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In M2-like MAMs, we observed enhanced IKZF1 levels that vanished through treatment with lenalidomide, yielding MAMs with a bioenergetic profile, T-cell stimulatory properties, and loss of tumor-promoting capabilities that resemble M1 cells. We also provide evidence that IMiDs interfere epigenetically, via degradation of IKZF1, with IFN regulatory factors 4 and 5, which in turn alters the balance of M1/M2 polarization. We validated our observations in vivo using the CrbnI391V mouse model that recapitulates the IMiD-triggered IKZF1 degradation. These data show a role for IKZF1 in macrophage polarization and can provide explanations for the clinical benefits observed when combining IMiDs with therapeutic antibodies.See related Spotlight on p. 254.Amino acid analysis or metabonomics requires large-scale sample collection, which makes sample storage a critical consideration. However, functional amino acids are often neglected in metabolite stability studies because of the difficulty in detecting and accurately quantifying them with most analysis methods. Here, we investigated the stability of amino acids and related amines in human serum following different preprocessing and pre-storage procedures. Serum samples were collected and subjected to three storage conditions; cold storage (4°C), room temperature storage (22°C), and freezing (-80°C). The concentration of amino acids and related amines were quantified using iTRAQ®-LC-MS/MS with isobaric tagging reagents. Approximately 54.84%, 58.06%, and 48.39% of detectable and target analytes were altered at the 4°C condition, 22°C condition, and when subjected to freeze-thaw cycles, respectively. Some amino acids which are unstable and relatively stable were found. Our study provides detailed amino acid profiles in human serum and suggests pre-treatment measures that could be taken to improve stability.Caudal autotomy in rodents is an evolutionarily acquired phenomenon enabling escape from predators, by discarding the tail skin after traumatic injuries. The histological mechanisms underlying caudal autotomy seem to differ among species. Cotton rats (Sigmodon hispidus), which are important laboratory rodents for human infectious diseases, possess a fragile tail. In this study, we compared the tail histology of cotton rats with that of laboratory rats (Rattus norvegicus), which have no fragility on their tail, to elucidate the process of rodent caudal autotomy. First, the cotton rats developed a false autotomy characterized by loss of the tail sheath with the caudal vertebrae remaining without tail regeneration. read more Second, we found the fracture plane was continuous from the interscale of the tail epidermis to the dermis, which was lined with an alignment of E-cadherin+ cells. Third, we found an obvious cleavage plane between the dermis and subjacent tissues of the cotton-rat tail, where the subcutis was composed of looser, finer, and fragmented collagen fibers compared with those of the rat. Additionally, the cotton-rat tail was easily torn, with minimum bleeding. The median coccygeal artery of the cotton rat had a thick smooth muscle layer, and its lumen was filled with the peeled intima with fibrin coagulation, which might be associated with reduced bleeding following caudal autotomy. Taken together, we reveal the unique histological features of the tail relating to the caudal autotomy process in the cotton rat, and provide novel insights to help clarify the rodent caudal autotomy mechanism.The blastula Chordin- and Noggin-expressing (BCNE) center comprises animal-dorsal and marginal-dorsal cells of the amphibian blastula and contains the precursors of the brain and the gastrula organizer. Previous findings suggested that the BCNE behaves as a homogeneous cell population that only depends on nuclear β-catenin activity but does not require Nodal and later segregates into its descendants during gastrulation. In contrast to previous findings, in this work, we show that the BCNE does not behave as a homogeneous cell population in response to Nodal antagonists. In fact, we found that chordin.1 expression in a marginal subpopulation of notochordal precursors indeed requires Nodal input. We also establish that an animal BCNE subpopulation of cells that express both, chordin.1 and sox2 (a marker of pluripotent neuroectodermal cells), and gives rise to most of the brain, persisted at blastula stage after blocking Nodal. Therefore, Nodal signaling is required to define a population of chordin.1+ cells and to restrict the recruitment of brain precursors within the BCNE as early as at blastula stage. We discuss our findings in Xenopus in comparison to other vertebrate models, uncovering similitudes in early brain induction and delimitation through Nodal signaling.Cells respond to mechanical cues from their environment through a process of mechanosensing and mechanotransduction. Cell stretching devices are important tools to study the molecular pathways responsible for cellular responses to mechanobiological processes. We describe the development and testing of a uniaxial cell stretcher that has applications for microscopic as well as biochemical analyses. By combining simple fabrication techniques with adjustable control parameters, the stretcher is designed to fit a variety of experimental needs. The stretcher can be used for static and cyclic stretching. As a proof of principle, we visualize stretch induced deformation of cell nuclei via incremental static stretch, and changes in IEX1 expression via cyclic stretching. This stretcher is easily modified to meet experimental needs, inexpensive to build, and should be readily accessible for most laboratories with access to 3D printing.

Exposure to cleaning and disinfection products has been associated with respiratory disorders such as asthma in cleaning and healthcare workers. Safety data sheets (SDSs) provide information on hazardous chemicals that are present in products to help users with risk assessment and implement appropriate control measures. However, they have potential limitations in identifying respiratory hazards due to a lack of regulatory test methods for respiratory sensitisation and irritation of chemicals.

SDSs were first used to identify chemicals on the database as respiratory sensitisers and irritants. A quantitative structure-activity relationship (QSAR) model and an asthmagen list established by the Association of Occupational and Environmental Clinics (AOEC) were used to identify potential respiratory sensitisers and irritants (by the AOEC list only) in the cleaning and disinfection products.

From a total of 459 cleaning and disinfection products used in healthcare organisations across England and Wales, 35 respiratory sensitisers not labelled as such on the SDS were identified by QSAR or AOEC. Only 2% of cleaning and disinfection products contained at least one respiratory sensitiser as identified by their SDSs; this was increased to 37.7% of products when the QSAR or the AOEC list was used.

A significantly higher proportion of cleaning products contain respiratory hazardous chemicals, particularly respiratory sensitisers than would be expected from the information provided by SDSs alone. Cleaners and healthcare workers may, therefore, be insufficiently protected.

A significantly higher proportion of cleaning products contain respiratory hazardous chemicals, particularly respiratory sensitisers than would be expected from the information provided by SDSs alone. Cleaners and healthcare workers may, therefore, be insufficiently protected.Obesity represents one of the most significant public health challenges worldwide. Current clinical practice relies on body mass index (BMI) to define the obesity status of an individual, even though the index has long been recognized for its limitations as a measure of body fat. In normal BMI individuals, increased central adiposity has been associated with worse health outcomes, including increased risks of cardiovascular disease and metabolic disorders. The condition leading to these outcomes has been described as metabolic obesity in the normal weight (MONW). More recent evidence suggests that MONW is associated with increased risk of several obesity-related malignancies, including postmenopausal breast, endometrial, colorectal, and liver cancers. In MONW patients, the false reassurance of a normal range BMI can lead to lost opportunities for implementing preventive interventions that may benefit a substantial number of people. A growing body of literature has documented the increased risk profile of MONW individuals and demonstrated practical uses for body composition and biochemical analyses to identify this at-risk population. In this review, we survey the current literature on MONW and cancer, summarize pathophysiology and oncogenic mechanisms, highlight potential strategies for diagnosis and treatment, and suggest directions for future research.

To investigate whether antibiotic exposure during pregnancy was associated with childhood asthma and if this relationship was conditional on timing of exposure and mode of delivery.

A cohort study using multivariable logistic regression models adjusting for a priori defined confounders. Pregnant women were recruited from 1996 to 2002.

The Danish National Birth Cohort.

Of the 96 832 children in the cohort, 32 651 children were included in the study population.

Parent-reported childhood asthma at 11 years.

A total of 5522 (17%) children were born to mothers exposed to antibiotics during pregnancy. In adjusted analyses, children born to exposed mothers had higher odds of asthma (OR 1.14, 95% CI 1.05 to 1.24). There was no association with antibiotic exposure in the first trimester (OR 1.02, 95% CI 0.83 to 1.26), but higher odds were observed for antibiotic exposure in the second to third trimester (OR 1.17, 95% CI 1.06 to 1.28), compared with unexposed children. The overall association between antibiotics during pregnancy and childhood asthma was only observed in vaginally born children (OR 1.17, 95% CI 1.07 to 1.28) but not in caesarean section born children (planned caesarean section OR 0.95, 95% CI 0.66 to 1.37; caesarean emergency OR 0.96, 95% CI 0.73 to 1.28). In exposed vaginally born children, the odds for childhood asthma requiring treatment during the preceding year were 34% higher (OR 1.34, 95% CI 1.21 to 1.49), compared with unexposed vaginally born children.

Antibiotic exposure in mid-to-late pregnancy is associated with higher odds of childhood asthma in vaginally born children. Mode of delivery may modify the association.

Antibiotic exposure in mid-to-late pregnancy is associated with higher odds of childhood asthma in vaginally born children. Mode of delivery may modify the association.The dorsal cochlear nucleus (DCN) is a region of particular interest for auditory and tinnitus research. However, lack of useful genetic markers for in vivo manipulations hinders elucidation of the DCN contribution to tinnitus pathophysiology. This work assesses whether adeno-associated viral vectors (AAV) containing the calcium/calmodulin-dependent protein kinase 2α (CaMKIIα) promoter and a mouse line of nicotinic acetylcholine receptor α2 subunit (Chrna2)-Cre can target specific DCN populations. We found that CaMKIIα cannot be used to target excitatory fusiform DCN neurons as labeled cells showed diverse morphology indicating they belong to different classes of DCN neurons. Light stimulation after driving Channelrhodopsin2 (ChR2) by the CaMKIIα promoter generated spikes in some units but firing rate decreased when light stimulation coincided with sound. Expression and activation of CaMKIIα-eArchaerhodopsin3.0 in the DCN produced inhibition in some units but sound-driven spikes were delayed by concomitant light stimulation.