The threat of groundwater pollution for petrifying springs; defining nutrient threshold values for an endangered bryophyte dominated habitat.

Eutrophication by human activities is increasingly affecting ecosystem functioning and plant community composition. So far, studies mainly focus on the effects of atmospheric nitrogen deposition, surface water eutrophication or soil nutrient accumulation. Groundwater pollution of spring habitats, however, has received much less attention, although numerous papers report groundwater nutrient enrichment worldwide.

Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1).

Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines.

Comparison of Pronase versus Manual Dechorionation of Zebrafish Embryos for Small Molecule Treatments.

Zebrafish are a powerful animal model for small molecule screening. Small molecule treatments of zebrafish embryos usually require that the chorion, an acellular envelope enclosing the embryo, is removed in order for chemical compounds to access the embryo from the bath medium. For large-scale studies requiring hundreds of embryos, manual dechorionation, using forceps, can be a time-consuming and limiting process.

Water channel aquaporin 4 is required for T cell receptor mediated lymphocyte activation.

Aquaporins are a family of ubiquitously expressed transmembrane water channels implicated in a broad range of physiological functions. We have previously reported that aquaporin 4 (AQP4) is expressed on T cells and that treatment with a small molecule AQP4 inhibitor significantly delays T cell mediated heart allograft rejection. Using either genetic deletion or small molecule inhibitor, we show that AQP4 supports T cell receptor mediated activation of both mouse and human T cells.

wnt16 regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome.

Bone and muscle are coupled through developmental, mechanical, paracrine, and autocrine signals. Genetic variants at the CPED1-WNT16 locus are dually associated with bone- and muscle-related traits. While Wnt16 is necessary for bone mass and strength, this fails to explain pleiotropy at this locus.

The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer.

Aim: Zinc is a key secondary messenger that can regulate multiple signalling pathways within cancer cells, thus its levels need to be strictly controlled. The Zrt, Irt-like protein (ZIP, SLC39A) family of zinc transporters increase cytosolic zinc from either extracellular or intracellular stores. This study examines the relevance of zinc transporters ZIP7 and ZIP6 as therapeutic targets in tamoxifen resistant (TAMR) breast cancer.

Impact of simplifications on numerical modelling of the shallow subsurface at city-scale and implications for shallow geothermal potential.

Anthropogenic infrastructures in the shallow subsurface, such as heated basements, tunnels or shallow geothermal systems, are known to increase ground temperatures, particularly in urban areas. Numerical modelling helps inform on the extent of thermal influence of such structures, and its potential uses. Realistic modelling of the subsurface is often computationally costly and requires large amounts of data which is often not readily available, necessitating the use of modelling simplifications.

Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail.

Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola-one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure.

Rapid range shifts and megafaunal extinctions associated with late Pleistocene climate change.

Large-scale changes in global climate at the end of the Pleistocene significantly impacted ecosystems across North America. However, the pace and scale of biotic turnover in response to both the Younger Dryas cold period and subsequent Holocene rapid warming have been challenging to assess because of the scarcity of well dated fossil and pollen records that covers this period. Here we present an ancient DNA record from Hall's Cave, Texas, that documents 100 vertebrate and 45 plant taxa from bulk fossils and sediment.

Groundwater heat pump feasibility in shallow urban aquifers: Experience from Cardiff, UK.

Ground source heat pumps have the potential to decarbonise heating and cooling in many urban areas. The impact of using shallow groundwater from unconsolidated sedimentary aquifers for heating in urban areas is often modelled, but rarely validated from field measurements. This study presents findings from the 'Cardiff Urban Geo-Observatory' project.

Increased cerebral vascularization and decreased water exchange across the blood-brain barrier in aquaporin-4 knockout mice.

Aquaporin-4 (AQP4) plays an important role in regulating water exchange across the blood-brain barrier (BBB) and brain-cerebrospinal fluid interface. Studies on AQP-4 knockout mice (AQP4-KO) have reported considerable protection from brain edema induced by acute water intoxication and ischemic stroke, identifying AQP4 as a potential target for therapeutic interventions. However, the long-term effects of chronic AQP4 suppression are yet to be elucidated.

Advancing pharmacy technician training and practice models in the United States: Historical perspectives, workforce development needs, and future opportunities.

The United States healthcare system faces immense challenges related to cost, quality, and access. As the pharmacy profession addresses these challenges by shifting toward a practice model centered around direct patient care clinical services, a competent and capable technician workforce is needed to support the roles of pharmacists. Until recently, little focus has been paid to pharmacy technicians or their role as they relate to practice model change.

Aquaporin 4 inhibition alters chemokine receptor expression and T cell trafficking.

Aquaporins (AQPs) are water channels that mediate a variety of biological processes. However, their role in the immune system is poorly understood. We recently reported that AQP4 is expressed by naïve and memory T cells and that AQP4 blockade with a small molecule inhibitor prolongs murine heart allograft survival at least partially through diminishing T cell activation, proliferation and trafficking.

Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury.

Cerebral edema in ischemic stroke can lead to increased intracranial pressure, reduced cerebral blood flow and neuronal death. Unfortunately, current therapies for cerebral edema are either ineffective or highly invasive. During the development of cytotoxic and subsequent ionic cerebral edema water enters the brain by moving across an intact blood brain barrier and through aquaporin-4 (AQP4) at astrocyte endfeet.

The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest.

Background: Cerebral edema after cardiac arrest (CA) is associated with increased mortality and unfavorable outcome in children and adults. Aquaporin-4 mediates cerebral water movement and its absence in models of ischemia improves outcome. We investigated early and selective pharmacologic inhibition of aquaporin-4 in a clinically relevant asphyxial CA model in immature rats in a threshold CA insult that produces primarily cytotoxic edema in the absence of blood-brain barrier permeability.

Functional testing of a human variant in zebrafish reveals a potential modifier role in congenital heart defects.

Whole-genome and exome sequencing efforts are increasingly identifying candidate genetic variants associated with human disease. However, predicting and testing the pathogenicity of a genetic variant remains challenging. Genome editing allows for the rigorous functional testing of human genetic variants in animal models.

Toll-like Receptor 3 Is a Therapeutic Target for Pulmonary Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. TLR3 (Toll-like receptor 3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection.

Objectives: To study the expression and role of TLR3 in PAH and to determine whether a TLR3 agonist reduces pulmonary hypertension in preclinical models.

A Comparison of Approaches to Student Pharmacist Business Planning in Pharmacy Practice Management.

To compare second-year student pharmacists' perspectives on two approaches for completing a pharmacy practice management business planning project. A mixed-methods approach was used to compare two options (traditional and experimental) for completing business plan projects that were offered to teams of second-year student pharmacists as part of a required pharmacy management course. Teams who chose the traditional project were required to develop a unique, pharmacy-related business plan while those who chose the experimental concept were paired with a pharmacy-focused firm within Tennessee and tasked with designing a potential service for the firm's consideration.

A two-domain folding intermediate of RuBisCO in complex with the GroEL chaperonin.

The chaperonins (GroEL and GroES in Escherichia coli) are ubiquitous molecular chaperones that assist a subset of essential substrate proteins to undergo productive folding to the native state. Using single particle cryo EM and image processing we have examined complexes of E. coli GroEL with the stringently GroE-dependent substrate enzyme RuBisCO from Rhodospirillum rubrum.

BMP and FGF signaling interact to pattern mesoderm by controlling basic helix-loop-helix transcription factor activity.

The mesodermal germ layer is patterned into mediolateral subtypes by signaling factors including BMP and FGF. How these pathways are integrated to induce specific mediolateral cell fates is not well understood. We used mesoderm derived from post-gastrulation neuromesodermal progenitors (NMPs), which undergo a binary mediolateral patterning decision, as a simplified model to understand how FGF acts together with BMP to impart mediolateral fate.

Lipid Nanoparticle Packaging Is an Effective and Nontoxic mRNA Delivery Platform in Embryonic Zebrafish.

Lipid nanoparticles (LNPs) are an attractive platform for the delivery of therapeutic RNA molecules because LNPs are versatile, have been validated in clinical trials, and are well tolerated. Here, we test whether LNPs can be used to deliver a reporter green fluorescent protein (gfp) mRNA to different tissues in zebrafish embryos. We show that LNP-packaged gfp mRNA can be delivered, through injection, and taken up by cells in multiple tissues in zebrafish embryos without any apparent detrimental effects on embryonic health or survival.