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Genome-wide association studies have yielded thousands of associations for many common diseases and disease-related complex traits. The identified associations made it possible to ...identify the causal risk factors underlying diseases and investigate the causal relationships among complex traits through Mendelian randomization. Mendelian randomization is a form of instrumental variable analysis that uses SNP associations from genome-wide association studies as instruments to study and uncover causal relationships between complex traits. By leveraging SNP genotypes as instrumental variables, or proxies, for the exposure complex trait, investigators can tease out causal effects from observational data, provided that necessary assumptions are satisfied. We discuss below the development of Mendelian randomization methods in parallel with the growth of genome-wide association studies. We argue that the recent availability of GWAS summary statistics for diverse complex traits has motivated new Mendelian randomization methods with relaxed causality assumptions and that this area continues to offer opportunities for robust biological discoveries.
Troposphere mapping functions are used in the analyses of Global Positioning System and Very Long Baseline Interferometry observations to map a priori zenith hydrostatic and wet delays to any ...elevation angle. Most analysts use the Niell Mapping Function (NMF) whose coefficients are determined from site coordinates and the day of year. Here we present the Global Mapping Function (GMF), based on data from the global ECMWF numerical weather model. The coefficients of the GMF were obtained from an expansion of the Vienna Mapping Function (VMF1) parameters into spherical harmonics on a global grid. Similar to NMF, the values of the coefficients require only the station coordinates and the day of year as input parameters. Compared to the 6‐hourly values of the VMF1 a slight degradation in short‐term precision occurs using the empirical GMF. However, the regional height biases and annual errors of NMF are significantly reduced with GMF.
Tens of millions of dried seahorses (genus Hippocampus) are traded annually, and the pressure from this trade along with their life history traits (involved parental care and small migration ...distances and home ranges) has led to near global population declines. This and other forms of overexploitation have led to all seahorse species being listed in Appendix II under the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). The signatory nations of CITES recommended a 10-cm size limit of seahorses to ensure harvested individuals have reached reproductive maturity, and have thus had the chance to produce offspring, to maintain a more sustainable global seahorse fishery. We assessed adherence to CITES recommendations using DNA barcoding and size measurements to compare two prominent U.S. dried seahorse markets: (1) traditional Chinese medicine (TCM), and (2) non-medicinal ecommerce and coastal curio (ECC). We also estimated U.S. import abundance from CITES records. Of the nine species identified among all samples (n = 532), eight were found in the TCM trade (n = 168); composed mostly (75%) of the Indo-Pacific species Hippocampus trimaculatus, and Hippocampus spinosissimus, and the Latin American Hippocampus ingens. In contrast, ECC samples (n = 344) included 5 species, primarily juvenile Indo-Pacific Hippocampus kuda (51.5%) and the western Atlantic Hippocampus zosterae (40.7). The majority of TCM samples (85.7%) met the CITES size recommendation, in contrast to 4.8% of ECC samples. These results suggest non-size discriminatory bycatch is the most likely source of imported ECC specimens. In addition, CITES records indicate that approximately 602,275 dried specimens were imported into the U.S. from 2004-2020, but the exact species composition remains unknown as many U.S. imports records list one species or Hippocampus spp. from confiscated shipments due to difficulties in morphological identification and large numbers of individuals per shipment. Molecular identification was used to identify the species composition of confiscated shipment imports containing undesignated species, and similar to TCM, found H. trimaculatus and H. spinosissimus the most abundant. By combining DNA barcoding, size comparisons, and CITES database records, these results provide an important glimpse into the two primary dried U.S. seahorse end-markets, and may further inform the conservation status of several Hippocampus species.
Understanding population structure and areas of demographic persistence and transients is critical for effective species management. However, direct observational evidence to address the geographic ...scale and delineation of ephemeral or persistent populations for many marine fishes is limited. The Lined seahorse (Hippocampus erectus) can be commonly found in three western Atlantic zoogeographic provinces, though inhabitants of the temperate northern Virginia Province are often considered tropical vagrants that only arrive during warm seasons from the southern provinces and perish as temperatures decline. Although genetics can locate regions of historical population persistence and isolation, previous evidence of Virginia Province persistence is only provisional due to limited genetic sampling (i.e., mitochondrial DNA and five nuclear loci). To test alternative hypotheses of historical persistence versus the ephemerality of a northern Virginia Province population we used a RADseq generated dataset consisting of 11,708 single nucleotide polymorphisms (SNP) sampled from individuals collected from the eastern Gulf of Mexico to Long Island, NY. Concordant results from genomic analyses all infer three genetically divergent subpopulations, and strongly support Virginia Province inhabitants as a genetically diverged and a historically persistent ancestral gene pool. These results suggest that individuals that emerge in coastal areas during the warm season can be considered "local" and supports offshore migration during the colder months. This research demonstrates how a large number of genes sampled across a geographical range can capture the diversity of coalescent histories (across loci) while inferring population history. Moreover, these results clearly demonstrate the utility of population genomic data to infer peripheral subpopulation persistence in difficult-to-observe species.
Abstract
STUDY QUESTION
What knowledge, attitudes and intentions do US obstetrics and gynecology (OB/GYN) residents have toward discussing age-related fertility decline and oocyte cryopreservation ...with their patients?
SUMMARY ANSWER
Most OB/GYN residents believe that age-related fertility decline, but not oocyte cryopreservation, should be discussed during well-woman annual exams; furthermore, nearly half of residents overestimated the age at which female fertility markedly declines.
WHAT IS KNOWN ALREADY
Oocyte cryopreservation can be utilized to preserve fertility potential. Currently, no studies of US OB/GYN residents exist that question their knowledge, attitudes, and intentions toward discussing age-related fertility decline and oocyte cryopreservation with patients.
STUDY DESIGN, SIZE, DURATION
A cross-sectional online survey was conducted during the fall of 2014 among residents in American Council for Graduate (ACOG) Medical Education-approved OB/GYN residency programs. Program directors were emailed via the ACOG Council on Resident Education in Obstetrics and Gynecology server listing and asked to solicit resident participation.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Participants included 238 residents evenly distributed between post-graduate years 1–4 with varied post-residency plans; 90% of residents were women and 75% were 26–30 years old. The survey was divided into three sections: demographics, fertility awareness, and attitudes toward discussing fertility preservation options with patients. Descriptive and inferential statistics were conducted.
MAIN RESULTS AND THE ROLE OF CHANCE
A strong majority of residents (83%) believed an OB/GYN should initiate discussions about age-related fertility decline with patients (mean patient age 31.8), and 73% percent believed these discussions should be part of an annual exam. One third of residents overestimated the age at which there is a slight decline in female fertility, while nearly half of residents overestimated the age at which female fertility markedly declines. Over three-quarters of residents (78.4%) also overestimated the likelihood of success using assisted reproductive treatments (ARTs). Residents were likely to support oocyte cryopreservation in cancer patients irrespective of the woman's age, but much less likely to support elective oocyte cryopreservation. For elective oocyte cryopreservation, 40% believed OB/GYNs should initiate discussions with patients (mean age 31.1), while only 20% believed this topic should be part of an annual exam.
LIMITATIONS, REASONS FOR CAUTION
Because the study invitation was sent through US OB/GYN residency program directors rather than directly to residents, it is possible that some residents did not receive the invitation to participate. This limits the generalizability of the findings.
WIDER IMPLICATIONS OF THE FINDINGS
Within the USA, there appears to be a critical need for improved education on fertility decline in OB/GYN residency programs. To promote informed reproductive decision-making among patients, efforts should be made to help OB/GYNs provide comprehensive fertility education to all women, while also respecting patient choices.
STUDY FUNDING/COMPETING INTEREST(S)
None.
During mitosis, duplicated sister chromatids attach to microtubules emanating from opposing sides of the bipolar spindle through large protein complexes called kinetochores. In the absence of stable ...kinetochore-microtubule attachments, a cell surveillance mechanism known as the spindle assembly checkpoint (SAC) produces an inhibitory signal that prevents anaphase onset. Precisely how the inhibitory SAC signal is extinguished in response to microtubule attachment remains unresolved. To address this, we induced formation of hyper-stable kinetochore-microtubule attachments in human cells using a non-phosphorylatable version of the protein Hec1, a core component of the attachment machinery. We find that stable attachments are sufficient to silence the SAC in the absence of sister kinetochore bi-orientation and strikingly in the absence of detectable microtubule pulling forces or tension. Furthermore, we find that SAC satisfaction occurs despite the absence of large changes in intra-kinetochore distance, suggesting that substantial kinetochore stretching is not required for quenching the SAC signal.
The empirical model GPT (Global Pressure and Temperature), which is based on spherical harmonics up to degree and order nine, provides pressure and temperature at any site in the vicinity of the ...Earth’s surface. It can be used for geodetic applications such as the determination of a priori hydrostatic zenith delays, reference pressure values for atmospheric loading, or thermal deformation of Very Long Baseline Interferometry (VLBI) radio telescopes. Input parameters of GPT are the station coordinates and the day of the year, thus also allowing one to model the annual variations of the parameters. As an improvement compared with previous models, it reproduces the large pressure anomaly over Antarctica, which can cause station height errors in the analysis of space-geodetic data of up to 1 cm if not considered properly in troposphere modelling. First tests at selected geodetic observing stations show that the pressure biases considerably decrease when using GPT instead of the very simple approaches applied to various Global Navigation Satellite Systems (GNSS) software packages so far. GPT also provides an appropriate model for the annual variability of global temperature.
The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota ...composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.
The dwarf seahorse (Hippocampus zosterae) is widely distributed throughout near-shore habitats of the Gulf of Mexico and is of commercial significance in Florida, where it is harvested for the ...aquarium and curio trades. Despite its regional importance, the genetic structure of dwarf seahorse populations remains largely unknown. As an aid to ongoing conservation efforts, we employed three commonly applied mtDNA markers (ND4, DLoop and CO1) to investigate the genetic structuring of H. zosterae in Florida using samples collected throughout its range in the state. A total of 1450 bp provided sufficient resolution to delineate four populations of dwarf seahorses, as indicated by significant fixation indices. Despite an overall significant population structure, we observed evidence of interbreeding between individuals from geographically distant sites, supporting the hypothesis that rafting serves to maintain a degree of population connectivity. All individuals collected from Pensacola belong to a single distinct subpopulation, which is highly differentiated from the rest of Floridian dwarf seahorses sampled. Our findings highlight the utility of mtDNA markers in evaluating barriers to gene flow and identifying genetically distinct populations, which are vital to the development of comprehensive conservation strategies for exploited taxa.
Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of ...resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, the BCl-2-associated death promoter, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.
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