Designing a visible light-mediated double photoswitch: a combination of biradical and azobenzene structural motifs that can be switched independently.

A new molecular switch is presented that combines both biradical and azobenzene motifs to perform visible light-induced constitutional and stereo-isomerisation within the same molecule. The insertion of isonitrile-functionalised azobenzenes into the four-membered biradical [˙P(μ-NTer)P˙] (1), yielding a phosphorus-centred cyclopentane-1,3-diyl (-4B and -5B), represents a straightforward method to generate the desired double switches (-4B and -5B) in excellent yields (>90%). The switching properties are demonstrated for the fluorinated species -5B and, interestingly, can occur either stepwise or simultaneously, depending on the order in which the sample is irradiated with red and/or green light.

Differential functionality of fluoropyrimidine nucleosides for safe cancer therapy.

Chemotherapies are standard care for most cancer types. Pyrimidine analogs including 5-fluorouracil, cytosine arabinoside, 5-azacytidine, and gemcitabine are effective drugs that are utilized as part of a number of anticancer regimens. However, their lack of cell-specificity results in severe side effects.

Daily Eicosapentaenoic Acid Infusion in IUGR Fetal Lambs Reduced Systemic Inflammation, Increased Muscle ADRβ2 Content, and Improved Myoblast Function and Muscle Growth.

Intrauterine growth-restricted (IUGR) fetuses exhibit systemic inflammation that contributes to programmed deficits in myoblast function and muscle growth. Thus, we sought to determine if targeting fetal inflammation improves muscle growth outcomes. Heat stress-induced IUGR fetal lambs were infused with eicosapentaenoic acid (IUGR+EPA; = 9) or saline (IUGR; = 8) for 5 days during late gestation and compared to saline-infused controls ( = 11).

CARD8: A Novel Inflammasome Sensor with Well-Known Anti-Inflammatory and Anti-Apoptotic Activity.

Inflammasomes comprise a group of protein complexes with fundamental roles in the induction of inflammation. Upon sensing stress factors, their assembly induces the activation and release of the pro-inflammatory cytokines interleukin (IL)-1β and -18 and a lytic type of cell death, termed pyroptosis. Recently, CARD8 has joined the group of inflammasome sensors.

Required knowledge for guideline panel members to develop healthcare related testing recommendations: a developmental study.

Objectives: To define the minimum knowledge required for guideline panel members (healthcare professionals and consumers) involved in developing recommendations about healthcare related testing.

Study Design And Setting: A developmental study with a multistaged approach. We derived a first set of knowledge components from literature and subsequently performed semistructured interviews with 9 experts.

Daily Injection of the β2 Adrenergic Agonist Clenbuterol Improved Muscle Glucose Metabolism, Glucose-Stimulated Insulin Secretion, and Hyperlipidemia in Juvenile Lambs Following Heat-Stress-Induced Intrauterine Growth Restriction.

Stress-induced fetal programming diminishes β2 adrenergic tone, which coincides with intrauterine growth restriction () and lifelong metabolic dysfunction. We determined if stimulating β2 adrenergic activity in IUGR-born lambs would improve metabolic outcomes. IUGR lambs that received daily injections of saline or the β2 agonist clenbuterol from birth to 60 days were compared with controls from pair-fed thermoneutral pregnancies.

Phosphaarsenes - Combining Phospha- and Arsa-Wittig-Reagents.

Dipnictenes of the type RPn=PnR (Pn=P, As, Sb, Bi) can be viewed as dimers of the corresponding pnictinidenes R-Pn. Phosphanylidene- and arsanylidenephosphoranes (R-Pn(PMe); Pn=P, As) have been shown to be versatile synthetic surrogates for the delivery of pnictinidene fragments. We now report that thermal treatment of 1 : 1 mixtures of R-P(PMe) and R'-As(PMe) gives access to arsaphosphenes of the type RP=AsR'.

Efficient Generation of CRISPR/Cas9-Mediated Knockout Human Primary Keratinocytes by Electroporation.

Due to their full differentiation capacity in vitro, the culture of human primary keratinocytes (HPKs) represents a physiological model for answering basic biological and dermatological research questions, including those related to skin diseases and the investigation of treatment options. When modified with the CRISPR/Cas9 gene editing approach and cultivated in organotypic 3D epidermal equivalents (EEs), these human cells have the potential to replace established mouse models. However, even when cultivated on feeder cells, HPKs have only a low proliferation capacity in 2D culture, limiting their application potential.

Consumer objective and subjective knowledge about healthy foods: An approach to promote healthy lifestyle choices in South Africa.

Unhealthy food choices and consumption, coupled with sedentary lifestyles among consumers, intensify public health concerns regarding the quadruple disease burden, despite Primary Health Care (PHC) policy. However, the current relationship between consumer knowledge about healthy foods and following a healthy lifestyle needs to be explored. Our study, therefore, aimed to determine the association between consumers' subjective and objective knowledge about healthy foods and various healthy lifestyle choices.

The mitochondrial DNA common deletion as a potential biomarker of cancer-associated fibroblasts from skin basal and squamous cell carcinomas.

Cancer-associated fibroblasts (CAFs) are components of the tumor microenvironment and represent appealing therapeutic targets for translational studies. Conventional protein-based biomarkers for CAFs have been reported to be limited in their specificity, rendering difficult the identification of CAFs from normal fibroblasts (NFs) in clinical samples and dampening the development of CAF-targeted therapies to treat cancer. In this study, we propose the mitochondrial RNA and the mitochondrial DNA (mtDNA) common deletion (CD) as novel indicators of CAF identity.

The gasdermins: a pore-forming protein family expressed in the epidermis.

Gasdermins comprise a family of pore-forming proteins, which play critical roles in (auto)inflammatory diseases and cancer. They are expressed as self-inhibited precursor proteins consisting of an aminoterminal cytotoxic effector domain (NT-GSDM) and a carboxyterminal inhibitor domain (GSDM-CT) separated by an unstructured linker region. Proteolytic processing in the linker region liberates NT-GSDM, which translocates to membranes, forms oligomers, and induces membrane permeabilization, which can disturb the cellular equilibrium that can lead to cell death.

Daily injection of the β2 adrenergic agonist clenbuterol improved poor muscle growth and body composition in lambs following heat stress-induced intrauterine growth restriction.

Intrauterine growth restriction () is associated with reduced β2 adrenergic sensitivity, which contributes to poor postnatal muscle growth. The objective of this study was to determine if stimulating β2 adrenergic activity postnatal would rescue deficits in muscle growth, body composition, and indicators of metabolic homeostasis in IUGR offspring. Time-mated ewes were housed at 40°C from day 40 to 95 of gestation to produce IUGR lambs.

["And zebras do exist after all"! : Pulmonary nocardiosis: case series and overview].

Nocardiosis is a rare disease that occurs primarily in patients with predisposing factors (immunosuppression/chronic lung disease). It is caused by aerobic, Gram-positive bacteria that are ubiquitous in soil. Cutaneous and pulmonary manifestations are most common, but disseminated forms also occur.

Human epidermis organotypic cultures, a reproducible system recapitulating the epidermis in vitro.

The translatability of research is highly dependent on models that recapitulate human tissues and organs. Here, we describe a procedure for the generation of human epidermis organotypic cultures (HEOCs) from primary keratinocytes isolated from foreskin and adult skin as well as from an immortalized keratinocyte cell line (KerTr). We tested several media conditions to develop a defined HEOC growing and expansion media.

Immunophenotyping of Monocyte Migration Markers and Therapeutic Effects of Selenium on IL-6 and IL-1β Cytokine Axes of Blood Mononuclear Cells in Preoperative and Postoperative Coronary Artery Disease Patients.

Multivessel coronary artery disease (CAD) is characterized by underlying chronic vascular inflammation and occlusion in the coronary arteries, where these patients undergo coronary artery bypass grafting (CABG). Since post-cardiotomy inflammation is a well known phenomenon after CABG, attenuation of this inflammation is required to reduce perioperative morbidity and mortality. In this study, we aimed to phenotype circulating frequencies and intensities of monocyte subsets and monocyte migration markers, respectively, and to investigate the plasma level of inflammatory cytokines and chemokines between preoperative and postoperative CAD patients and later, to intervene the inflammation with sodium selenite.

Listening to What Matters Most: Consumer Endorsed Patient Reported Outcome Measures (PROMs) for Use in Multiple Myeloma Clinical Trials: A Descriptive Exploratory Study.

Background: Patients with multiple myeloma (MM) experience some of the highest levels of symptom burden of all hematological malignancies. Therefore, assessment of quality of life (QoL) is critical for the delivery of patient-centered cancer care. Patient reported outcome measures (PROMs) are commonly used to measure QoL in people with MM.

Thrombophilia and outcomes of venous thromboembolism in older patients.

Background: Limited data exist on thrombophilic risk factors and clinical outcomes in the elderly with venous thromboembolism (VTE).

Objectives: To describe the prevalence of laboratory thrombophilic risk factors and their association with VTE recurrence or death in a cohort of elderly people with VTE.

Methods: In 240 patients aged ≥65 years with acute VTE without active cancer or an indication for extended anticoagulation, we performed laboratory thrombophilia testing 1 year after the index VTE.

On the Reactivity of Mes*P(PMe ) towards Aluminum(I) Compounds - Evidence for the Intermediate Formation of Phosphaalumenes.

Phosphaalumenes are the heavier isoelectronic analogs of alkynes and have eluded facile synthesis until recently. We have reported that the combination of a phosphinidene transfer agent, TerP(PMe ) ( Ter=2,6-Ar -C H ), with (Cp*Al) (Cp*=C (CH ) ) afforded the phosphaalumenes TerPAlCp* as isolable, violet, thermally stable compounds. In here we describe attempts to utilize Mes*P(PMe ) (Mes*=2,4,6-tBu -C H ) as a phosphinidene source in combination with different Al(I) precursors, namely NacnacAl ( Nacnac=HC[C(Me)NDip] , Dip=2,6-iPr -C H ), (Cp*Al) and Cp Al (Cp =1,2,4-tBu -C H ).

High p62 expression suppresses the NLRP1 inflammasome and increases stress resistance in cutaneous SCC cells.

NLRP1 is the primary inflammasome sensor in human keratinocytes. Sensing of UVB radiation by NLRP1 is believed to underlie the induction of sunburn. Although constitutive NLRP1 activation causes skin inflammation and predisposes patients to the development of cutaneous SCCs, the NLRP1 pathway is suppressed in established SCCs.

NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development.

Protein complexes termed inflammasomes ensure tissue protection from pathogenic and sterile stressors by induction of inflammation. This is mediated by different caspase-1-induced downstream pathways, including activation of the pro-inflammatory cytokines proIL-1β and -18, induction of a lytic type of cell death, and regulation of the release of other pro-inflammatory molecules. Aberrant inflammasome activation underlies the pathology of numerous (auto)inflammatory diseases.

Quantitative Proteomics Identifies Reduced NRF2 Activity and Mitochondrial Dysfunction in Atopic Dermatitis.

Atopic dermatitis is the most common inflammatory skin disease and is characterized by a deficient epidermal barrier and cutaneous inflammation. Genetic studies suggest a key role of keratinocytes in atopic dermatitis pathogenesis, but the alterations in the proteome that occur in the full epidermis have not been defined. Using a pressure-cycling technology and data-independent acquisition approach, we performed quantitative proteomics of epidermis from healthy volunteers and lesional and nonlesional patient skin.

GRADE guidance 35: update on rating imprecision for assessing contextualized certainty of evidence and making decisions.

Objectives: Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance to rate the certainty domain of imprecision is presently not fully operationalized for rating down by two levels and when different baseline risk or uncertainty in these risks are considered. In addition, there are scenarios in which lowering the certainty of evidence by three levels for imprecision is more appropriate than lowering it by two levels. In this article, we conceptualize and operationalize rating down for imprecision by one, two and three levels for imprecision using the contextualized GRADE approaches and making decisions.

NLRP1 Inflammasome Activation in Keratinocytes: Increasing Evidence of Important Roles in Inflammatory Skin Diseases and Immunity.

In 2007, it was shown that DNA sequence variants of the human NLRP1 gene are associated with autoimmune and autoinflammatory diseases affecting mainly the skin. However, at that time, the underlying cellular and molecular mechanisms were poorly characterized. Meanwhile, increasing evidence suggests that the NLRP1 inflammasome expressed by keratinocytes not only plays a part in the pathology of common inflammatory skin diseases and cancer development but also contributes to skin immunity.

Synthesis of Bicyclic P,S-Heterocycles via the Addition of Thioketones to a Phosphorus-Centered Open-Shell Singlet Biradical.

Formal addition reactions between the open-shell singlet biradical [P(μ-NTer)] () and xanthione, thioxanthione, as well as ferrocenyl naphthyl thioketone were studied in detail. Reactions were performed at room temperature and led to the formation of strained [2.1.