Bioengineering the Human Intestinal Mucosa and the Importance of Stromal Support for Pharmacological Evaluation In Vitro.

Drug discovery is associated with high levels of compound elimination in all stages of development. The current practices for the pharmacokinetic testing of intestinal absorption combine Transwell inserts with the Caco-2 cell line and are associated with a wide range of limitations. The improvement of pharmacokinetic research relies on the development of more advanced in vitro intestinal constructs that better represent human native tissue and its response to drugs, providing greater predictive accuracy.

Dietary intakes and nutritional issues in inborn errors of immunity: a systematic review.

Introduction: Inborn errors of immunity (IEI) are characterized by an inherited dysregulation or absence of immune system components that can manifest clinically in complications that predispose an individual to feeding difficulties or impaired swallowing, digestion, and absorption. Treatment side-effects or altered requirements may further impair nutritional status. While adequate nutrition is necessary for optimal growth and immune function, little is known about nutritional intakes in IEI, and best practice nutrition guidelines are limited.

In vitro assessment of nanomedicines' propensity to cause palmar-plantar erythrodysesthesia: A Doxil vs. doxorubicin case study.

Palmar-plantar erythrodysesthesia (PPE), also known as hand and foot syndrome, is a condition characterized by inflammation-mediated damage to the skin on the palms and soles of the hands and feet. PPE limits the successful therapeutic applications of anticancer drugs. However, identifying this toxicity during preclinical studies is challenging due to the lack of accurate in vitro and in vivo animal-based models.

An In Vitro Human Skin Test for Predicting Skin Sensitization and Adverse Immune Reactions to Biologics.

Unlabelled: Biologics, including monoclonal antibodies (mAb), have proved to be effective and successful therapeutic agents, particularly in the treatment of cancer and immune-inflammatory conditions, as well as allergies and infections. However, their use carries an inherent risk of an immune-mediated adverse drug reaction. In this study, we describe the use of a novel pre-clinical human in vitro skin explant test for predicting skin sensitization and adverse immune reactions.

A Human Skin Explant Test as a Novel In Vitro Assay for the Detection of Skin Sensitization to Aggregated Monoclonal Antibodies.

Monoclonal antibodies (mAbs) are important therapeutics. However, the enhanced potential for aggregation has become a critical quality parameter during the production of mAbs. Furthermore, mAb aggregation may also present a potential health risk in a clinical setting during the administration of mAb therapeutics to patients.

Drug review process advancement and required manufacturer and contract research oraganization responses.

The United States Senate passed the "FDA Modernization Act 2.0." on September 29, 2022.

Effect of lower body negative pressure on cardiac and cerebral function in postural orthostatic tachycardia syndrome: A pilot MRI assessment.

Postural orthostatic tachycardia syndrome (POTS) is characterized by an excessive heart rate (HR) response upon standing and symptoms indicative of inadequate cerebral perfusion. We tested the hypothesis that during lower body negative pressure (LBNP), individuals with POTS would have larger decreases in cardiac and cerebrovascular function measured using magnetic resonance (MR) imaging. Eleven patients with POTS and 10 healthy controls were studied at rest and during 20 min of -25 mmHg LBNP.

Development of a mammalian neurosensory full-thickness skin equivalent and its application to screen sensitizing stimuli.

Human skin equivalents (HSEs) are an increasingly popular research tool due to limitations associated with animal testing for dermatological research. They recapitulate many aspects of skin structure and function, however, many only contain two basic cell types to model dermal and epidermal compartments, which limits their application. We describe advances in the field skin tissue modeling to produce a construct containing sensory-like neurons that is responsive to known noxious stimuli.

Convolutional Neural Networks for Challenges in Automated Nuclide Identification.

Improvements in Radio-Isotope IDentification (RIID) algorithms have seen a resurgence in interest with the increased accessibility of machine learning models. Convolutional Neural Network (CNN)-based models have been developed to identify arbitrary mixtures of unstable nuclides from gamma spectra. In service of this, methods for the simulation and pre-processing of training data were also developed.

Use of Porous Polystyrene Scaffolds to Bioengineer Human Epithelial Tissues In Vitro.

In vitro epithelial models are valuable tools for both academic and industrial laboratories to investigate tissue physiology and disease. Epithelial tissues comprise the surface epithelium, basement membrane, and underlying supporting stromal cells. There are various types of epithelial tissue and they have a diverse and intricate architecture in vivo, which cannot be successfully recapitulated using two-dimensional (2D) cell culture.

Bioengineering Novel Co-culture Models That Represent the Human Intestinal Mucosa With Improved Caco-2 Structure and Barrier Function.

The Caco-2 monolayer is the most widely used model of the human intestinal mucosa to study absorption. However, models lack communication from other cells present in the native intestine, such as signals from fibroblasts in the lamina propria. In this study, we have investigated the effects of fibroblasts upon the Caco-2 epithelium through two mechanisms: indirect signaling from fibroblasts and direct contact with fibroblasts.

Strong Neutron Pairing in core+4n Nuclei.

The emission of neutron pairs from the neutron-rich N=12 isotones ^{18}C and ^{20}O has been studied by high-energy nucleon knockout from ^{19}N and ^{21}O secondary beams, populating unbound states of the two isotones up to 15 MeV above their two-neutron emission thresholds. The analysis of triple fragment-n-n correlations shows that the decay ^{19}N(-1p)^{18}C^{*}→^{16}C+n+n is clearly dominated by direct pair emission. The two-neutron correlation strength, the largest ever observed, suggests the predominance of a ^{14}C core surrounded by four valence neutrons arranged in strongly correlated pairs.

Quasifree (p, 2p) Reactions on Oxygen Isotopes: Observation of Isospin Independence of the Reduced Single-Particle Strength.

Quasifree one-proton knockout reactions have been employed in inverse kinematics for a systematic study of the structure of stable and exotic oxygen isotopes at the R^{3}B/LAND setup with incident beam energies in the range of 300-450  MeV/u. The oxygen isotopic chain offers a large variation of separation energies that allows for a quantitative understanding of single-particle strength with changing isospin asymmetry. Quasifree knockout reactions provide a complementary approach to intermediate-energy one-nucleon removal reactions.

New Measurement of the Direct 3α Decay from the ^{12}C Hoyle State.

Excited states in certain atomic nuclei possess an unusual structure, where the dominant degrees of freedom are those of α clusters rather than individual nucleons. It has been proposed that the diffuse 3α system of the ^{12}C Hoyle state may behave like a Bose-Einstein condensate, where the α clusters maintain their bosonic identities. By measuring the decay of the Hoyle state into three α particles, we obtained an upper limit for the rare direct 3α decay branch of 0.

Evidence for triangular D3h symmetry in 12C.

We report a measurement of a new high spin Jπ=5- state at 22.4(2) MeV in 12C which fits very well to the predicted (ground state) rotational band of an oblate equilateral triangular spinning top with a D3h symmetry characterized by the sequence 0+, 2+, 3-, 4±, 5- with almost degenerate 4+ and 4- (parity doublet) states. Such a D3h symmetry was observed in triatomic molecules, and it is observed here for the first time in nuclear physics.

Infusion of noradrenaline through the proximal line of a migrated central venous catheter.

A 41-year-old, obese, patient was admitted to Accident and Emergency with a history of leg cellulitis. A central line was inserted. Documented aspiration of blood from all lines, central venous pressure trace obtained and correct position noted on the chest X-ray (CXR).

Migration of nuclear shell gaps studied in the d(24Ne,pγ)25Ne reaction.

The transfer of neutrons onto 24Ne has been measured using a reaccelerated radioactive beam of 24Ne to study the (d,p) reaction in inverse kinematics. The unusual raising of the first 3/2+ level in 25Ne and its significance in terms of the migration of the neutron magic number from N=20 to N=16 is put on a firm footing by confirmation of this state's identity. The raised 3/2+ level is observed simultaneously with the intruder negative parity 7/2- and 3/2- levels, providing evidence for the reduction in the N=20 gap.

Increased expression of the pro-apoptotic Bcl2 family member PUMA is required for mitochondrial release of cytochrome C and the apoptosis associated with skeletal myoblast differentiation.

We have previously shown that when skeletal myoblasts are cultured in differentiation medium (DM), roughly 30% undergo caspase 3-dependent apoptosis rather than differentiation. Herein, we investigate the molecular mechanism responsible for the activation of caspase 3 and the ensuing apoptosis. When 23A2 myoblasts are cultured in DM, caspase 9 activity is increased and pharmacological abrogation of caspase 9 activation impairs caspase 3 activation and apoptosis.

Signaling through the TRAIL receptor DR5/FADD pathway plays a role in the apoptosis associated with skeletal myoblast differentiation.

Apoptosis rather than differentiation is a physiological process during myogenesis and muscle regeneration. When cultured myoblasts were induced to differentiate, we detected an increase in caspase 8 activity. Pharmacological inhibition of caspase 8 activity decreased apoptosis.

ZXDC, a novel zinc finger protein that binds CIITA and activates MHC gene transcription.

The class II trans-activator (CIITA) is recognized as the master regulator of major histocompatibility complex (MHC) class II gene transcription and contributes to the transcription of MHC class I genes. To better understand the function of CIITA, we performed yeast two-hybrid with the C-terminal 807 amino acids of CIITA, and cloned a novel human cDNA named zinc finger, X-linked, duplicated family member C (ZXDC). The 858 amino acid ZXDC protein contains 10 zinc fingers and a transcriptional activation domain, and was found to interact with the region of CIITA containing leucine-rich repeats.

Alpha:2n:alpha molecular band in 10Be.

The 10.15 MeV resonance in 10Be has been probed via resonant 6He+4He elastic scattering. It is demonstrated that it is the Jpi=4+ member of a rotational band built on the 6.

Structure of 12Be: intruder d-wave strength at N=8.

The breaking of the N=8 shell-model magic number in the 12Be ground state has been determined to include significant occupancy of the intruder d-wave orbital. This is in marked contrast with all other N=8 isotones, both more and less exotic than 12Be. The occupancies of the [FORMULA: SEE TEXT]orbital and the [FORMULA: SEE TEXT], intruder orbital were deduced from a measurement of neutron removal from a high-energy 12Be beam leading to bound and unbound states in 11Be.

Reevaluation of the 22Na(p,gamma) reaction rate: implications for the detection of 22Na gamma rays from novae.

Understanding the processes which create and destroy 22Na is important for diagnosing classical nova outbursts. Conventional 22Na(p,gamma) studies are complicated by the need to employ radioactive targets. In contrast, we have formed the particle-unbound states of interest through the heavy-ion fusion reaction, 12C(12C,n)23Mg and used the Gammasphere array to investigate their radiative decay branches.