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The relationship between traditional metrics of research impact (e.g., number of citations) and alternative metrics (altmetrics) such as Twitter activity are of great interest, but remain imprecisely quantified. We used generalized linear mixed modeling to estimate the relative effects of Twitter activity, journal impact factor, and time since publication on Web of Science citation rates of 1,599 primary research articles from 20 ecology journals published from 2012-2014. We found a strong positive relationship between Twitter activity (i.e., the number of unique tweets about an article) and number of citations. Twitter activity was a more important predictor of citation rates than 5-year journal impact factor. Moreover, Twitter activity was not driven by journal impact factor; the 'highest-impact' journals were not necessarily the most discussed online. The effect of Twitter activity was only about a fifth as strong as time since publication; accounting for this confounding factor was critical for estimating the true effects of Twitter use. Articles in impactful journals can become heavily cited, but articles in journals with lower impact factors can generate considerable Twitter activity and also become heavily cited. Authors may benefit from establishing a strong social media presence, but should not expect research to become highly cited solely through social media promotion. Our research demonstrates that altmetrics and traditional metrics can be closely related, but not identical. We suggest that both altmetrics and traditional citation rates can be useful metrics of research impact.

Habitat connectivity is vital to the persistence of migratory fishes. Native tropical island stream fish assemblages composed of diadromous species require intact corridors between ocean and riverine habitats. High dams block fish migration, but low-head artificial barriers are more widespread and are rarely assessed for impacts. Among all 46 drainages in Puerto Rico, we identified and surveyed 335 artificial barriers that hinder fish migration to 74.5% of the upstream habitat. We also surveyed occupancy of native diadromous fishes (Anguillidae, Eleotridae, Gobiidae, and Mugilidae) in 118 river reaches. Occupancy models demonstrated that barriers 2 meters (m) high restricted nongoby fish migration and extirpated those fish upstream of 4-m barriers. Gobies are adapted to climbing and are restricted by 12-m barriers and extirpated upstream of 32-m barriers. Our findings quantitatively illustrate the extensive impact of low-head structures on island stream fauna and provide guidance for natural resource management, habitat restoration, and water development strategies.

We assessed effects of groundwater pumping to elevate lake levels on lake water chemistry and fish population metrics at seven Florida lakes. Following groundwater pumping, lake level fluctuation was reduced and lake water samples increased in mean pH, total alkalinity, total phosphorus, chloride and Secchi depth compared to historical means, indicating a close resemblance to the chemistry of aquifer water in the region. Fish community metrics from the augmented lakes were compared to 36 non-augmented lakes in Florida. The mean values for catch per unit effort, species richness and biomass of harvestable fishes, determined by electrofishing, were lower in augmented lakes compared to non-augmented lakes. Canonical correspondence analysis (CCA) indicated a high probability of a low abundance of individual species in augmented lakes compared to a majority of non-augmented lakes. The augmented lake with the lowest pumping rate exhibited less of a shift in limnological variables from historical values, and had fish population characteristics more closely resembling those of non-augmented lakes. Thus, reduced volumes of groundwater introduction could lower impacts to limnological and fish population characteristics. Augmentation allows for lakes to be utilized for recreational activities, and without augmentation some lakes in central Florida would likely go dry due to groundwater withdrawals for water supply. Therefore, allowing more natural water level fluctuations and possible reductions in total pumpage are recommended to reduce impacts to limnological and fish population characteristics, while still allowing sufficient groundwater pumping to preserve lake habitats.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation. Nearly 90% of people with CF have at least one copy of the ΔF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities. A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation. After the discovery of the CFTR gene in 1989, the in vitro proof-of-concept for gene therapy for CF was quickly established in 1990. In 1993, the first of many gene therapy clinical trials attempted to rescue the CF defect in airway epithelia. Despite the initial enthusiasm, there is still no FDA-approved gene therapy for CF. Here we discuss the history of CF gene therapy, from the discovery of the CFTR gene to current state-of-the-art gene delivery vector designs. While implementation of CF gene therapy has proven more challenging than initially envisioned; thanks to continued innovation, it may yet become a reality.

The transposon piggyBac is being used increasingly for genetic studies. Here, we describe modified versions of piggyBac transposase that have potentially wide-ranging applications, such as reversible transgenesis and modified targeting of insertions. piggyBac is distinguished by its ability to excise precisely, restoring the donor site to its pretransposon state. This characteristic makes piggyBac useful for reversible transgenesis, a potentially valuable feature when generating induced pluripotent stem cells without permanent alterations to genomic sequence. To avoid further genome modification following piggyBac excision by reintegration, we generated an excision competent/integration defective (Exc ⁺Int ⁻) transposase. Our findings also suggest the position of a target DNA–transposase interaction. Another goal of genome engineering is to develop reagents that can guide transgenes to preferred genomic regions. Others have shown that piggyBac transposase can be active when fused to a heterologous DNA-binding domain. An Exc ⁺Int ⁻ transposase, the intrinsic targeting of which is defective, might also be a useful intermediate in generating a transposase whose integration activity could be rescued and redirected by fusion to a site-specific DNA-binding domain. We show that fusion to two designed zinc finger proteins rescued the Int ⁻ phenotype. Successful guided transgene integration into genomic DNA would have broad applications to gene therapy and molecular genetics. Thus, an Exc ⁺Int ⁻ transposase is a potentially useful reagent for genome engineering and provides insight into the mechanism of transposase–target DNA interaction.

Pulmonary surfactant is critically important to prevent atelectasis by lowering the surface tension of the alveolar lining liquid. While respiratory distress syndrome (RDS) is common in premature infants, severe RDS in term and late preterm infants suggests an underlying genetic etiology. Pathogenic variants in the genes encoding key components of pulmonary surfactant including surfactant protein B (SP-B, SFTPB gene), surfactant protein C (SP-C, SFTPC gene), and the ATP-Binding Cassette transporter A3 (ABCA3, ABCA3 gene) result in severe neonatal RDS or childhood interstitial lung disease (chILD). These proteins play essential roles in pulmonary surfactant biogenesis and are expressed in alveolar epithelial type II cells (AEC2), the progenitor cell of the alveolar epithelium. SP-B deficiency most commonly presents in the neonatal period with severe RDS and requires lung transplantation for survival. SFTPC mutations act in an autosomal dominant fashion and more commonly presents with chILD or idiopathic pulmonary fibrosis than neonatal RDS. ABCA3 deficiency often presents as neonatal RDS or chILD. Gene therapy is a promising option to treat monogenic lung diseases. Successes and challenges in developing gene therapies for genetic disorders of surfactant dysfunction include viral vector design and tropism for target cell types. In this review, we explore adeno-associated virus (AAV), lentiviral, and adenoviral (Ad)-based vectors as delivery vehicles. Both gene addition and gene editing strategies are compared to best design treatments for lung diseases resulting from pathogenic variants in the SFTPB, SFTPC, and ABCA3 genes .

Prostate cancer runs in families. However, the genes that affect the incidence remain largely undefined. The authors have identified a rare germline variant of a homeobox gene, HOXB13, in four families with a history of prostate cancer. Prostate cancer is the most common noncutaneous cancer diagnosed in men in the United States, with more than 240,000 new cases expected in 2011. 1 Despite the demonstration of a strong familial component, identification of the genetic basis for hereditary prostate cancer has been challenging. Linkage studies of families with hereditary prostate cancer have provided inconsistent results. 2 In contrast, genomewide association studies have led to the identification of more than 30 single-nucleotide polymorphisms (SNPs) that are consistently associated with prostate cancer. 3 However, the magnitude of risk elevation attributed to each individual SNP is low, with an increased elevation in risk by . . .

BackgroundRecently, a novel HOXB13 variant (X285K) was observed in men of African descent with prostate cancer (PCa) in Martinique. Little is known about this or other variants in HOXB13 which may play a role in PCa susceptibility in African-American (AA) men.MethodsWe sequenced HOXB13 in an AA population of 1048 men undergoing surgical treatment for PCa at Johns Hopkins Hospital.ResultsSeven non-synonymous germline variants were observed in the patient population. While six of these variants were seen only once, X285K was found in eight patients. In a case–case analysis, we find that carriers of this latter variant are at increased risk of clinically significant PCa (1.2% carrier rate in Gleason Score ≥7 PCa vs. 0% in Gleason Score <7 PCa, odds ratio, OR = inf; 95% Confidence Interval, 95%CI:1.05-inf, P = 0.028), as well as PCa with early age at diagnosis (2.4% carrier rate in patients <50 year vs. 0.5% carrier rate in patients ≥50 year, OR = 5.25, 95% CI:1.00–28.52, P = 0.03).ConclusionsWhile this variant is rare in the AA population (~0.2% MAF), its ancestry-specific occurrence and apparent preferential association with risk for the more aggressive disease at an early age emphasizes its translational potential as an important, novel PCa susceptibility marker in the high-risk AA population.

Cystic fibrosis is an autosomal-recessive disease that is caused by a mutant (cystic fibrosis transmembrane conductance regulator) gene and is characterized by chronic bacterial lung infections and inflammation. Complementation with functional normalizes anion transport across the airway surface. Adeno-associated virus (AAV) is a useful vector for gene therapy because of its low immunogenicity and ability to persist for months to years. However, because its episomal expression may decrease after cell division, readministration of the AAV vector may be required. To overcome this, we designed an integrating AAV-based CFTR-expressing vector, termed (PB)/AAV, carrying CFTR flanked by the terminal repeats of the transposon. With codelivery of the transposase, PB/AAV can integrate into the host genome. Because of the packaging constraints of AAV, careful consideration was required to ensure that the vector would package and express its CFTR cDNA cargo. In this short-term study, PB/AAV-CFTR was aerosolized to the airways of CF pigs in the absence of the transposase. Two weeks later, transepithelial Cl current was restored in freshly excised tracheal and bronchial tissue. Additionally, we observed an increase in tracheal airway surface liquid pH and bacterial killing in comparison with untreated CF pigs. Airway surface liquid from primary airway cells cultured from treated CF pigs exhibited increased pH correlating with decreased viscosity. Together, these results show that complementing in CF pigs with PB/AAV rescues the anion transport defect in a large-animal CF model. Delivery of this integrating viral vector system to airway progenitor cells could lead to persistent, life-long expression .

Considerable effort has been devoted to developing adeno-associated virus (AAV)-based vectors for gene therapy in cystic fibrosis (CF). As a result of directed evolution and capsid shuffling technology, AAV capsids are available with widespread tropism for airway epithelial cells. For example, AAV2.5T and AAV6.2 are two evolved capsids with improved airway epithelial cell transduction properties over their parental serotypes. However, limited research has been focused on identifying their specific cellular tropism. Restoring cystic fibrosis transmembrane conductance regulator ( CFTR ) expression in surface columnar epithelial cells is necessary for the correction of the CF airway phenotype. Basal cells are a progenitor population of the conducting airways responsible for replenishing surface epithelial cells (including secretory cells and ionocytes), making correction of this cell population vital for a long-lived gene therapy strategy. In this study, we investigate the tropism of AAV capsids for three cell types in primary cultures of well-differentiated human airway epithelial (HAE) cells and primary human airway basal cells. We observed that AAV2.5T transduced surface epithelial cells better than AAV6.2, while AAV6.2 transduced airway basal cells better than AAV2.5T. We also investigated a recently developed capsid, AAV6.2FF, which has two surface tyrosines converted to phenylalanines. Next, we incorporated reciprocal mutations to create AAV capsids with further improved surface and basal cell transduction characteristics. Lastly, we successfully employed a split-intein approach using AAV to deliver an adenine base editor (ABE) to repair the CFTR R553X mutation. Our results suggest that rational incorporation of AAV capsid mutations improves AAV transduction of the airway surface and progenitor cells and may ultimately lead to improved pulmonary function in people with CF.