Unmarried women face a significantly lower average federal income tax rate than unmarried men, 6.3% versus 10.9%. Some of the difference arises because women have lower income on average and the tax ...system is progressive. Using a non-parametric decomposition analysis, we show that tax progressivity accounts for less than 60% of the gender tax rate difference, leaving the rest being explained by gender differences within income classes. This conclusion remains when the decomposition exercise uses an equivalence-scale-adjusted income and considers gender differences in nontaxable income and time use. Regression results reveal that much of the gender tax difference arises because unmarried women are more likely to live with dependents, making them more likely to claim child-related tax benefits relative to unmarried men. Our findings indicate that the current tax system places a high value of raising children beyond the consideration of the families’ larger consumption needs. Because our analysis does not consider the higher risk of economic insecurity facing single parents and the various externalities generated by women’s higher commitment to childcare, future research should focus on determining whether these additional considerations could justify the extent of the gender tax differential.
The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of ...unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities.
•Most mouse Cre driver lines tested exhibited variable rates of germline recombination•Germline recombination exhibits parental sex bias and target locus selectivity•Similar principles apply to multiple organisms and recombinase systems•Guidelines are provided for detecting and minimizing unwanted germline recombination
Luo et al. report variable rates of germline recombination in commonly used mouse Cre driver lines, influenced by sex of Cre-carrying parents and target loci. Guidelines are provided to optimize cell-type-specific recombination in genetically targeted organisms expressing site-specific recombinases.
An understanding of how heterozygous loss-of-function mutations in autism spectrum disorder (ASD) risk genes, such as TBR1, contribute to ASD remains elusive. Conditional Tbr1 deletion during late ...mouse gestation in cortical layer 6 neurons (Tbr1layer6 mutants) provides novel insights into its function, including dendritic patterning, synaptogenesis, and cell-intrinsic physiology. These phenotypes occur in heterozygotes, providing insights into mechanisms that may underlie ASD pathophysiology. Restoring expression of Wnt7b largely rescues the synaptic deficit in Tbr1layer6 mutant neurons. Furthermore, Tbr1layer6 heterozygotes have increased anxiety-like behavior, a phenotype seen ASD. Integrating TBR1 chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data from layer 6 neurons and activity of TBR1-bound candidate enhancers provides evidence for how TBR1 regulates layer 6 properties. Moreover, several putative TBR1 targets are ASD risk genes, placing TBR1 in a central position both for ASD risk and for regulating transcriptional circuits that control multiple steps in layer 6 development essential for the assembly of neural circuits.
•Tbr1 specifies layer 6 dendritic patterning and cell-intrinsic physiology•Tbr1 promotes synapse numbers through Wnt7b•Tbr1 heterozygotes provide insight into ASD pathophysiology•TBR1 directly regulates transcriptional circuits that controls ASD risk genes
TBR1 directly regulates transcriptional circuits in heterozygous mutant mice that specify layer 6 identity and synapse number. As TBR1 is an ASD risk gene, our results provide insights into mechanisms that underlie ASD pathophysiology.
Blockade of the programmed death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that ...gastric and gastroesophageal junction (GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability (MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatment-refractory solid tumors with MSI status and the third-line or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.
Chimeric RNAs and their encoded proteins have been traditionally viewed as unique features of neoplasia, and have been used as biomarkers and therapeutic targets for multiple cancers. Recent studies ...have demonstrated that chimeric RNAs also exist in non-cancerous cells and tissues, although large-scale, genome-wide studies of chimeric RNAs in non-diseased tissues have been scarce. Here, we explored the landscape of chimeric RNAs in 9495 non-diseased human tissue samples of 53 different tissues from the GTEx project. Further, we established means for classifying chimeric RNAs, and observed enrichment for particular classifications as more stringent filters are applied. We experimentally validated a subset of chimeric RNAs from each classification and demonstrated functional relevance of two chimeric RNAs in non-cancerous cells. Importantly, our list of chimeric RNAs in non-diseased tissues overlaps with some entries in several cancer fusion databases, raising concerns for some annotations. The data from this study provides a large repository of chimeric RNAs present in non-diseased tissues, which can be used as a control dataset to facilitate the identification of true cancer-specific chimeras.
The TNF-α pathway plays as a double-edged sword that simultaneously regulates cell apoptosis and proliferation. The dysregulated TNF-α signaling can trigger cytokine storms that lead to profound cell ...death during the phase of acute tissue injury. On the other hand, an optimal level of TNF-α signaling is required for tissue repair following the acute injury phase. The TNF-α pathway is commonly upregulated in acute lung injury (ALI) and acute liver failure (ALF). Previous studies investigated the feasibility of adopting protein-based TNF-α blockers as disease modifiers in ALI and ALF, but none of these came out with a positive result. One of the potential reasons that resides behind the failure of the trials might be the long half-life of these inhibitors that led to undesired side effects. Developing alternative TNF-α blockers with manageable half-lives remain an unmet need in this regard.
In the current study, we developed a novel TNF-α-targeting aptamer (aptTNF-α) and its PEG-derivate (aptTNF-α-PEG) with antagonistic functions. We investigated the
antagonistic effects using mouse ALI and ALF models.
Our data showed that aptTNF-α possessed good
binding affinity towards human/mouse TNF-α and successfully targeted TNF-α
. In the mouse ALI model, aptTNF-α/aptTNF-α-PEG treatment attenuated the severity of LPS-induced ALI, as indicated by the improvement of oxygen saturation and lung injury scores, the reduction of protein-rich fluid leakage and neutrophil infiltration in the alveolar spaces, and the suppression of pro-inflammatory cytokines/chemokines expressions in the lung tissues. In the mouse ALF model, we further showed that aptTNF-α/aptTNF-α-PEG treatment not only attenuated the degree of hepatocyte damage upon acute injury but also potentiated early regeneration of the liver tissues.
The results implicated potential roles of aptTNF-α/aptTNF-α-PEG in ALI and ALF. The data also suggested their translational potential as a new category of TNF-α blocking agent.
Background
Nasal air conditioning (ie, heating and humidification of inspired air) is an important function of the nasal cavity. This function may be reduced in cases of aggressive nasal surgery. ...Future virtual surgery planning tools may be used to design surgical approaches that preserve the nasal air conditioning capacity while decreasing airflow resistance. However, it is unclear whether there is a threshold below which impaired nasal air conditioning is associated with negative health consequences.
Objective
This study aims to review the literature on the clinical impact of reduced nasal air conditioning and its implications for nasal surgery outcomes.
Methods
A literature search was performed on PubMed and Scopus databases for articles that investigated the effect of air temperature and humidity on mucociliary clearance, respiratory epithelial structure, and the prevalence and severity of respiratory diseases.
Results
Inspiration of cold, dry air has direct effects on the respiratory epithelium, such as reduced mucociliary clearance and loss of cilia. Nasal surgeries do inflict some changes to the nasal mucosa and geometry that may result in decreased heating and humidification, but it is unclear how long these effects last. Laryngectomy patients serve as a human model for the absence of nasal air conditioning. The heat and moisture exchangers that many laryngectomy patients wear have been shown to improve lung function and reduce pulmonary symptoms associated with breathing unconditioned air, such as increased coughing and thickened mucus.
Conclusion
Nasal air conditioning is an important mechanism to maintain mucociliary clearance and prevent infection by inhaled pathogens. Preservation of nasal air conditioning capacity should be considered in the implementation of future virtual surgery planning tools. However, a threshold for the onset of negative health consequences due to impaired nasal air conditioning is not yet available.
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