bluuebunny/crossref_metadata_2025 huggingface dataset:
Inappropriate Azithromycin Use in Nine Primary-Care Clinics Before and After Implementation of Provider Guidance in the EMR
Authors: May Alexandria , Hester Allison , Quairoli Kristi , Kandiah Sheetal
Published: November 2020

Background: According to the CDC Core Elements of Outpatient Stewardship, the first step in optimizing outpatient antibiotic use the identification of high-priority conditions in which antibiotics are commonly used inappropriately. Azithromycin is a broad-spectrum antimicrobial commonly used inappropriately in clinical practice for nonspecific upper respiratory infections (URIs). In 2017, a medication use evaluation at Grady Health System (GHS) revealed that 81.4% of outpatient azithromycin prescriptions were inappropriate. In an attempt to optimize outpatient azithromycin prescribing at GHS, a tool was designed to direct the prescriber toward evidence-based therapy; it was implemented in the electronic medical record (EMR) in January 2019. Objective: We evaluated the effect of this tool on the rate of inappropriate azithromycin prescribing, with the goal of identifying where interventions to improve prescribing are most needed and to measure progress. Methods: This retrospective chart review of adult patients prescribed oral azithromycin was conducted in 9 primary care clinics at GHS between February 1, 2019, and April 30, 2019, to compare data with that already collected over a 6-month period in 2017 before implementation of the antibiotic prescribing guidance tool. The primary outcome of this study was the change in the rate of inappropriate azithromycin prescribing before and after guidance tool implementation. Appropriateness was based on GHS internal guidelines and national guidelines. Inappropriate prescriptions were classified as inappropriate indication, unnecessary prescription, excessive or insufficient treatment duration, and/or incorrect drug. Results: Of the 560 azithromycin prescriptions identified during the study period, 263 prescriptions were included in the analysis. Overall, 181 (68.8%) of azithromycin prescriptions were considered inappropriate, representing a 12.4% reduction in the primary composite outcome of inappropriate azithromycin prescriptions. Bronchitis and unspecified upper respiratory tract infections (URI) were the most common indications where azithromycin was considered inappropriate. Attending physicians prescribed more inappropriate azithromycin prescriptions (78.1%) than resident physicians (37.0%) or midlevel providers (37.0%). Also, 76% of azithromycin prescriptions from nonacademic clinics were considered inappropriate, compared with 46% from academic clinics. Conclusions: Implementation of a provider guidance tool in the EMR lead to a reduction in the percentage of inappropriate outpatient azithromycin prescriptions. Future targeted interventions and stewardship initiatives are needed to achieve the stewardship program’s goal of reducing inappropriate outpatient azithromycin prescriptions by 20% by 1 year after implementation.

Funding: None

Disclosures: None
Incidence Trends of Central-Line–Associated Bloodstream Infections in Acute-Care Hospitals, NHSN, 2009–2018
Authors: Nkwata Allan , Soe Minn , Li Qunna , Godfrey-Johnson Dominque , Edwards Jonathan , Dudeck Margaret
Published: November 2020

Background: Central-line–associated bloodstream infections (CLABSIs) are an important cause of healthcare-associated morbidity and mortality in the United States. CLABSI surveillance in the CDC NHSN began in 2005 and has been propelled by state CLABSI reporting requirements, first introduced in 2005, and subsequently by the CMS requirements for intensive care units (ICUs) in 2011 and select ward locations in 2015. Although trend analyses were previously reported, no recent assessment of the NHSN CLABSI incidence rate changes has been performed. In this analysis, we evaluated trends in CLABSI rates in nonneonatal ICUs and all wards reported from acute-care hospitals. Methods: CLABSI rates, including blood stream infections attributed to mucosal barrier injury reported to the NHSN from 2009 to 2018, were analyzed. To evaluate trends in CLABSI incidence and to account for the potential impact of definitional changes in catheter-associated urinary tract infections (CAUTIs) that indirectly impacted CLABSI rates, as well as the CMS mandate for select wards, we conducted an interrupted time-series analysis using negative binomial random-effects modeling with an interruption in 2015. ICUs and ward locations were analyzed separately. Models were adjusted for patient care location type and hospital-level characteristics: hospital type, medical affiliation, teaching status, bed size, number of ICU beds, and average length of inpatient stay. Random intercept and slope models were used to account for differential baseline incidence and trends among reporting hospitals. Results: The overall crude incidence of CLABSI per 1,000 central-line days decreased from 1.6 infections in 2009 to 0.9 infections in 2018, except for an increase in 2015. Similar trends were observed by location type. Among the ICUs, adjusted CLABSI incidence decreased by 10% annually in 2009–2014, increased nearly 29% in 2015, and thereafter decreased at an average of 6.8% per year. Among the wards, adjusted CLABSI incidence decreased at an average of 7.9% annually, except for a 29.3% increase in 2015. Conclusions: Substantial progress has been made in reducing CLABSIs in both ICUs and wards over the last 10 years. Indirect effects of CAUTI definitional changes may explain the immediate increase in ICUs, whereas the CMS mandate may explain the similar increase in wards in 2015. Despite this increase, these findings suggest that policies and practices aimed at prevention of CLABSI have likely been effective on a national level.

Funding: None

Disclosures: None
Infection Prevention and Control Policies and Staffing: A National Survey of Home Health Agencies in the United States
Authors: Shang Jingjing , Chastain Ashley , Perera U. Gayani , Pogorzelska-Maziarz Monika , Stone Patricia
Published: November 2020

Background: Infection prevention and control (IPC) is a national priority in all healthcare settings, and IPC staffing characteristics have been linked to patient safety outcomes. However, there is a lack of knowledge about IPC in home healthcare (HHC), the fastest growing healthcare sector. Our aim was to better understand the current state of IPC in HHC, as well as the HHC staff involved with IPC policy implementation. Methods: A national survey was conducted between October 2018 and November 2019. The participants included (1) agencies recruited from a national HHC conference and (2) a national random sample of 1,501 agencies stratified by census region, ownership status, and rural or urban location. Survey items included staff influenza vaccination policies, antibiotic stewardship, infection surveillance, and IPC staffing. Descriptive statistics were computed, and differences by ownership were calculated using 2 and Student t tests. Results: Of the 535 HHC agencies that responded to the survey (response rate, 33%), 64% were for-profit agencies. Overall, 30.8% of the agencies (17.9% for-profit, 57.6% nonprofit; P < .01) required staff influenza vaccination. Most nonprofit agencies (84.1%) and about half of the for-profit agencies (48.1%) offered free influenza vaccinations to staff (P < .01). During the past influenza season, 62.6% of agencies (81.5% nonprofit vs 51.6% for-profit; P < .01) had 75% of their employees vaccinated for influenza, and 9.3% (2% nonprofit vs 13.5% for-profit; P < .01) reported that they did not track this data. Only 17.9% of HHC agencies used antibiotic prescribing guidelines, and 33.3% reported that they reviewed cases to assess the appropriateness of antibiotic administration and/or indication. Most HHC agencies (86%) reported collecting and reviewing infection data to identify trends, which was often done quarterly or more frequently. Almost every responding agency reported that the staff member in charge of IPC had other responsibilities including administrative, education/training, or quality improvement, and 33.5% of those personnel had received no specific IPC training. Also, ~6% of agencies (12.5% of government-owned agencies) reported that they currently did not have a staff member in charge of IPC. Conclusions: This is the first national study of IPC in HHC, which can be used as a benchmark for quality improvement initiatives in the home care environment. Compared to other healthcare settings, HHC agencies have substantial challenges related to IPC. Most HHC agencies do not have a staff member exclusively dedicated to IPC, and staff training is inadequate. Furthermore, a significant number of agencies have no staff influenza vaccination or antibiotic stewardship policies in place. The situation is worse at for-profit agencies, which dominate the current US HHC industry.

Funding: None

Disclosures: None
Infection Prevention and Control Practices Implemented for Congenital Measles in an Extremely Low Birth Weight Infant
Authors: Saiman Lisa , Hanft Erin , Brachio Sandhya , Messina Maria , Zachariah Philip , Goffman Dena , Pike Janett , Covington Lesley , Graham Krishika A , Ahmad Nina , Rausch-Phung Elizabeth , Bryant Patrick , Khandekar Anagha , Kulas Karen
Published: November 2020

Background: Measles can cause miscarriages and preterm birth in nonimmune pregnant women. During the 2018–2019 measles outbreak in New York, a woman with measles delivered an extremely low birth weight preterm infant at our Women and Children’s Hospital. We describe our measles preparedness strategies and infection prevention and control (IPC) management relevant to congenital measles. Methods: Because of the measles outbreak, in Q4 2018, IPC verified measles immunity in all obstetric and pediatric staff, per state regulations, and recommended determining the measles immune status of all pregnant women. To prevent measles exposure, visitor restrictions for the neonatal intensive care unit (NICU) were implemented (May 2019); only 3 visitors were permitted for each infant, including parents. All visitors had to provide written documentation of immunity to measles, regardless of epidemiologic risk factors or receive an MMR vaccine prior to visiting. New York state and New York City health departments performed measles diagnostic testing for maternal and infant specimens. Results: Our hospital was informed of the imminent transfer of a woman in preterm labor with suspected measles. To avoid any exposure, the mother was masked in the ambulance bay and taken by commandeered elevator to the obstetrical operating room suite, which was cleared of other patients. She delivered by C-section and was transferred to an airborne infection isolation (AII) room. The 25-week-gestation infant was transported by isolette to the NICU and was placed on AII. Testing confirmed measles in the mother (measles PCR- and IgM-positive) and congenital measles in the infant (Table 1). The mother was allowed to visit the NICU when her respiratory symptoms and rash resolved, as confirmed by her provider, ~10 days after discharge. The infant never developed a rash, pneumonia, or neurologic findings. AII was discontinued on day of life 61 in consultation with the health departments. The infant was discharged at ~36 weeks gestation. No secondary cases of measles occurred among patients, visitors, or staff. Conclusions: We safely cared for an extremely preterm infant with congenital measles. Laboratory testing suggested prolonged presence of measles virus, but it is unknown how long an infant in the NICU should remain on AII. The current Council of State and Territorial Epidemiologists case definition for measles requires the presence of rash. This case provides support to revise this case definition if laboratory findings are consistent with congenital measles.

Funding: None

Disclosures: None
Progress in Preventing Bloodstream Infections in Hemodialysis: Data From the National Healthcare Safety Network, 2014–2018
Authors: Novosad Shannon , Soe Lucy Fike Minn , Woolfolk Erikka , Moccia Lauren , Nguyen Duc , Patel Priti
Published: November 2020

Background: More than 450,000 patients receive outpatient hemodialysis in the United States. Patients on hemodialysis are at high risk of bloodstream infections (BSIs), which are associated with significant morbidity and mortality. National prevention efforts targeting hemodialysis facilities have resulted in widespread changes in practice, including modifications to central venous catheter (CVC) maintenance procedures. We analyzed dialysis event surveillance data submitted to the CDC NHSN to describe changes in BSI rates among hemodialysis outpatients from 2014 to 2018. Methods: Outpatient hemodialysis facilities report BSIs (ie, positive blood cultures collected in the outpatient setting or within 1 calendar day after hospital admission) and the number of hemodialysis outpatients treated during the first 2 working days of each month to the NHSN. For each BSI, the suspected source (ie, vascular access, another site, contamination, or uncertain) and vascular access type are indicated: CVC, arteriovenous fistula (AVF) or arteriovenous graft (AVG). Pooled mean rates (per 100 patient months) were calculated for BSIs, access-related BSIs (ARBSIs), and BSIs and ARBSIs were stratified by vascular access type. Annual BSI rate trends were evaluated using a negative binomial regression model, which treated patient months as an offset variable and included access type, year, and an access-year interaction variable. Results: More than 6,000 outpatient hemodialysis facilities reported 134,961 BSIs from 2014 to 2018. Of these BSIs, 102,505 (76%) were categorized as access related. CVCs were present in 63% of BSIs and 70% of ARBSIs. Pooled mean BSI rates decreased 27% from 0.64 to 0.47 per 100 patient months; rates of ARBSIs decreased 27% from 0.49 to 0.36 per 100 patient months. Significant decreases in event rates occurred across vascular access strata (Fig. 1). The reduction in BSI and ARBSI burden was most pronounced among patients with CVCs. BSI rates in patients with CVCs decreased 32% from 2.16 per 100 patient months to 1.46 (annual average decrease, 9.5%), and ARBSI rates in patients with CVCs decreased 32% from 1.83 per 100 patient months to 1.24 (annual average decrease, 9.4%). Conclusions: Substantial reductions in BSI and ARBSI rates among hemodialysis outpatients occurred during this 5-year period, and these reductions appear to be most prominent among CVC and AVF patients. Improvements in infection prevention and control practices, including CVC care, have likely contributed to these reductions. Additional efforts to increase the uptake of known prevention practices and to identify new strategies for prevention might contribute to continued decreases in infections among this highly vulnerable population.

Funding: None

Disclosures: None
Rapid PCR Influenza Testing Decreases Inappropriate Empiric Antibiotic Use
Authors: Sandhu Avnish , Polistico Jordan , Ganesan Ashwin , Goldman Erin , LeRose Jennifer , Chopra Teena
Published: November 2020

Background: The clinical picture of influenza-like illness can mimic bacterial pneumonia, and empiric treatment is often initiated with antibacterial agents. Molecular testing such as polymerase chain reaction (PCR) is often used to diagnose influenza. However, traditional PCR tests have a slow turnaround time and cannot deliver results soon enough to influence the clinical decision making. The Detroit Medical Center (DMC) implemented the Xpert Flu test for all patients presenting with influenza-like illness (ILI). We evaluated antibacterial use after implementation of rapid influenza PCR Xpert Flu. Methods: We conducted a retrospective study comparing all pediatric and adult patients tested using traditional RT PCR during the 2017–2018 flu season to patients tested using the rapid influenza Xpert Flu during the 2018–2019 flu season in a tertiary-care hospital in Detroit, Michigan. These patients were further divided into 3 groups: not admitted (NA), admitted to acute-care floor (ACF), or admitted to intensive care unit (ICU). The groups were then compared with respect to percentage of antibacterial use after traditional RT PCR versus rapid influenza Xpert Flu testing during their hospital visit for ILI. The χ2 test was used for statistical analyses. Results: In total, 20,923 patients presented with influenza-like illness during the study period: 26% (n = 5,569) had the rapid influenza Xpert Flu and 73.4% (n= 15,354) had traditional RT PCR. For a comparison of the number of patients in 3 groups (NA, ACF, and ICU) and type of influenza PCR performed among these patients, please refer to Table 1. When comparing antibacterial use in the NA group, the proportions of patients who received antibacterial agents in the traditional RT PCR group versus the rapid influenza Xpert Flu group were 24.4% (n = 695) versus 3.9% (n = 450), respectively (P < .0001). In the ACF group, the proportions of patients who received antibacterial agents in the traditional RT PCR group versus the rapid influenza Xpert Flu group was 62.3% (n = 1,406) versus 27.7% (n = 994), respectively (P < .001). In the ICU group, the proportions of patients who received antibacterials in the traditional RT PCR group versus the rapid influenza Xpert Flu group were 80.3% (n = 382) versus 38.3% (n = 204), respectively (P < .0001). Conclusions: With rising antimicrobial resistance and increasing influenza morbidity and mortality, rapid diagnostics not only can help diagnose influenza faster but also can reduce inappropriate antimicrobial use.

Funding: None

Disclosures: None
Negotiating French Wine and European Identities at the European Community
Authors: Chen Maria X.
Published: November 2020

This article examines the French role in creating an integrated wine policy at the European level and demonstrates that political negotiations over the policy revealed competing European conceptions of agriculture and identity. Drawing on research in EEC and French historical archives, this article argues that in spite of the risks involved in relinquishing sovereignty over a key national industry with deep cultural resonance, the French government was determined to transfer responsibility for much of the sector to the European Community due to continued domestic pressure. Further, it suggests that common values around the centrality of agriculture in the European project meant that countries were persistent in realising a wine policy even though wine was not a natural fit in the pantheon of other goods for which common markets were created.
No significant association between vitamin D and COVID-19: A	retrospective study from a northern Italian hospital
Authors: Ferrari Davide , Locatelli Massimo
Published: November 2020

Abstract. The world is currently overwhelmed by a novel coronavirus disease (COVID-19). Clinically, COVID-19 shows a broad range of manifestations: from asymptomatic to severe and possibly lethal interstitial pneumonia. Several studies suggested the involvement of Vitamin-D (VitD) in reducing the risk of COVID-19 infections/severity. However, most of them are based on circumstantial evidences, like the association between latitude-related sunlight exposure and mortality rate, while studies based on patients’ VitD measurements are still scarce. Therefore, we retrospectively analyzed the VitD levels (measured as 25-hydroxyvitamin-D) from a cohort of 347 patients admitted to a northern Italian Hospital as suspected COVID-19s. Of them, 128 were positive (83 males, aged 62.7 ± 14.2 and 45 females, aged 69.3 ± 15.6) and 219 were negative (107 males, aged 62.8 ± 19.5 and 112 females, aged 54.3 ± 20.1). The averaged VitD levels were similar in the two groups: 21.8 ± 16.1 ng/mL and 22.8 ± 14.0 ng/mL for the COVID-19 positive and negative group respectively ( p-value: 0.39), as well as the percentage of individuals having VitD levels below 30 ng/mL: 78.9% and 73.5% for the COVID-19 positive and negative group respectively. Because a large portion of patients were below the suggested 30 ng/mL threshold, we can’t exclude that VitD supplementation, restoring normal levels, might be beneficial in reducing the risk of infection.
Preclinical studies using cisplatin/carboplatin to restore the Enzalutamide sensitivity via degrading the androgen receptor splicing variant 7 (ARv7) to further suppress Enzalutamide resistant prostate cancer
Authors: Chou Fu-Ju , Lin ChangYi , Tian Hao , Lin WanYing , You Bosen , Lu Jieyang , Sahasrabudhe Deepak , Huang Chi-Ping , Yang Vanessa , Yeh Shuyuan , Niu Yuanjie , Chang Chawnshang
Published: November 2020

The FDA-approved anti-androgen Enzalutamide (Enz) has been used successfully as the last line therapy to extend castration-resistant prostate cancer (CRPC) patients’ survival by an extra 4.8 months. However, CRPC patients eventually develop Enz-resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we found that Cisplatin (Cis) or Carboplatin, currently used in chemotherapy/radiation therapy to suppress tumor progression, could restore the Enz sensitivity in multiple Enz-resistant (EnzR) CRPC cells via directly degrading/suppressing the ARv7. Combining Cis or Carboplatin with Enz therapy can also delay the development of Enz-resistance in CRPC C4-2 cells. Mechanism dissection found that Cis or Carboplatin might decrease the ARv7 expression via multiple mechanisms including targeting the lncRNA-Malat1/SF2 RNA splicing complex and increasing ARv7 degradation via altering ubiquitination. Preclinical studies using in vivo mouse model with implanted EnzR1-C4-2 cells also demonstrated that Cis plus Enz therapy resulted in better suppression of EnzR CRPC progression than Enz treatment alone. These results not only unveil the previously unrecognized Cis mechanism to degrade ARv7 via targeting the Malat1/SF2 complex and ubiquitination signals, it may also provide a novel and ready therapy to further suppress the EnzR CRPC progression in the near future.
Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance
Authors: Kapoor Isha , Bodo Juraj , Hill Brian T. , Hsi Eric D. , Almasan Alexandru
Published: November 2020

Defects in apoptosis can promote tumorigenesis and impair responses of malignant B cells to chemotherapeutics. Members of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins are key regulators of the intrinsic, mitochondrial apoptotic pathway. Overexpression of antiapoptotic BCL-2 family proteins is associated with treatment resistance and poor prognosis. Thus, inhibition of BCL-2 family proteins is a rational therapeutic option for malignancies that are dependent on antiapoptotic BCL-2 family proteins. Venetoclax (ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor that represents the first approved agent of this class and is currently widely used in the treatment of chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML). Despite impressive clinical activity, venetoclax monotherapy for a prolonged duration can lead to drug resistance or loss of dependence on the targeted protein. In this review, we provide an overview of the mechanism of action of BCL-2 inhibition and the role of this approach in the current treatment paradigm of B-cell malignancies. We summarize the drivers of de novo and acquired resistance to venetoclax that are closely associated with complex clonal shifts, interplay of expression and interactions of BCL-2 family members, transcriptional regulators, and metabolic modulators. We also examine how tumors initially resistant to venetoclax become responsive to it following prior therapies. Here, we summarize preclinical data providing a rationale for efficacious combination strategies of venetoclax to overcome therapeutic resistance by a targeted approach directed against alternative antiapoptotic BCL-2 family proteins (MCL-1, BCL-xL), compensatory prosurvival pathways, epigenetic modifiers, and dysregulated cellular metabolism/energetics for durable clinical remissions.
Low serum neutralizing anti-SARS-CoV-2 S antibody levels in mildly affected COVID-19 convalescent patients revealed by two different detection methods
Authors: Bošnjak Berislav , Stein Saskia Catherina , Willenzon Stefanie , Cordes Anne Katrin , Puppe Wolfram , Bernhardt Günter , Ravens Inga , Ritter Christiane , Schultze-Florey Christian R. , Gödecke Nina , Martens Jörg , Kleine-Weber Hannah , Hoffmann Markus , Cossmann Anne , Yilmaz Mustafa , Pink Isabelle , Hoeper Marius M. , Behrens Georg M. N. , Pöhlmann Stefan , Blasczyk Rainer , Schulz Thomas F. , Förster Reinhold
Published: November 2020

Neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells via surface-expressed angiotensin-converting enzyme 2 (ACE2). We used a surrogate virus neutralization test (sVNT) and SARS-CoV-2 S protein-pseudotyped vesicular stomatitis virus (VSV) vector-based neutralization assay (pVNT) to assess the degree to which serum antibodies from coronavirus disease 2019 (COVID-19) convalescent patients interfere with the binding of SARS-CoV-2 S to ACE2. Both tests revealed neutralizing anti-SARS-CoV-2 S antibodies in the sera of ~90% of mildly and 100% of severely affected COVID-19 convalescent patients. Importantly, sVNT and pVNT results correlated strongly with each other and to the levels of anti-SARS-CoV-2 S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies correlated with the duration and severity of clinical symptoms but not with patient age. Compared to pVNT, sVNT is less sophisticated and does not require any biosafety labs. Since this assay is also much faster and cheaper, sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.
Subdividing Y-chromosome haplogroup R1a1 reveals Norse Viking dispersal lineages in Britain
Authors: Lall Gurdeep Matharu , Larmuseau Maarten H. D. , Wetton Jon H. , Batini Chiara , Hallast Pille , Huszar Tunde I. , Zadik Daniel , Aase Sigurd , Baker Tina , Balaresque Patricia , Bodmer Walter , Børglum Anders D. , de Knijff Peter , Dunn Hayley , Harding Stephen E. , Løvvik Harald , Dupuy Berit Myhre , Pamjav Horolma , Tillmar Andreas O. , Tomaszewski Maciej , Tyler-Smith Chris , Verdugo Marta Pereira , Winney Bruce , Vohra Pragya , Story Joanna , King Turi E. , Jobling Mark A.
Published: November 2020

The influence of Viking-Age migrants to the British Isles is obvious in archaeological and place-names evidence, but their demographic impact has been unclear. Autosomal genetic analyses support Norse Viking contributions to parts of Britain, but show no signal corresponding to the Danelaw, the region under Scandinavian administrative control from the ninth to eleventh centuries. Y-chromosome haplogroup R1a1 has been considered as a possible marker for Viking migrations because of its high frequency in peninsular Scandinavia (Norway and Sweden). Here we select ten Y-SNPs to discriminate informatively among hg R1a1 sub-haplogroups in Europe, analyse these in 619 hg R1a1 Y chromosomes including 163 from the British Isles, and also type 23 short-tandem repeats (Y-STRs) to assess internal diversity. We find three specifically Western-European sub-haplogroups, two of which predominate in Norway and Sweden, and are also found in Britain; star-like features in the STR networks of these lineages indicate histories of expansion. We ask whether geographical distributions of hg R1a1 overall, and of the two sub-lineages in particular, correlate with regions of Scandinavian influence within Britain. Neither shows any frequency difference between regions that have higher (≥10%) or lower autosomal contributions from Norway and Sweden, but both are significantly overrepresented in the region corresponding to the Danelaw. These differences between autosomal and Y-chromosomal histories suggest either male-specific contribution, or the influence of patrilocality. Comparison of modern DNA with recently available ancient DNA data supports the interpretation that two sub-lineages of hg R1a1 spread with the Vikings from peninsular Scandinavia.
CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module
Authors: Dougherty Gerard W. , Mizuno Katsutoshi , Nöthe-Menchen Tabea , Ikawa Yayoi , Boldt Karsten , Ta-Shma Asaf , Aprea Isabella , Minegishi Katsura , Pang Yuan-Ping , Pennekamp Petra , Loges Niki T. , Raidt Johanna , Hjeij Rim , Wallmeier Julia , Mussaffi Huda , Perles Zeev , Elpeleg Orly , Rabert Franziska , Shiratori Hidetaka , Letteboer Stef J. , Horn Nicola , Young Samuel , Strünker Timo , Stumme Friederike , Werner Claudius , Olbrich Heike , Takaoka Katsuyoshi , Ide Takahiro , Twan Wang Kyaw , Biebach Luisa , Große-Onnebrink Jörg , Klinkenbusch Judith A. , Praveen Kavita , Bracht Diana C. , Höben Inga M. , Junger Katrin , Gützlaff Jana , Cindrić Sandra , Aviram Micha , Kaiser Thomas , Memari Yasin , Dzeja Petras P. , Dworniczak Bernd , Ueffing Marius , Roepman Ronald , Bartscherer Kerstin , Katsanis Nicholas , Davis Erica E. , Amirav Israel , Hamada Hiroshi , Omran Heymut
Published: November 2020

Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45−/− mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.
Allomorphy as a mechanism of post-translational control of enzyme activity
Authors: Wood Henry P. , Cruz-Navarrete F. Aaron , Baxter Nicola J. , Trevitt Clare R. , Robertson Angus J. , Dix Samuel R. , Hounslow Andrea M. , Cliff Matthew J. , Waltho Jonathan P.
Published: November 2020

Enzyme regulation is vital for metabolic adaptability in living systems. Fine control of enzyme activity is often delivered through post-translational mechanisms, such as allostery or allokairy. β-phosphoglucomutase (βPGM) from Lactococcus lactis is a phosphoryl transfer enzyme required for complete catabolism of trehalose and maltose, through the isomerisation of β-glucose 1-phosphate to glucose 6-phosphate via β-glucose 1,6-bisphosphate. Surprisingly for a gatekeeper of glycolysis, no fine control mechanism of βPGM has yet been reported. Herein, we describe allomorphy, a post-translational control mechanism of enzyme activity. In βPGM, isomerisation of the K145-P146 peptide bond results in the population of two conformers that have different activities owing to repositioning of the K145 sidechain. In vivo phosphorylating agents, such as fructose 1,6-bisphosphate, generate phosphorylated forms of both conformers, leading to a lag phase in activity until the more active phosphorylated conformer dominates. In contrast, the reaction intermediate β-glucose 1,6-bisphosphate, whose concentration depends on the β-glucose 1-phosphate concentration, couples the conformational switch and the phosphorylation step, resulting in the rapid generation of the more active phosphorylated conformer. In enabling different behaviours for different allomorphic activators, allomorphy allows an organism to maximise its responsiveness to environmental changes while minimising the diversion of valuable metabolites.
The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations
Authors: Jia Junqiao , Absmeier Eva , Holton Nicole , Pietrzyk-Brzezinska Agnieszka J. , Hackert Philipp , Bohnsack Katherine E. , Bohnsack Markus T. , Wahl Markus C.
Published: November 2020

The ASCC3 subunit of the activating signal co-integrator complex is a dual-cassette Ski2-like nucleic acid helicase that provides single-stranded DNA for alkylation damage repair by the α-ketoglutarate-dependent dioxygenase AlkBH3. Other ASCC components integrate ASCC3/AlkBH3 into a complex DNA repair pathway. We mapped and structurally analyzed interacting ASCC2 and ASCC3 regions. The ASCC3 fragment comprises a central helical domain and terminal, extended arms that clasp the compact ASCC2 unit. ASCC2–ASCC3 interfaces are evolutionarily highly conserved and comprise a large number of residues affected by somatic cancer mutations. We quantified contributions of protein regions to the ASCC2–ASCC3 interaction, observing that changes found in cancers lead to reduced ASCC2–ASCC3 affinity. Functional dissection of ASCC3 revealed similar organization and regulation as in the spliceosomal RNA helicase Brr2. Our results delineate functional regions in an important DNA repair complex and suggest possible molecular disease principles.
Gamma estimator of Jarzynski equality for recovering binding energies from noisy dynamic data sets
Authors: Kuang Zhifeng , Singh Kristi M. , Oliver Daniel J. , Dennis Patrick B. , Perry Carole C. , Naik Rajesh R.
Published: November 2020

A fundamental problem in thermodynamics is the recovery of macroscopic equilibrated interaction energies from experimentally measured single-molecular interactions. The Jarzynski equality forms a theoretical basis in recovering the free energy difference between two states from exponentially averaged work performed to switch the states. In practice, the exponentially averaged work value is estimated as the mean of finite samples. Numerical simulations have shown that samples having thousands of measurements are not large enough for the mean to converge when the fluctuation of external work is above 4 kBT, which is easily observable in biomolecular interactions. We report the first example of a statistical gamma work distribution applied to single molecule pulling experiments. The Gibbs free energy of surface adsorption can be accurately evaluated even for a small sample size. The values obtained are comparable to those derived from multi-parametric surface plasmon resonance measurements and molecular dynamics simulations.
Solid-phase hetero epitaxial growth of α-phase formamidinium perovskite
Authors: Lee Jin-Wook , Tan Shaun , Han Tae-Hee , Wang Rui , Zhang Lizhi , Park Changwon , Yoon Mina , Choi Chungseok , Xu Mingjie , Liao Michael E. , Lee Sung-Joon , Nuryyeva Selbi , Zhu Chenhui , Huynh Kenny , Goorsky Mark S. , Huang Yu , Pan Xiaoqing , Yang Yang
Published: November 2020

Conventional epitaxy of semiconductor films requires a compatible single crystalline substrate and precisely controlled growth conditions, which limit the price competitiveness and versatility of the process. We demonstrate substrate-tolerant nano-heteroepitaxy (NHE) of high-quality formamidinium-lead-tri-iodide (FAPbI3) perovskite films. The layered perovskite templates the solid-state phase conversion of FAPbI3 from its hexagonal non-perovskite phase to the cubic perovskite polymorph, where the growth kinetics are controlled by a synergistic effect between strain and entropy. The slow heteroepitaxial crystal growth enlarged the perovskite crystals by 10-fold with a reduced defect density and strong preferred orientation. This NHE is readily applicable to various substrates used for devices. The proof-of-concept solar cell and light-emitting diode devices based on the NHE-FAPbI3 showed efficiencies and stabilities superior to those of devices fabricated without NHE.
Full genome viral sequences inform patterns of SARS-CoV-2 spread into and within Israel
Authors: Miller Danielle , Martin Michael A. , Harel Noam , Tirosh Omer , Kustin Talia , Meir Moran , Sorek Nadav , Gefen-Halevi Shiraz , Amit Sharon , Vorontsov Olesya , Shaag Avraham , Wolf Dana , Peretz Avi , Shemer-Avni Yonat , Roif-Kaminsky Diana , Kopelman Naama M. , Huppert Amit , Koelle Katia , Stern Adi
Published: November 2020

Full genome sequences are increasingly used to track the geographic spread and transmission dynamics of viral pathogens. Here, with a focus on Israel, we sequence 212 SARS-CoV-2 sequences and use them to perform a comprehensive analysis to trace the origins and spread of the virus. We find that travelers returning from the United States of America significantly contributed to viral spread in Israel, more than their proportion in incoming infected travelers. Using phylodynamic analysis, we estimate that the basic reproduction number of the virus was initially around 2.5, dropping by more than two-thirds following the implementation of social distancing measures. We further report high levels of transmission heterogeneity in SARS-CoV-2 spread, with between 2-10% of infected individuals resulting in 80% of secondary infections. Overall, our findings demonstrate the effectiveness of social distancing measures for reducing viral spread.
APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
Authors: Zhao Jing , Fu Yuan , Yamazaki Yu , Ren Yingxue , Davis Mary D. , Liu Chia-Chen , Lu Wenyan , Wang Xue , Chen Kai , Cherukuri Yesesri , Jia Lin , Martens Yuka A. , Job Lucy , Shue Francis , Nguyen Thanh Thanh , Younkin Steven G. , Graff-Radford Neill R. , Wszolek Zbigniew K. , Brafman David A. , Asmann Yan W. , Ertekin-Taner Nilüfer , Kanekiyo Takahisa , Bu Guojun
Published: November 2020

APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.
Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies
Authors: Wang Jiawen , Zheng Sujuan , Rajkumar Subramani , Xie Jinglei , Yu Na , Peng Qian , Yang Xiaoyu
Published: November 2020

Chiral molecules with multiple stereocenters are widely present in natural products and pharmaceuticals, whose absolute and relative configurations are both critically important for their physiological activities. In spite of the fact that a series of ingenious strategies have been developed for asymmetric diastereodivergent catalysis, most of these methods are limited to the divergent construction of point chirality. Here we report an enantioselective and diastereodivergent synthesis of trisubstituted allenes by asymmetric additions of oxazolones to activated 1,3-enynes enabled by chiral phosphoric acid (CPA) catalysis, where the divergence of the allenic axial stereogenicity is realized by modifications of CPA catalysts. Density functional theory (DFT) calculations are performed to elucidate the origin of diastereodivergence by the stacking- and stagger-form in the transition state (TS) of allene formation step, as well as to disclose a Münchnone-type activation mode of oxazolones under Brønsted acid catalysis.
Electrochromic two-dimensional covalent organic framework with a reversible dark-to-transparent switch
Authors: Yu Fei , Liu Wenbo , Ke Si-Wen , Kurmoo Mohamedally , Zuo Jing-Lin , Zhang Qichun
Published: November 2020

Electrochromic (EC) materials with a dark-to-transmissive switch have great applications in optical communications, infrared wavelength detectors for spacecraft, and infrared camouflage coatings. However, such electroactive materials with high stability and cyclability are rare. Considering the advantages of the donor-acceptor approach (wide-range tuneable band position) and porous two-dimensional (2D) covalent organic framework (COF, well-ordered crystalline framework with stable structure and high surface area), in this work we constructed an extended delocalised π-electron layered dark purple EC-COF-1 by reacting the donor N,N,N′,N′-tetrakis(p-aminophenyl)-p-benzenediamine (TPBD) with the acceptor 2,1,3-benzothiadiazole-4,7-dicarboxaldehyde (BTDD). A sandwiched device made of EC-COF-1 exhibits the two-band bleaching (370 nm and 574 nm) in the visible region and becomes transparent under the applied potential with an induced absorption centring at 1400 nm. This discovery of a stable dark-to-transmissive switch in COF might open another door for their application in many EC devices for various purposes.
RNF115 plays dual roles in innate antiviral responses by catalyzing distinct ubiquitination of MAVS and MITA
Authors: Zhang Zhi-Dong , Xiong Tian-Chen , Yao Shu-Qi , Wei Ming-Cong , Chen Ming , Lin Dandan , Zhong Bo
Published: November 2020

MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115−/− organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115−/− cells compared to the wild-type counterparts. Consequently, the Rnf115−/− mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.
Extensive 5′-surveillance guards against non-canonical NAD-caps of nuclear mRNAs in yeast
Authors: Zhang Yaqing , Kuster David , Schmidt Tobias , Kirrmaier Daniel , Nübel Gabriele , Ibberson David , Benes Vladimir , Hombauer Hans , Knop Michael , Jäschke Andres
Published: November 2020

The ubiquitous redox coenzyme nicotinamide adenine dinucleotide (NAD) acts as a non-canonical cap structure on prokaryotic and eukaryotic ribonucleic acids. Here we find that in budding yeast, NAD-RNAs are abundant (>1400 species), short (<170 nt), and mostly correspond to mRNA 5′-ends. The modification percentage of transcripts is low (<5%). NAD incorporation occurs mainly during transcription initiation by RNA polymerase II, which uses distinct promoters with a YAAG core motif for this purpose. Most NAD-RNAs are 3′-truncated. At least three decapping enzymes, Rai1, Dxo1, and Npy1, guard against NAD-RNA at different cellular locations, targeting overlapping transcript populations. NAD-mRNAs are not translatable in vitro. Our work indicates that in budding yeast, most of the NAD incorporation into RNA seems to be disadvantageous to the cell, which has evolved a diverse surveillance machinery to prematurely terminate, decap and reject NAD-RNAs.
High-performance and stable photoelectrochemical water splitting cell with organic-photoactive-layer-based photoanode
Authors: Yu Je Min , Lee Jungho , Kim Yoon Seo , Song Jaejung , Oh Jiyeon , Lee Sang Myeon , Jeong Mingyu , Kim Yongseon , Kwak Ja Hun , Cho Seungho , Yang Changduk , Jang Ji-Wook
Published: November 2020

Considering their superior charge-transfer characteristics, easy tenability of energy levels, and low production cost, organic semiconductors are ideal for photoelectrochemical (PEC) hydrogen production. However, organic-semiconductor-based photoelectrodes have not been extensively explored for PEC water-splitting because of their low stability in water. Herein, we report high-performance and stable organic-semiconductors photoanodes consisting of p-type polymers and n-type non-fullerene materials, which is passivated using nickel foils, GaIn eutectic, and layered double hydroxides as model materials. We achieve a photocurrent density of 15.1 mA cm−2 at 1.23 V vs. reversible hydrogen electrode (RHE) with an onset potential of 0.55 V vs. RHE and a record high half-cell solar-to-hydrogen conversion efficiency of 4.33% under AM 1.5 G solar simulated light. After conducting the stability test at 1.3 V vs. RHE for 10 h, 90% of the initial photocurrent density are retained, whereas the photoactive layer without passivation lost its activity within a few minutes.
A catalogue of biochemically diverse CRISPR-Cas9 orthologs
Authors: Gasiunas Giedrius , Young Joshua K. , Karvelis Tautvydas , Kazlauskas Darius , Urbaitis Tomas , Jasnauskaite Monika , Grusyte Mantvyda M. , Paulraj Sushmitha , Wang Po-Hao , Hou Zhenglin , Dooley Shane K. , Cigan Mark , Alarcon Clara , Chilcoat N. Doane , Bigelyte Greta , Curcuru Jennifer L. , Mabuchi Megumu , Sun Zhiyi , Fuchs Ryan T. , Schildkraut Ezra , Weigele Peter R. , Jack William E. , Robb G. Brett , Venclovas Česlovas , Siksnys Virginijus
Published: November 2020

Bacterial Cas9 nucleases from type II CRISPR-Cas antiviral defence systems have been repurposed as genome editing tools. Although these proteins are found in many microbes, only a handful of variants are used for these applications. Here, we use bioinformatic and biochemical analyses to explore this largely uncharacterized diversity. We apply cell-free biochemical screens to assess the protospacer adjacent motif (PAM) and guide RNA (gRNA) requirements of 79 Cas9 proteins, thus identifying at least 7 distinct gRNA classes and 50 different PAM sequence requirements. PAM recognition spans the entire spectrum of T-, A-, C-, and G-rich nucleotides, from single nucleotide recognition to sequence strings longer than 4 nucleotides. Characterization of a subset of Cas9 orthologs using purified components reveals additional biochemical diversity, including both narrow and broad ranges of temperature dependence, staggered-end DNA target cleavage, and a requirement for long stretches of homology between gRNA and DNA target. Our results expand the available toolset of RNA-programmable CRISPR-associated nucleases.
Electron-phonon coupling induced intrinsic Floquet electronic structure
Authors: Song Zhigang , Wang Lin-Wang
Published: November 2020

Floquet states are a topic of intense contemporary interest, which is often induced by coherent external oscillating perturbation (e.g., laser, or microwave) which breaks the continuous time translational symmetry of the systems. Usually, electron–phonon coupling modifies the electronic structure of a crystal as a non-coherent perturbation and seems difficult to form Floquet states. Surprisingly, we found that the thermal equilibrium electron–phonon coupling in M(MoS)3 and M(MoSe)3 (where M is a metallic element) exhibits a coherent behavior, and the electronic structure can be described by the Floquet theorem. Such a coherent Floquet state is caused by a selective giant electron–phonon coupling, with thermodynamic phonon oscillation serving as a driving force on the electronic part of the system. The quasi-1D Dirac cone at the Fermi energy has its band gap open and close regularly. Similarly, the electric current will oscillate even under a constant voltage.