Novel Amanitin-based Antibody Drug Conjugates (ATAC®) targeting TROP2 for the treatment of Pancreatic Cancer.

Trophoblast cell surface antigen 2 (TROP2) exhibits aberrant expression in pancreatic cancer, correlating with metastasis, advanced tumor stage and poor prognosis of pancreatic ductal adenocarcinoma (PDAC) patients. TROP2 has been recognized as a promising therapeutic target for antibody drug conjugates (ADCs), as evidenced by the approval of the anti-TROP2 ADC Trodelvy® for the treatment of triple negative breast cancer. In this study we report the generation of novel second-generation amanitin based ADCs (ATAC®s) targeting TROP2, comprising the humanized RS7 antibody of Trodelvy® (hRS7) and the highly potent payload amanitin.

Renal sinus adipose tissue: exploratory study of metabolic features and transcriptome compared with omental and subcutaneous adipose tissue.

Objective: The objective was to study metabolic characteristics and transcriptome of renal sinus adipose tissue (RSAT) located around renal arteries and veins.

Methods: Adipose tissue biopsies from RSAT, omental (OAT), and subcutaneous (SAT) depots were obtained from healthy kidney donors (20 female, 20 male). Adipocyte glucose uptake rate and cell size were measured, and gene expression analyses using transcriptomics were performed.

Direct laser acceleration: A model for the electron injection from the walls of a cylindrical guiding structure.

We use analytical methods and particle-in-cell simulation to investigate the origin of electrons accelerated by the process of direct laser acceleration driven by high-power laser pulses in preformed narrow cylindrical plasma channels. The simulation shows that the majority of accelerated electrons are originally located along the interface between the channel wall and the channel interior. The analytical model based on the electron hydrodynamics illustrates the underlying physical mechanism of the release of electrons from the channel wall when irradiated by an intense laser, the subsequent electron dynamics, and the corresponding evolution of the channel density profile.

Effect of Dietary Eicosapentaenoic and Docosahexaenoic Fatty Acid Supplementation during the Last Month of Gestation on Fatty Acid Metabolism and Oxidative Status in Charolais Cows and Calves.

Fatty acids (FAs) are of utmost importance in the peripartal period for the development of the central nervous and immune systems of the newborn. The transport of polyunsaturated fatty acids (PUFAs) through the placenta is considered to be minimal in ruminants. Nevertheless, the cow's FAs are the main source of FAs for the calf during gestation.

Subcutaneous adipose tissue dopamine D2 receptor is increased in prediabetes and T2D.

Purpose: To evaluate the dopaminergic signaling in human adipose tissue in the context of obesity and type 2 diabetes (T2D) and potential direct implications in adipose tissue metabolism.

Methods: mRNA and protein expression of dopamine receptors D1 and D2 (DRD1 and DRD2) were determined in subcutaneous adipose tissue from subjects without or with T2D and with different body weight, and correlated with markers of obesity, hyperglycemia, and insulin resistance. Glucose uptake and lipolysis were measured in adipocytes ex vivo following short-term exposure to dopamine, DRD1 receptor agonist (SKF81297), or DRD2 receptor agonist (bromocriptine).

expression is reduced in human subcutaneous adipose tissue in obesity and type 2 diabetes but may not directly impact adipocyte glucose and lipid metabolism.

Cdk5 and Abl enzyme substrate 1 (CABLES1) is a cell cycle regulator that has previously been identified as a candidate gene for obesity-related phenotypes, but little is known about its role in adipose tissue metabolism. In this study, we explore the role of CABLES1 in obesity and type 2 diabetes (T2D) in human subcutaneous adipose tissue (SAT). We performed gene expression analysis of SAT obtained from subjects with and without T2D, and from a second validation cohort consisting of subjects without T2D.

Transcriptional Profiling Reveals the Wheat Defences against Fusarium Head Blight Disease Regulated by a NAC Transcription Factor.

The wheat NAC transcription factor TaNACL-D1 enhances resistance to the economically devastating Fusarium head blight (FHB) disease. The objective of this study was to decipher the alterations in gene expression, pathways and biological processes that led to enhanced resistance as a result of the constitutive expression of TaNACL-D1 in wheat. Transcriptomic analysis was used to determine the genes and processes enhanced in wheat due to TaNACL-D1 overexpression, both in the presence and absence of the causal agent of FHB, (0- and 1-day post-treatment).

Charged particle beam transport in a flying focus pulse with orbital angular momentum.

We demonstrate the capability of flying focus (FF) laser pulses with ℓ=1 orbital angular momentum (OAM) to transversely confine ultrarelativistic charged particle bunches over macroscopic distances while maintaining a tight bunch radius. A FF pulse with ℓ=1 OAM creates a radial ponderomotive barrier that constrains the transverse motion of particles and travels with the bunch over extended distances. As compared with freely propagating bunches, which quickly diverge due to their initial momentum spread, the particles cotraveling with the ponderomotive barrier slowly oscillate around the laser pulse axis within the spot size of the pulse.

Effects of the second-generation antipsychotic drugs aripiprazole and olanzapine on human adipocyte differentiation.

Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effects (e.g. obesity and type 2 diabetes).

Comprehensive analysis of pathogen-responsive wheat NAC transcription factors: new candidates for crop improvement.

Wheat NAC (TaNAC) transcription factors are important regulators of stress responses and developmental processes. This study proposes a new TaNAC nomenclature and identified defense-associated TaNACs based on the analysis of RNA-sequencing datasets of wheat tissue infected with major fungal pathogens. A total of 146 TaNACs were pathogen-responsive, of which 52 were orthologous with functionally characterized defense-associated NACs from barley, rice, and Arabidopsis, as deduced via phylogenetic analysis.

expression in subcutaneous adipose tissue is related to body fat distribution in women, and knockdown impairs preadipocyte differentiation.

Oestrogen receptor 2 () expression has been shown to be higher in subcutaneous adipose tissue (SAT) from postmenopausal compared to premenopausal women. The functional significance of altered expression is not fully known. This study investigates the role of for adipose tissue lipid and glucose metabolism.

Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women.

Context: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood.

Objective: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes.

Methods: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2.

CDKN2C expression in adipose tissue is reduced in type II diabetes and central obesity: impact on adipocyte differentiation and lipid storage?

CDKN2C/p18 (Cyclin-Dependent Kinase Inhibitor 2C) is a cell growth regulator that controls cell cycle progression and has previously been associated with increased risk for type II diabetes (T2D) and reduced peripheral adipose tissue (AT) storage capacity. This study explored the role of CDKN2C in AT lipid and glucose metabolism in T2D. Expression of CDKN2C and other genes was analyzed by transcriptomics, or real-time PCR in subcutaneous AT (SAT) samples obtained from T2D and control subjects matched for sex, age and BMI and also in paired SAT and omental AT (OAT) samples.

Collisionless shock acceleration in the corona of an inertial confinement fusion pellet with possible application to ion fast ignition.

Two-dimensional particle-in-cell simulations are used to explore collisionless shock acceleration in the corona plasma surrounding the compressed core of an inertial confinement fusion pellet. We show that an intense laser pulse interacting with the long scale-length plasma corona is able to launch a collisionless shock around the critical density. The nonlinear wave travels up-ramp through the plasma reflecting and accelerating the background ions.

Does conventional early life academic excellence predict later life scientific discovery? An assessment of the lives of great medical innovators.

Background: Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice?

Aims: We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements.

Methods: The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada.

A wheat NAC interacts with an orphan protein and enhances resistance to Fusarium head blight disease.

Taxonomically-restricted orphan genes play an important role in environmental adaptation, as recently demonstrated by the fact that the Pooideae-specific orphan TaFROG (Triticum aestivum Fusarium Resistance Orphan Gene) enhanced wheat resistance to the economically devastating Fusarium head blight (FHB) disease. Like most orphan genes, little is known about the cellular function of the encoded protein TaFROG, other than it interacts with the central stress regulator TaSnRK1α. Here, we functionally characterized a wheat (T.

Investigations of the Copper Peptide Hepcidin-25 by LC-MS/MS and NMR.

Hepcidin-25 was identified as the main iron regulator in the human body, and it by binds to the sole iron-exporter ferroportin. Studies showed that the N-terminus of hepcidin is responsible for this interaction, the same N-terminus that encompasses a small copper(II)-binding site known as the ATCUN (amino-terminal Cu(II)- and Ni(II)-binding) motif. Interestingly, this copper-binding property is largely ignored in most papers dealing with hepcidin-25.

Multi-GeV electron-positron beam generation from laser-electron scattering.

The new generation of laser facilities is expected to deliver short (10 fs-100 fs) laser pulses with 10-100 PW of peak power. This opens an opportunity to study matter at extreme intensities in the laboratory and provides access to new physics. Here we propose to scatter GeV-class electron beams from laser-plasma accelerators with a multi-PW laser at normal incidence.

QED cascade with 10 PW-class lasers.

The intensities of the order of 10 W/cm are required to efficiently generate electron-positron pairs in laser-matter interaction when multiple laser beam collision is employed. To achieve such intense laser fields with the upcoming generation of 10 PW laser beams, focusing to sub-micron spot size is required. In this paper, the possibility of pair production cascade development is studied for the case of a standing wave created by two tightly focused colliding laser pulses.

Collimated protons accelerated from an overdense gas jet irradiated by a 1 µm wavelength high-intensity short-pulse laser.

We have investigated proton acceleration in the forward direction from a near-critical density hydrogen gas jet target irradiated by a high intensity (10 W/cm), short-pulse (5 ps) laser with wavelength of 1.054 μm. We observed the signature of the Collisionless Shock Acceleration mechanism, namely quasi-monoenergetic proton beams with small divergence in addition to the more commonly observed electron-sheath driven proton acceleration.

Seeded QED cascades in counterpropagating laser pulses.

The growth rates of seeded QED cascades in counterpropagating lasers are calculated with first-principles two- and three-dimensional QED-PIC (particle-in-cell) simulations. The dependence of the growth rate on the laser polarization and intensity is compared with analytical models that support the findings of the simulations. The models provide insight regarding the qualitative trend of the cascade growth when the intensity of the laser field is varied.

Glucagon responses to exercise-induced hypoglycaemia are improved by somatostatin receptor type 2 antagonism in a rat model of diabetes.

Aims/hypothesis: Regular exercise is at the cornerstone of care in type 1 diabetes. However, relative hyperinsulinaemia and a blunted glucagon response to exercise promote hypoglycaemia. Recently, a selective antagonist of somatostatin receptor 2, PRL-2903, was shown to improve glucagon counterregulation to hypoglycaemia in resting streptozotocin-induced diabetic rats.