Miracle-dz/UniFAR-FTUs huggingface dataset:
Amphetamine extended-release oral suspension for attention-deficit/hyperactivity disorder

ABSTRACT Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder known to respond to amphetamine (AMPH). Multiple AMPH formulations have been developed during the past two decades and have focused mainly on extending the duration of effect. AMPH extended-release oral suspension, Dyanavel XR, (AMPH EROS) was developed to address the unmet needs of patients who have difficulty swallowing intact extended-release (ER) tablets and capsules. Areas covered: The pharmacokinetic profile of the AMPH EROS in children and adults is discussed along with the technology responsible for its release profile. Efficacy data from two clinical trials are presented and AMPH EROS is compared with other marketed AMPH ER formulations in the United States. Expert opinion: Multiple AMPH ER formulations that do not require ingestion of an intact tablet or capsule have been developed. Initial products allowed for sprinkling or dissolving of capsule contents. Recently, oral disintegrating tablets, chewable tablets, and oral suspensions have been marketed. Each formulation has positive attributes. Tablets may be more portable. However, as a suspension, AMPH EROS dosing can differ depending on daily requirements. Dose can also be titrated with a single prescription. Despite its convenience, AMPH EROS is a branded product, so price may be prohibitive for some patients.
Efficacy of doxycycline in the treatment of early stages of mycosis fungoides: a randomized controlled trial

Abstract Background Mycosis fungoides is the most common type of primary cutaneous T cell lymphomas. Doxycycline promoted apoptosis in different human malignant cell lines and in vivo models. Objectives To test for the therapeutic efficacy of doxycycline in comparison to PUVA in early stages of classic MF and its effect on T cell apoptosis. Methods Thirty-six patients were randomized into either: doxycycline 200 mg daily (n = 18) or PUVA (3 weekly sessions) (n = 18) for 12 weeks. The primary outcome (therapeutic efficacy) was defined in terms of objective response rate (ORR) which was measured according to changes in the modified severity weighted assessment tool (mSWAT). Results Doxycycline achieved significantly less ORR (partial response) in comparison to PUVA (11.1%, 50%, respectively, p = .016). The percent reduction in mSWAT, CAILS, histopathology score and CD3 expression was significantly less in the doxycycline group (p = .001, p = .001, p ˂ .001, and p = .004, respectively). Within the doxycycline group, changes in mSWAT and CAILS showed no correlation with changes in the CD3 or Bcl-2 expression. Gastric upset was significantly more encountered in the doxycycline group (p = .001). Conclusion Doxycycline is not suitable as a sole agent in the treatment of early stages of classic MF, acting mainly by anti-inflammatory rather apoptotic function. Register number NCT03454945 (www.clinicaltrials.gov).
Clinical outcomes of bortezomib-based therapy in Taiwanese patients with multiple myeloma: A nationwide population-based study and a single-institute analysis

Purpose In a retrospective cohort study, we report the current epidemiology of patients with multiple myeloma (MM) and analyze the real-world clinical outcomes of bortezomib-based therapy. Materials and methods This retrospective study was mainly designed to evaluate the characteristics, treatment outcomes, and prognostic factors of patients with MM who received bortezomib-based therapy. We identified 5,726 patients in Taiwan with MM newly diagnosed between 2007 and 2015. Confidential data from the National Health Insurance Research Database (NHIRD) was used under strict guidelines, as it was made available in an electronic format for research purposes. In addition, we analyzed 96 patients who have been diagnosed with MM and were treated at the Tri-Service General Hospital (TSGH) between January 1, 2002, and December 31, 2018. Results Patients receiving first-line treatment with bortezomib had longer overall survival (OS) compared to those who received non-first-line treatment (p<0.001). In addition, the statistically lowest risk of mortality was when patients received first-line bortezomib followed by an autologous hematopoietic stem cell transplant (adjusted hazard ratio = 0.39, p<0.001). In the TSGH study, the patients were enrolled between January 1, 2002, and December 31, 2018, with an initial diagnosis of MM; there were 96 individuals treated with bortezomib. There was no statistically significant difference in the OS or progression-free survival (PFS) according to the gender, myeloma type, International Staging System stage, or treatment regimen. There was a significant difference in the PFS in patients receiving first-line bortezomib treatment with transplantation compared to those without transplantation (p = 0.021). Conclusions Bortezomib as a first-line treatment extended the OS in four-year mortality tracking and lowered the mortality risk according to the NHIRD analysis. In the TSGH analysis, the results indicated that the initial conditions of patients with MM have a lower influence on the OS and PFS after bortezomib-based therapy was administered.
Bacillus cabrialesii sp. nov., an endophytic plant growth promoting bacterium isolated from wheat (Triticum turgidum subsp. durum) in the Yaqui Valley, Mexico.

Strain TE3T, an endophytic plant growth promoting bacterium, was isolated from wheat (Triticumturgidum subsp. durum) sampled in the Yaqui Valley, Mexico. Biochemical, phenotypic and genotypic approaches were used to clarify the taxonomic affiliation of this strain. Based on analysis of its full-length 16S rRNA gene, strain TE3T was assigned to the genus Bacillus (similarity ≥98.7 %). This finding was supported by morphological and metabolic characteristics, such as rod shape, strictly aerobic metabolism, spore formation, Gram-positive staining, catalase-positive activity, reduction of nitrate to nitrite, starch and casein hydrolysis, growth in presence of lysozyme and 2 % NaCl, citrate utilization, growth pH from 6.0 to 8.0, and acid and indole production from glucose and tryptophan, respectively. The whole-genome phylogenetic relationship showed that TE3T formed an individual clade with Bacillus tequilensis KCTC 13622T, distant from that generated by all Bacillus subtilis subspecies. The maximum values for average nucleotide identity and in silico DNA-DNA hybridization were 93.85 and 54.30 %, respectively, related to Bacillus subtilissubsp. inaquosorum KCTC 13429T. Analysis of its fatty acid content showed the ability of strain TE3T to bio-synthetize fatty acids that are not present in closely related Bacillus species, such as C12 : 0, C12 : 0 2OH, C12 : 0 3OH, C17 : 0, iso-C17 : 0 3OH and C18 : 1ω9c. These results provide evidence that strain TE3T is a novel species of the genus Bacillus, for which the name Bacilluscabrialesii sp. nov. is proposed. The type strain of Bacilluscabrialesii is TE3T (CM-CNRG TB54T=CCStamb A1T).
Concordance Between Electronic Clinical Documentation and Physicians’ Observed Behavior

Key Points Question How closely does documentation in electronic health records match the review of systems and physical examination performed by emergency physicians? Findings In this case series of 9 licensed emergency physician trainees and 12 observers of 180 patient encounters, 38.5% of the review of systems groups and 53.2% of the physical examination systems documented in the electronic health record were corroborated by direct audiovisual or reviewed audio observation. Meaning These findings raise the possibility that some physician documentation may not accurately represent actions taken, but further research is needed to assess this in more detail.
Interfacial charge-transfer Mott state in iridate–nickelate superlattices

Significance Heterojunctions between dissimilar materials provide an opportunity to generate emergent properties not present in their individual components. These properties are often linked to interfacial charge transfer, an important mechanism allowing one to access and control novel quantum states. Here, we have grown unit-cell scale superlattices composed of 5d SrIrO3 and 3d LaNiO3. We have discovered a massive interfacial charge transfer from Ir to Ni, triggering dramatic electronic and magnetic reconstructions at the interface that suppress strong spin–orbit coupling effects normally present in the iridates. These findings call for careful evaluation and reinterpretation of experiments on spin–orbit-driven physics in thin films and heterostructures based on prototypical 5d transition metal oxides. We investigate SrIrO3/LaNiO3 superlattices in which we observe a full electron transfer at the interface from Ir to Ni, triggering a massive structural and electronic reconstruction. Through experimental characterization and first-principles calculations, we determine that a large crystal field splitting from the distorted interfacial IrO6 octahedra surprisingly dominates over the spin–orbit coupling and together with the Hund’s coupling results in the high-spin (S = 1) configurations on both the Ir and Ni sites. This demonstrates the power of interfacial charge transfer in coupling lattice, charge, orbital, and spin degrees of freedom, opening fresh avenues of investigation of quantum states in oxide superlattices.
Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies

The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505.N279K. G458Y.SOSIP. 664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.
Unstable chromosome rearrangements in Staphylococcus aureus cause phenotype switching associated with persistent infections

Significance Staphylococcus aureus is a major human pathogen known to exhibit subpopulations of small-colony variants (SCVs) that cause persistent or recurrent infections. The underlying mechanisms promoting the SCV phenotypic switching and adaptation to persistent infection are poorly understood. Moreover, the instability of this frequently reverting phenotype hampers diagnosis and study. Here we show that SCVs with reduced virulence but increased immune evasion and persistence properties can arise from reversible chromosomal instability. This mechanism of SCV generation implies an asymmetric chromosome inversion and the activation of prophage-encoding genes used for immune evasion. Assessment of major S. aureus lineages indicates this genomic plasticity is a common but previously unrecognized mechanism used by S. aureus to cause persistent and relapsing infections. Staphylococcus aureus small-colony variants (SCVs) are associated with unusually chronic and persistent infections despite active antibiotic treatment. The molecular basis for this clinically important phenomenon is poorly understood, hampered by the instability of the SCV phenotype. Here we investigated the genetic basis for an unstable S. aureus SCV that arose spontaneously while studying rifampicin resistance. This SCV showed no nucleotide differences across its genome compared with a normal-colony variant (NCV) revertant, yet the SCV presented the hallmarks of S. aureus linked to persistent infection: down-regulation of virulence genes and reduced hemolysis and neutrophil chemotaxis, while exhibiting increased survival in blood and ability to invade host cells. Further genome analysis revealed chromosome structural variation uniquely associated with the SCV. These variations included an asymmetric inversion across half of the S. aureus chromosome via recombination between type I restriction modification system (T1RMS) genes, and the activation of a conserved prophage harboring the immune evasion cluster (IEC). Phenotypic reversion to the wild-type–like NCV state correlated with reversal of the chromosomal inversion (CI) and with prophage stabilization. Further analysis of 29 complete S. aureus genomes showed strong signatures of recombination between hsdMS genes, suggesting that analogous CI has repeatedly occurred during S. aureus evolution. Using qPCR and long-read amplicon deep sequencing, we detected subpopulations with T1RMS rearrangements causing CIs and prophage activation across major S. aureus lineages. Here, we have discovered a previously unrecognized and widespread mechanism of reversible genomic instability in S. aureus associated with SCV generation and persistent infections.
Increased ALK activity induces a poorly differentiated thyroid carcinoma in mice.

BACKGROUND Radioiodine refractory dedifferentiated thyroid cancer is a major clinical challenge. Anaplastic lymphoma kinase (ALK) mutations with increased ALK activity, especially fusion genes, have been suggested to promote thyroid carcinogenesis, leading to development of poorly differentiated and anaplastic thyroid cancer (PDTC and ATC). To determine the oncogenic potential of increased ALK activity in thyroid carcinogenesis in vivo, we studied mice with thyrocyte-specific expression of a constitutively active ALK mutant. METHODS Mice carrying a Cre-activated allele of a constitutively active ALK mutant (F1174L) were crossed with mice expressing tamoxifen-inducible Cre recombinase (CreERT2) under control of the thyroglobulin promoter to achieve thyrocyte-specific expression of the ALK mutant (ALKF1174L mice). Survival, thyroid hormone serum concentration and tumor development were recorded. Thyroids and lungs were studied histologically. To maintain euthyroidism despite dedifferentiation of the thyroid, a cohort was substituted with L-thyroxine via drinking water. RESULTS ALKF1174L mice developed massively enlarged thyroids, which showed an early loss of normal follicular architecture 12 weeks after tamoxifen injection. A significant decrease in thyroglobulin and Nkx-2.1 expression as well as impaired thyroid hormone synthesis confirmed dedifferentiation. Histologically, the mice developed a carcinoma resembling human PDTC with a predominantly trabecular/solid growth pattern and an increased mitotic rate. The tumors showed extrathyroidal extension into the surrounding strap muscles and developed lung metastases. Median survival of ALKF1174L mice was significantly reduced to 5 months after tamoxifen injection. Reduced thyroglobulin expression and loss of follicular structure led to hypothyroidism with elevated TSH. To test whether TSH stimulation played a role in thyroid carcinogenesis, we kept ALKF1174L mice euthyroid by L-thyroxine substitution. These mice developed PDTC with identical histological features compared to hypothyroid mice, demonstrating that PDTC development was due to increased ALK activity and not dependent on TSH stimulation. CONCLUSION Expression of a constitutively activated ALK mutant in thyroids of mice leads to development of metastasizing thyroid cancer resembling human PDTC. These results demonstrate in vivo that increased ALK activity is a driver mechanism in thyroid carcinogenesis.
Spatial organization of RNA polymerase and its relationship with transcription in Escherichia coli

Significance In fast-growing Escherichia coli cells, RNA polymerase (RNAP) has been reported to form dense clusters, which were proposed to be active transcription centers for ribosomal RNA (rRNA) synthesis. Understanding how and why RNAP is spatially organized in bacterial cells could offer insights into the mechanism of transcription regulation in the native cellular environment. Using quantitative superresolution imaging coupled with genetic and biochemical analyses, we found that RNAP clusters were indeed active transcription centers engaged in rRNA synthesis under a rich media growth condition, but their formation was independent of rRNA transcription activity. Instead, the underlying nucleoid structure played a significant role in spatially organizing RNAP clusters. These results shed new light on the relationship between RNAP clusters and transcription activity. Recent studies have shown that RNA polymerase (RNAP) is organized into distinct clusters in Escherichia coli and Bacillus subtilis cells. Spatially organized molecular components in prokaryotic systems imply compartmentalization without the use of membranes, which may offer insights into unique functions and regulations. It has been proposed that the formation of RNAP clusters is driven by active ribosomal RNA (rRNA) transcription and that RNAP clusters function as factories for highly efficient transcription. In this work, we examined these hypotheses by investigating the spatial organization and transcription activity of RNAP in E. coli cells using quantitative superresolution imaging coupled with genetic and biochemical assays. We observed that RNAP formed distinct clusters that were engaged in active rRNA synthesis under a rich medium growth condition. Surprisingly, a large fraction of RNAP clusters persisted in the absence of high rRNA transcription activities or when the housekeeping σ70 was sequestered, and was only significantly diminished when all RNA transcription was inhibited globally. In contrast, the cellular distribution of RNAP closely followed the morphology of the underlying nucleoid under all conditions tested irrespective of the corresponding transcription activity, and RNAP redistributed into dispersed, smaller clusters when the supercoiling state of the nucleoid was perturbed. These results suggest that RNAP was organized into active transcription centers under the rich medium growth condition; its spatial arrangement at the cellular level, however, was not dependent on rRNA synthesis activity and was likely organized by the underlying nucleoid.
Patients’ perspectives on imagery rescripting for aversive memories in social anxiety disorder

Abstract Background: Imagery rescripting (IR) for early aversive memories in patients with social anxiety disorder (SAD) has shown promising results, but no study has investigated the reactions and perspectives of patients who received IR. Aims: This study aimed to gain understanding of patients’ experiences/perspectives on IR as an adjunct to cognitive behavioural therapy (CBT) for SAD. Method: Twenty-five individuals with SAD received one or two sessions of IR over 16 CBT sessions. Contents of recurrent images and linked memories were identified during IR. Outcome measures included social anxiety, image and memory distress and vividness, and encapsulated belief. Patients completed a questionnaire about their perspectives of IR after the session. Thematic analysis was used to analyse the qualitative data. Results: IR resulted in significant within-session improvement in most outcome measures. Linked memories to negative recurrent images in social situations were categorized into nine groups. Common memories were ‘Being criticized by others’, ‘Being made fun of’, ‘Failing or not doing something well’ and ‘Being left out in a group’. Most patients (82%) experienced IR as impressive, and more than half of patients (59%) found IR effective. Themes of reasons of impressiveness and effectiveness were categorized as ‘Results of IR session’ and ‘Processes of IR session’. The theme ‘Results of IR session’ included six subthemes, and the theme ‘Processes of the IR session’ included five subthemes. Conclusions: Regarding patients’ perspectives, although they may experience negative emotions in the process of an IR session, our results suggest that many patients with SAD found IR sessions effective.
Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target

Significance This study identifies the source of the toxic glycolipid, galactosylsphingosine (psychosine), which accumulates in the inherited demyelinating disorder, Krabbe disease. It was suggested that psychosine was produced anabolically by the addition of galactose to sphingosine. We show here instead that psychosine is derived from the catabolic deacylation of galactosylceramide by the lysososomal enzyme acid ceramidase. These findings allow us to test and confirm the ∼45-y-old “psychosine hypothesis,” which states that psychosine causes the pathological and clinical signs of Krabbe disease. Finally, these data suggest that acid ceramidase could be a substrate reduction target for treating Krabbe disease. We show that pharmacological inhibition of acid ceramidase significantly increases the life span of the twitcher mouse, an authentic murine model of Krabbe disease. Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing “psychosine hypothesis. ” We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized l-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease.