is the objectively correct or best categorization. It is shown that this is unlikely to be the case because categorized variables typically exist in webs of statistical relationships with other variables. The choice of cut points for a categorized variable can influence the values of many statistics relating that variable to others. This essay explores the substantive trade‐offs that can arise between different possible cut points to categorize a continuous variable, making it difficult to say that any particular categorization is objectively best. Limitations of different approaches to selecting cut points are discussed. Contextual trade‐offs may often be an argument against categorization. At the very least, such trade‐offs mean that research inferences, or decisions about policy or practice, that involve categorized variables should be framed and acted upon with flexibility and humility.
Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment

Abstract Hereditary hearing impairment (HI) is a common disease with the highest incidence among sensory defects. Several genes have been identified to affect stereocilia structure causing HI, including the unconventional myosin3A. Interestingly, we noticed that variants in MYO3A gene have been previously found to cause variable HI onset and severity. Using clinical exome sequencing, we identified a novel pathogenic variant p.(Lys50Arg) in the MYO3A kinase domain (MYO3A-KD). Previous in vitro studies supported its damaging effect as a ‘kinase-dead’ mutant. We further analyzed this variation through molecular dynamics which predicts that changes in flexibility of MYO3A structure would influence the protein-ATP binding properties. This Lys50Arg mutation segregated with congenital profound non-syndromic HI. To better investigate this variability, we collected previously identified MYO3A-KDs variants, p.(Tyr129Cys), p.(His142Gln) and p.(Pro189Thr), and built both wild type and mutant 3 D MYO3A-KD models to assess their impact on the protein structure and function. Our results suggest that KD mutations could either cause a congenital profound form of HI, when particularly affecting the kinase activity and preventing the auto-phosphorylation of the motor, or a late onset and progressive form, when partially or completely inactivating the MYO3A protein. In conclusion, we report a novel pathogenic variant affecting the ATP-binding site within the MYO3A-KD causing congenital profound HI. Through computational approaches we provide a deeper understanding on the correlation between the effects of MYO3A-KD mutations and the variable hearing phenotypes. To the best of our knowledge this is the first study to correlate mutations’ genotypes with the variable phenotypes of DFNB30. Communicated by Ramaswamy H. Sarma
Two methods for constructing ZIF-8 nanomaterials with good bio compatibility and robust antibacterial applied to biomedical

Metal-organic framework materials not only possess porous structures, but also have excellent antibacterial properties. It is of great practical significance to prepare new antibacterial materials with excellent antibacterial effect by metal-organic framework materials. In our study, Zeolitic Imidazolate Framework-8 (ZIF-8) nanomaterials with antibacterial properties were prepared via the solvent method and diethanolamine template method. The materials were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), cold field-emission scanning electron microscope (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption experiment, antibacterial experiment, and biocompatibility experiment. Results showed that ZIF-8 prepared by solvent method has a more typical hexagonal structure, larger specific surface area, and smaller pore size, and the values are 1812.07 m2g−1 and 2.2412 nm, respectively. At the same time, the materials prepared by the two methods have excellent antibacterial properties, and exhibit good biocompatibility at low concentrations, the antibacterial activity against Escherichia coli and Staphylococcus aureus are higher than 95%, and the cell viabilities of the selected five material concentrations of 12.5 µg mL−1, 25 µg mL−1, 50 µg mL−1, 100 µg mL−1 and 200 µg mL−1 are more than 70%. Therefore, this study provides a feasible method for preparing Nano-scale antibacterial functional particles, and it is of great significance to broaden the application field of ZIF-8 materials and prepare ZIF-8 drug-delivery functional materials.
High-intensity focused ultrasound ablation of liver tumors in difficult locations

Abstract High-intensity focused ultrasound (HIFU) has been shown to be a valuable tool in the management of small liver tumors such as hepatocellular carcinoma (HCC). It has been shown to be a safe and effective means to ablate small HCC even in the presence of advanced cirrhosis. This review examines the challenges faced during HIFU ablation when the target tumors are located in difficult locations such as the liver dome, close to the rib cage, near large blood vessels or the heart, or adjacent to hollow viscera; and the special maneuvers employed to tackle such lesions.
The joint association of serum vitamin D status and cardiorespiratory fitness with obesity and metabolic syndrome in Tehranian adults

Abstract We aimed to assess the individual and joint association of serum vitamin D and cardiorespiratory fitness (CRF) with obesity and metabolic syndrome (MetSyn). In this cross-sectional study 270 adults with an age range of 18 years and older were recruited from health centers from five districts in Tehran, Iran. CRF was assessed with Bruce protocol. MetSyn was defined based on International Diabetes Federation 2009. The odds ratio (OR) and 95 % confidence interval (CI) of obesity and MetSyn across tertiles of serum vitamin D and CRF were estimated with control for confounders. The results indicated that neither 25(OH)D nor 1,25(OH)D was associated with obesity and MetSyn. There was a strong inverse association between CRF and general (P -trend < 0.001) and abdominal adiposity (P -trend: 0.001). The joint association of vitamin D and CRF indicated that the inverse association of CRF with obesity was stronger in those with high serum vitamin D than those with low serum vitamin D and this joint association remained after considering age and diet quality. There was a significant inverse association for those with low serum 25(OH)D and high CRF (OR: 0.12, 95 % CI: 0.04–0.81; P = 0.02) compared to those with low serum 25(OH)D and low CRF in the crude model. Also, the OR of general obesity was 0.17 (95 % CI: 0.02–0.79; P = 0.03) for those with high CRF and low serum 1,25(OH)D compare with the reference group. Our findings indicated a strong inverse association between CRF and obesity, especially in those with high serum vitamin D.
Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine.

This paper updates the American Academy of Sleep Medicine's (AASM) protocols for the administration of the Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness Test (MWT). The AASM commissioned a task force of clinical experts in sleep medicine to review published literature on the performance of these tests since the publication of the 2005 AASM practice parameter paper. Although no evidence-based changes to the protocols were warranted, the task force made several changes based on consensus. These changes included guidance on patient preparation, medication and substance use, sleep prior to testing, test scheduling, optimum test conditions, and documentation. This paper provides guidance to providers who order and administer the MSLT and MWT.
Impact of Aortic Diameter Measurements at Three Anatomical Landmarks on Left Ventricular Output Calculation in Neonates

To assess reproducibility and accuracy of left ventricular output (LVO) quantifications in neonates, when left ventricular outflow tract diameter (LVOTD) was measured at the hinges of the aortic valve (AV), at the aortic sinus (AS), and at the sinotubular junction (STJ).
Exploring the binding mode of PQ912 against secretory glutaminyl cyclase through systematic exploitation of conformational ensembles

Secretory glutaminyl cyclase (sQC) plays an important role in the formation of the pyroglutamate‐amyloid beta (pGlu‐Aβ) peptide, one of the most abundant variants of Aβ found in the Alzheimer's disease (AD) brain. This post‐translationally modified pGlu‐Aβ possesses high toxicity and rapid aggregation propensity when compared to the wild‐type Aβ (WT‐Aβ). Since pGlu‐Aβ acts as seed for WT‐Aβ, the inhibition of sQC limits the formation of pGlu‐Aβ and reduces the overall load of Aβ plaques in the AD brain. PQ912 is a potent inhibitor of sQC and has been enrolled in phase 2b clinical trial of the AD drug development pipeline; however, the binding mode of PQ912 against sQC is not elucidated yet. Understanding the binding mode of PQ912 is important as it helps in the discovery against AD where sQC as a target. To explore the binding mode of PQ912, we employed ensemble docking towards 9 sQC structures that differ either in active site geometry or in the bound ligands. Further pose clustering and binding energy calculations yielded three possible binding modes for PQ912. Finally, all atom molecular dynamics simulations determined the most energetically favorable binding mode for PQ912, in the active site of sQC, which is similar to that of LSB‐09, a recently reported sQC inhibitor containing benzimidazole‐6‐carboxamide moiety.