Miracle-dz/UniFAR-FTUs huggingface dataset:
Precipitation and Phase Transformation of Dicalcium Phosphate Dihydrate in Electrolyte Solutions of Simulated Body Fluids. Thermodynamic Modeling and Kinetic Studies.

The metastable and stable equilibria of a precipitation in the biomimetic system Simulated Body Fluid (SBF)-CaCl2 -K2 HPO4 -KOH-H2 O were modeled in the pH region 3-7 at a Ca/P molar ratio of 1 using a thermodynamic approach. Saturation indices (SI) of the solid phases were calculated and used to prognose the salt precipitation/dissolution processes. At pH< 4 the solutions are undersaturated (SI < 0) in respect of all solid phases; co-precipitation of dicalcium phosphate dihydrate (DCPD) and hydroxyapatite (HA) occurs at рН 4 while at рН > 4 the stable phase is DCPD but the number of other co-precipitated solid phases increases. This result is associated with the increase in HPO4 2- , CaHPO4 0 and KНРО4 - species in the studied solution. The phase transformations of five model DCPD-based calcium phosphate precursors in three simulated body fluids differing in their composition, to more stable octacalcium phosphate and hydroxyapatite was thermodynamically prognosed and experimentally confirmed by kinetic studies, as well as by chemical, XRD, SEM and IR methods. This article is protected by copyright. All rights reserved.
Microvascular damage assessed by optical coherence tomography angiography for glaucoma diagnosis: a systematic review of the most discriminative regions

Abstract A growing number of studies have reported a link between vascular damage and glaucoma based on optical coherence tomography angiography (OCTA) imaging. This multitude of studies focused on different regions of interest (ROIs) which offers the possibility to draw conclusions on the most discriminative locations to diagnose glaucoma. The objective of this work was to review and analyse the discriminative capacity of vascular density, retrieved from different ROIs, on differentiating healthy subjects from glaucoma patients. PubMed was used to perform a systematic review on the analysis of glaucomatous vascular damage using OCTA. All studies up to 21 April 2019 were considered. The ROIs were analysed by region (macula, optic disc and peripapillary region), layer (superficial and deep capillary plexus, avascular, whole retina, choriocapillaris and choroid) and sector (according to the Garway–Heath map). The area under receiver operator characteristic curve (AUROC) and the statistical difference (p‐value) were used to report the importance of each ROI for diagnosing glaucoma. From 96 screened studies, 43 were eligible for this review. Overall, the peripapillary region showed to be the most discriminative region with the highest mean AUROC (0.80 ± 0.09). An improvement of the AUROC from this region is observed when a sectorial analysis is performed, with the highest AUROCs obtained at the inferior and superior sectors of the superficial capillary plexus in the peripapillary region (0.86 ± 0.03 and 0.87 ± 0.10, respectively). The presented work shows that glaucomatous vascular damage can be assessed using OCTA, and its added value as a complementary feature for glaucoma diagnosis depends on the region of interest. A sectorial analysis of the superficial layer at the peripapillary region is preferable for assessing glaucomatous vascular damage.
Utilization of Direct Oral Anticoagulants in People with HIV: Observational Data from the DC Cohort.

BACKGROUND Direct oral anticoagulants (DOACs) have become first-line treatment for venous thrombotic events. DOAC prescribing trends among people with HIV (PWH) are not well described. Co-administration of DOACs with the antiretroviral (ARV) pharmacokinetic boosters ritonavir (RTV) or cobicistat (COBI) may be complicated by pharmacokinetic interactions. METHODS A longitudinal cohort study was conducted using the DC Cohort Database in Washington, D.C., from January 2011-March 2017, to describe oral anticoagulant prescribing among PWH ≥ 18 years old and the prevalence of DOAC use with RTV or COBI. Data collection included demographic and clinical characteristics, ARV and anticoagulant prescriptions and ICD-9/10 diagnosis codes. RESULTS Among 8,315 PWH, there were 236 anticoagulant prescriptions (96 DOAC, 140 warfarin) for 206 persons. PWH prescribed anticoagulants were predominantly Black (82%), male (82%), with a median age at anticoagulant initiation of 56 years. DOAC use increased from 3% of total anticoagulant prescribing in 2011 to 43% in 2016, accounting for 64% of all newly recorded anticoagulant prescriptions by 2016. Nineteen bleeding events were recorded among 16 individuals. Despite the FDA label recommendation to avoid rivaroxaban with boosted ARVs, 41% remained on boosted ARVs after rivaroxaban initiation. CONCLUSION DOAC use increased substantially in PWH by 2016. Although rivaroxaban is not recommended with RTV or COBI, concomitant use was recorded in 41% of rivaroxaban recipients in this cohort. As DOAC usage increases, clinicians need to be aware of potential DOAC-ARV interactions in order to select the most appropriate oral anticoagulant and monitoring plan for PWH.
A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain

It is increasingly accepted that early cognitive impairment in Alzheimer's disease results in considerable part from synaptic dysfunction caused by the accumulation of a range of oligomeric assemblies of amyloid β‐protein (Aβ). Most studies have used synthetic Aβ peptides to explore the mechanisms of memory deficits in rodent models, but recent work suggests that Aβ assemblies isolated from human (AD) brain tissue are far more potent and disease‐relevant. Although reductionist experiments show Aβ oligomers to impair synaptic plasticity and neuronal viability, the responsible mechanisms are only partly understood. Glutamatergic receptors, GABAergic receptors, nicotinic receptors, insulin receptors, the cellular prion protein, inflammatory mediators, and diverse signaling pathways have all been suggested. Studies using AD brain‐derived soluble Aβ oligomers suggest that only certain bioactive forms (principally small, diffusible oligomers) can disrupt synaptic plasticity, including by binding to plasma membranes and changing excitatory–inhibitory balance, perturbing mGluR, PrP, and other neuronal surface proteins, down‐regulating glutamate transporters, causing glutamate spillover, and activating extrasynaptic GluN2B‐containing NMDA receptors. We synthesize these emerging data into a mechanistic hypothesis for synaptic failure in Alzheimer's disease that can be modified as new knowledge is added and specific therapeutics are developed.
Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa

ABSTRACT Introduction Junctional epidermolysis bullosa (JEB) is a rare inherited genetic disorder with limited treatments beyond palliative care. A major hallmark of JEB is skin blistering caused by functional loss or complete absence of major structural proteins of the skin. Impaired wound healing in patients with JEB gives rise to chronic cutaneous ulcers that require daily care. Wound care and infection control are the current standard of care for this patient population. Areas covered This review covers research and clinical implementation of emerging drug, cell, and gene therapies for JEB. Current clinical trials use topical drug delivery to manipulate the inflammation and re-epithelialization phases of wound healing or promote premature stop codon readthrough to accelerate chronic wound closure. Allogeneic cell therapies for JEB have been largely unsuccessful, with autologous skin grafting emerging as a reliable method of resolving the cutaneous manifestations of JEB. Genetic correction and transplant of autologous keratinocytes have demonstrated persistent amelioration of chronic wounds in a subset of patients. Expert Opinion Emerging therapies address the cutaneous symptoms of JEB but are unable to attend to systemic manifestations of the disease. Investigations into the molecular mechanism(s) underpinning the failure of systemic allogeneic cell therapies are necessary to expand the range of effective JEB therapies.
Personalized medicine in rheumatic diseases: how close are we to being able to use genetic biomarkers to predict response to TNF inhibitors?

ABSTRACT Introduction: A genetic biomarker to select which drug will work best for which patients with rheumatic diseases is a goal of pharmacogenetic precision medicine approaches and one that patients and the public support. However, studies to date have yielded inconsistent findings with no robustly replicated or clinically useful genetic biomarkers emerging. Areas covered: Using studies investigating biomarkers to predict response to tumor necrosis factor inhibitor therapies in rheumatoid arthritis as an exemplar, we consider factors that reduce the power to detect such predictive biomarkers, including non-adherence, immunogenicity, the use of clinical outcome measures comprising composite scores and sample size. We argue that the biologic therapies were developed to target joint inflammation and so the outcome measure should be closer to the biology and, ideally, should be a biological measure. Given that heritability studies have shown a substantial genetic contribution, there is merit in designing studies to optimize the chance of identifying robust genetic markers and that includes testing drug levels for adherence. Expert opinion: Ultimately, we think that genetics will be used as part of an algorithm to assess likely response to individual drugs but that other factors will also be important including clinical and environmental factors.
CCAP regulates feeding behavior via the NPF pathway in Drosophila adults

Significance The ability of an animal to sense what to eat, such as carbohydrate-rich food, as well as to reject food that may be disadvantageous or even deadly is essential for survival and adaptation to metabolic demands compounded by continuous changes in the environment. Here we investigate evolutionarily conserved pathways central for either choosing or rejecting nutrients based on neuronal system interactions between internal signals and the external milieu. These pathways are likely to be necessary for the ability to perform quick adaptation to the immediate conditions and in general provide clues to the structure of the fly’s internal network governing nutrient sensing. The intake of macronutrients is crucial for the fitness of any animal and is mainly regulated by peripheral signals to the brain. How the brain receives and translates these peripheral signals or how these interactions lead to changes in feeding behavior is not well-understood. We discovered that 2 crustacean cardioactive peptide (CCAP)-expressing neurons in Drosophila adults regulate feeding behavior and metabolism. Notably, loss of CCAP, or knocking down the CCAP receptor (CCAP-R) in 2 dorsal median neurons, inhibits the release of neuropeptide F (NPF), which regulates feeding behavior. Furthermore, under starvation conditions, flies normally have an increased sensitivity to sugar; however, loss of CCAP, or CCAP-R in 2 dorsal median NPF neurons, inhibited sugar sensitivity in satiated and starved flies. Separate from its regulation of NPF signaling, the CCAP peptide also regulates triglyceride levels. Additionally, genetic and optogenetic studies demonstrate that CCAP signaling is necessary and sufficient to stimulate a reflexive feeding behavior, the proboscis extension reflex (PER), elicited when external food cues are interpreted as palatable. Dopaminergic signaling was also sufficient to induce a PER. On the other hand, although necessary, NPF neurons were not able to induce a PER. These data illustrate that the CCAP peptide is a central regulator of feeding behavior and metabolism in adult flies, and that NPF neurons have an important regulatory role within this system.
ENO regulates tomato fruit size through the floral meristem development network

Significance Fruit-size increase is one of the major changes associated with tomato domestication, and it currently represents an important objective for breeding. Regulatory mutations at the LOCULE NUMBER and FASCIATED loci, the orthologues of the Arabidopsis WUSCHEL and CLAVATA3, have mainly contributed to enlarging fruit size by altering meristem activity. Here, we identify ENO as a tomato fruit regulator, which may function by regulating WUSCHEL gene expression to restrict stem-cell proliferation in a flower-specific manner. Our findings also show that a mutation in the ENO promoter was selected during domestication to establish the background for enhancing fruit size in cultivated tomatoes, denoting that transcriptional changes in key regulators have significant effects on agronomic traits. A dramatic evolution of fruit size has accompanied the domestication and improvement of fruit-bearing crop species. In tomato (Solanum lycopersicum), naturally occurring cis-regulatory mutations in the genes of the CLAVATA-WUSCHEL signaling pathway have led to a significant increase in fruit size generating enlarged meristems that lead to flowers with extra organs and bigger fruits. In this work, by combining mapping-by-sequencing and CRISPR/Cas9 genome editing methods, we isolated EXCESSIVE NUMBER OF FLORAL ORGANS (ENO), an AP2/ERF transcription factor which regulates floral meristem activity. Thus, the ENO gene mutation gives rise to plants that yield larger multilocular fruits due to an increased size of the floral meristem. Genetic analyses indicate that eno exhibits synergistic effects with mutations at the LOCULE NUMBER (encoding SlWUS) and FASCIATED (encoding SlCLV3) loci, two central players in the evolution of fruit size in the domestication of cultivated tomatoes. Our findings reveal that an eno mutation causes a substantial expansion of SlWUS expression domains in a flower-specific manner. In vitro binding results show that ENO is able to interact with the GGC-box cis-regulatory element within the SlWUS promoter region, suggesting that ENO directly regulates SlWUS expression domains to maintain floral stem-cell homeostasis. Furthermore, the study of natural allelic variation of the ENO locus proved that a cis-regulatory mutation in the promoter of ENO had been targeted by positive selection during the domestication process, setting up the background for significant increases in fruit locule number and fruit size in modern tomatoes.
Delayed (14-30 Days) Percutaneous Repair of Achilles Tendon Ruptures Offers Equally Good Results As Compared With Acute Repair

Background: Minimally invasive repair of acute Achilles tendon ruptures has been performed for several years, resulting in reduced morbidity as compared with open repair. Hypothesis: A minimally invasive technique can be used to manage Achilles tendon ruptures in patients presenting between 14 and 30 days from injury. Study Design: Cohort study; Level of evidence, 3. Methods: We prospectively recruited 21 consecutive patients who presented between 14 and 30 days after the index injury, and we compared them with 21 patients who were matched according to sex, age (±2 years), and level of activity, who presented within 14 days of the index injury. All patients underwent the same minimally invasive procedure under local anesthesia: a core suture repair consisting of a modified Bunnell suture in the proximal stump and a modified Kessler suture in the distal stump. Results: At 12 months after minimally invasive repair, patients with delayed treatment had a median Achilles tendon rupture score of 91 (SD, 2.4; range, 87-96) as compared with 91 (SD, 2.2; range, 86-96) in patients treated acutely, who presented at a median 2.4 days (range 1-6 days) from the injury. There were no significant differences between groups in terms of mean (SD) Achilles tendon resting angle: delayed repair group, −3.9° (2.0); acute repair group, −3.7° (1.9) (P = .69). No patient in either group developed a wound infection. One patient in the acute group experienced an iatrogenic sural nerve injury. Conclusion: Patients with Achilles tendon rupture treated by percutaneous repair 14 to 30 days after injury achieved similar results at 1 year as patient treated <14 after injury.
Why the –omic future of Apicomplexa should include gregarines

Gregarines, a polyphyletic group of apicomplexan parasites infecting mostly non‐vertebrates hosts, remains poorly known at taxonomic, phylogenetic and genomic levels. However, it represents an essential group for understanding evolutionary history and adaptive capacities of apicomplexan parasites to the remarkable diversity of their hosts. Because they have a mostly extracellular lifestyle, gregarines have developed other cellular developmental forms and host–parasite interactions, compared with their much better studied apicomplexan cousins, intracellular parasites of vertebrates (Hemosporidia, Coccidia, Cryptosporidia). This review highlights the promises offered by the molecular exploration of gregarines, that have been until now left on the side of the road of the comparative –omic exploration of apicomplexan parasites. Elucidating molecular bases for both their ultrastructural, functional and behavioural similarities and differences, compared with those of the typical apicomplexan models, is expected to provide entirely novel clues on the adaptive capacities developed by Apicomplexa over evolution. A challenge remains to identify which gregarines should be explored in priority, as recent metadata from open and host‐associated environments have confirmed how underestimated is our current view on true gregarine biodiversity. It is now time to turn to gregarines to widen the currently highly skewed view we have of adaptive mechanisms developed by Apicomplexa.
In-clinic event related potentials after sports concussion: A 4-year study

PURPOSE: Electrophysiological event-related potentials (ERP’s) have been reported to change after concussion. The objective of this study is to use a simple 2-tone auditory P300 ERP in routine clinical settings to measure changes from baseline after concussion and to determine if these changes persist at return to play when other standard measures have normalized. METHODS: Three-hundred sixty-four (364) student athletes, aged 17–23 years, participating in contact sports were tracked over consecutive years. In this blinded study P300, plus physical reaction times and Trail Making tests, were collected alongside standard clinical evaluations. Changes in these measures after concussion were compared to clinical outcomes over various stages of post-injury recovery. RESULTS: Concussed players experienced significant reaction time and/or P300 amplitude changes compared to pre-concussion baseline measurements (p< 0.005). P300 changes persisted in 38% of the players after standard measures, including reaction times, had cleared. Many of those players slow to normalize were part of the sub-concussive symptom group and/or appeared more prone to repeat concussions. CONCLUSION: These data suggest significant P300 amplitude changes after concussion that are quantifiable and consistent. These changes often normalized slower than other standard assessments. More data are needed to determine if slow normalization relates to sub-concussive or repeated events.
Design features and performance of a CsI(Na) array based gamma camera for small animal gene research

The authors report on the development of a radiation imaging system based on a matrix of CsI(Na) scintillating crystals. This detector system has been optimized for high resolution radiation imaging of the distribution of iodine 125 (/sup 125/I) in a laboratory animal. The radioisotope /sup 125/I is readily available as a label to molecular biology probes that can be used in gene research. Iodine 125 decays via electron capture emitting a 35 keV gamma-ray with the prompt emission of several 27-32 keV X-rays. A coincidence condition can be set to detect the /sup 125/I decays thus reducing background radiation contribution to the image. The system utilizes the Hamamatsu 5 inch diameter 3292 position sensitive photomultiplier tube (PSPMT) coupled to the CsI(Na) matrix and a custom built high resolution copper-beryllium collimator. A conventional photomultiplier coupled to a NaI(Ti) crystal scintillator is used to detect the coincident radiation resulting from the decay of /sup 125/I.
Experimental facilitation of heat loss affects work rate and innate immune function in a breeding passerine bird

ABSTRACT The capacity to get rid of excess heat produced during hard work is a possible constraint on parental effort during reproduction [heat dissipation limit (HDL) theory]. We released hard-working blue tits (Cyanistes caeruleus) from this constraint by experimentally removing ventral plumage. We then assessed whether this changed their reproductive effort (feeding rate and nestling size) and levels of self-maintenance (change in body mass and innate immune function). Feather-clipped females reduced the number of feeding visits and increased levels of constitutive innate immunity compared with unclipped females but did not fledge smaller nestlings. Thus, they increased self-maintenance without compromising current reproductive output. In contrast, feather clipping did not affect the number of feeding visits or innate immune function in males, despite increased heat loss rate. Our results show that analyses of physiological parameters, such as constitutive innate immune function, can be important when trying to understand sources of variation in investment in self-maintenance versus reproductive effort and that risk of overheating can influence innate immune function during reproduction. Summary: Facilitation of heat loss in blue tits allows increased female investment in innate immune function (self-maintenance) without compromising current reproduction.