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1.
Int J Med Microbiol ; 314: 151607, 2024 Mar.
Article En | MEDLINE | ID: mdl-38367508

Measles is a highly contagious airborne viral disease. It can lead to serious complications and death and is preventable by vaccination. The live-attenuated measles vaccine (LAMV) derived from a measles virus (MV) isolated in 1954 has been in use globally for six decades and protects effectively by providing a durable humoral and cell-mediated immunity. Our study addresses the temporal stability of epitopes on the viral surface glycoprotein hemagglutinin (H) which is the major target of MV-neutralizing antibodies. We investigated the binding of seven vaccine-induced MV-H-specific monoclonal antibodies (mAbs) to cell-free synthesized MV-H proteins derived from the H gene sequences obtained from a lung specimen of a fatal case of measles pneumonia in 1912 and an isolate from a current case. The binding of four out of seven mAbs to the H protein of both MV strains provides evidence of epitopes that are stable for more than 100 years. The binding of the universally neutralizing mAbs RKI-MV-12b and RKI-MV-34c to the H protein of the 1912 MV suggests the long-term stability of highly conserved epitopes on the MV surface.


Measles virus , Measles , Humans , Measles virus/genetics , Antibodies, Neutralizing , Neutralization Tests , Measles Vaccine/genetics , Measles/prevention & control , Antibodies, Viral , Epitopes/genetics , Hemagglutinins, Viral/genetics , Antibodies, Monoclonal
2.
Viruses ; 15(11)2023 Nov 13.
Article En | MEDLINE | ID: mdl-38005925

Advances in viral discovery techniques have led to the identification of numerous novel viruses in human samples. However, the low prevalence of certain viruses in humans raises doubts about their association with our species. To ascertain the authenticity of a virus as a genuine human-infecting agent, it can be useful to investigate the diversification of its lineage within hominines, the group encompassing humans and African great apes. Building upon this rationale, we examined the case of the New Jersey polyomavirus (NJPyV; Alphapolyomavirus terdecihominis), which has only been detected in a single patient thus far. In this study, we obtained and analyzed sequences from closely related viruses infecting all African great ape species. We show that NJPyV nests within the diversity of these viruses and that its lineage placement is compatible with an ancient origin in humans, despite its apparent rarity in human populations.


Hominidae , Polyomavirus Infections , Polyomavirus , Animals , Humans , Polyomavirus/genetics , New Jersey/epidemiology , Biological Evolution , Polyomavirus Infections/epidemiology , Phylogeny
3.
Nat Commun ; 13(1): 5477, 2022 09 17.
Article En | MEDLINE | ID: mdl-36115862

Human herpes simplex virus 2 (HSV-2) is a ubiquitous, slowly evolving DNA virus. HSV-2 has two primary lineages, one found in West and Central Africa and the other found worldwide. Competing hypotheses have been proposed to explain how HSV-2 migrated out-of-Africa (i)HSV-2 followed human migration out-of-Africa 50-100 thousand years ago, or (ii)HSV-2 migrated via the trans-Atlantic slave trade 150-500 years ago. Limited geographic sampling and lack of molecular clock signal has precluded robust comparison. Here, we analyze newly sequenced HSV-2 genomes from Africa to resolve geography and timing of divergence events within HSV-2. Phylogeographic analysis consistently places the ancestor of worldwide dispersal in East Africa, though molecular clock is too slow to be detected using available data. Rates 4.2 × 10-8-5.6 × 10-8 substitutions/site/year, consistent with previous age estimates, suggest a worldwide dispersal 22-29 thousand years ago. Thus, HSV-2 likely migrated with humans from East Africa and dispersed after the Last Glacial Maximum.


Genome , Herpesvirus 2, Human , Adult , Africa , Base Sequence , Herpesvirus 2, Human/genetics , Humans , Phylogeography , Young Adult
4.
Nat Commun ; 13(1): 2314, 2022 05 10.
Article En | MEDLINE | ID: mdl-35538057

The 1918 influenza pandemic was the deadliest respiratory pandemic of the 20th century and determined the genomic make-up of subsequent human influenza A viruses (IAV). Here, we analyze both the first 1918 IAV genomes from Europe and the first from samples prior to the autumn peak. 1918 IAV genomic diversity is consistent with a combination of local transmission and long-distance dispersal events. Comparison of genomes before and during the pandemic peak shows variation at two sites in the nucleoprotein gene associated with resistance to host antiviral response, pointing at a possible adaptation of 1918 IAV to humans. Finally, local molecular clock modeling suggests a pure pandemic descent of seasonal H1N1 IAV as an alternative to the hypothesis of origination through an intrasubtype reassortment.


Influenza A Virus, H1N1 Subtype , Influenza A virus , Influenza, Human , Genome, Viral/genetics , Genomics , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A virus/genetics , Influenza, Human/epidemiology , Influenza, Human/genetics
5.
Transfusion ; 61(7): 2082-2089, 2021 07.
Article En | MEDLINE | ID: mdl-33955577

BACKGROUND: Massive transfusions are associated with a high mortality rate, but there is little evidence indicating when such efforts are futile. The purpose of this study was to identify clinical variables that could be used as futility indicators in massively transfused patients. METHODS: We retrospectively analyzed 138 adult surgical patients at our institution receiving a massive transfusion (2016-2019). Peak lactate and nadir pH within 24 h of massive transfusion initiation, along with other clinical variables, were assessed as predictors of the primary outcome, in-hospital mortality. RESULTS: The overall rate of in-hospital mortality among our patient population was 52.9% (n = 73). Increasing lactate and decreasing pH were associated with greater mortality among massively transfused patients. Mortality rates were ~2-fold higher for patients in the highest lactate category (≥10.0 mmol/L: 25 of 37; 67.6%) compared to the lowest category (0.0-4.9 mmol/L: 17 of 48; 35.4%) (p = .005), and ~2.5-fold higher for patients in the lowest pH category (<7.00: 8 of 9; 88.9%) compared to the highest category (≥7.40: 8 of 23; 34.7%) (p = .016). Increasing age was also associated with higher mortality (≥65 years: 24 of 33; 72.7%) when compared to younger patients (18-64 years: 49 of 105; 46.7%) (p = .010). CONCLUSIONS: Peak lactate ≥10.0 mmol/L, nadir pH <7.00, and age ≥65 years were significantly associated with higher rates of in-hospital mortality among massively transfused patients. Incorporating these clinical parameters into a futility index for massive transfusions will be useful in situations where blood products are scarce and/or mortality may be unavoidable.


Blood Transfusion , Hospital Mortality , Hydrogen-Ion Concentration , Lactates/blood , Medical Futility , Adult , Age Factors , Aged , Area Under Curve , Biomarkers/blood , Female , Hospital Departments , Humans , Male , Middle Aged , Postoperative Complications/mortality , Prognosis , ROC Curve , Retrospective Studies , Surgical Procedures, Operative , Young Adult
6.
Mol Biol Evol ; 38(7): 2818-2830, 2021 06 25.
Article En | MEDLINE | ID: mdl-33720357

Viruses closely related to human pathogens can reveal the origins of human infectious diseases. Human herpes simplexvirus type 1 (HSV-1) and type 2 (HSV-2) are hypothesized to have arisen via host-virus codivergence and cross-species transmission. We report the discovery of novel herpes simplexviruses during a large-scale screening of fecal samples from wild gorillas, bonobos, and chimpanzees. Phylogenetic analysis indicates that, contrary to expectation, simplexviruses from these African apes are all more closely related to HSV-2 than to HSV-1. Molecular clock-based hypothesis testing suggests the divergence between HSV-1 and the African great ape simplexviruses likely represents a codivergence event between humans and gorillas. The simplexviruses infecting African great apes subsequently experienced multiple cross-species transmission events over the past 3 My, the most recent of which occurred between humans and bonobos around 1 Ma. These findings revise our understanding of the origins of human herpes simplexviruses and suggest that HSV-2 is one of the earliest zoonotic pathogens.


Hominidae/virology , Phylogeny , Simplexvirus/genetics , Viral Zoonoses , Animals , Herpesvirus 2, Human , Humans , Sequence Analysis, DNA
7.
J Cardiothorac Vasc Anesth ; 35(4): 1060-1066, 2021 Apr.
Article En | MEDLINE | ID: mdl-32928652

OBJECTIVE: To assess the ratio of non-red blood cell to red blood cell components required to avoid coagulopathy when transfusing large amounts of salvaged blood using laboratory test-guided therapy. DESIGN: Retrospective cohort study. SETTING: Single-center, academic hospital. PARTICIPANTS: Thoracoabdominal and abdominal open aortic surgery patients. MEASUREMENT AND MAIN RESULTS: Thirty-eight patients in whom at least 1,000 mL of salvaged red blood cells were transfused were identified and divided into the following 2 cohorts: 1,000-to-2,000 mL of salvaged red blood cells (high dose) (n = 20) and >2,000 mL of salvaged red blood cells (ultra-high dose) (n = 18). Compared with the high-dose cohort, the ultra high-dose cohort received ∼4 times more salvaged red blood cells (1,240 ± 279 mL v 5,550 ± 3,801 mL). With transfusion therapy guided by intraoperative coagulation tests and thromboelastography, the adjusted ratio of non-red blood cell to red blood cell components (plasma + platelets + cryoprecipitate:allogeneic + salvaged red blood cells) was 0.59 ± 0.66 in the high-dose and 0.93 ± 0.27 in the ultra high-dose cohorts. Multiple coagulation parameters were normal and similar between cohorts at the end of surgery, as determined by the mean, median, and 95% confidence intervals. CONCLUSIONS: When transfusing large volumes of salvaged blood, it is important to balance the ratio between non-red blood cell and red blood cell components. Through a laboratory test-guided approach, coagulopathy was not detected when transfusing blood in ratios of approximately 1:2 for patients receiving 1,000-to-2,000 mL of salvaged blood and 1:1 for patients receiving >2,000 mL of salvaged blood.


Blood Transfusion , Operative Blood Salvage , Blood Coagulation , Blood Component Transfusion , Blood Transfusion, Autologous , Humans , Retrospective Studies , Thrombelastography
8.
Transfusion ; 60(11): 2581-2590, 2020 11.
Article En | MEDLINE | ID: mdl-32897635

BACKGROUND: Over the past decade, patient blood management (PBM) programs have been developed to reduce allogeneic blood utilization. This is particularly important in pancreatic surgery, which has historically been associated with high transfusion requirements and morbid event rates. This study investigated blood utilization and clinical outcomes in pancreatic surgery before, during, and after the implementation of PBM. STUDY DESIGN AND METHODS: A total of 3482 pancreatic surgery patients were assessed in a 10-year retrospective cohort study (2009-2019) at a single academic center. Baseline patient characteristics, transfusion practices, postoperative morbidity (infectious, thrombotic, ischemic, respiratory, and renal complications), mortality, and length of stay were compared between patients in the pre-PBM (2009-2013), early-PBM (2014-2016), and mature-PBM (2017-2019) time periods. Multivariable analysis assessed the odds for composite morbidity/mortality. RESULTS: Comparing the mature-PBM to pre-PBM cohorts, transfused units per 100 discharged patients decreased by 53% for erythrocytes (155 to 73; P < .0001), 81% for plasma (79 to 15; P < .038), and 75% for platelets (10 to 2.5; P < .005). Clinical outcomes improved as well, with composite morbid event rates decreasing by more than 50%, from 236 in 1438 patients (16.4%) to 85 in 1145 patients (7.4%) (P < .0001). Mortality and length of stay remained unchanged. Compared to the pre-PBM time period, early-PBM was associated with a risk-adjusted decrease in composite morbidity/mortality (OR 0.73; 95% CI 0.57-0.93; P = .010), while mature-PBM demonstrated a further incremental decrease (OR 0.44; 95% CI 0.33-0.57; P < .0001). CONCLUSIONS: The implementation of PBM was associated with substantially decreased blood utilization in pancreatic surgery, without negatively impacting clinical outcomes.


Blood Component Transfusion , Digestive System Surgical Procedures/adverse effects , Length of Stay , Pancreas/surgery , Adult , Disease-Free Survival , Female , Humans , Male , Middle Aged , Postoperative Complications/metabolism , Postoperative Complications/prevention & control , Retrospective Studies , Survival Rate
9.
Jt Comm J Qual Patient Saf ; 46(9): 524-530, 2020 09.
Article En | MEDLINE | ID: mdl-32682692

BACKGROUND: The objective of this study was to determine if anesthesia providers can accurately estimate the cost of commonly used medications, supplies, and blood products. METHODS: This study was conducted between April and June 2019 at an academic tertiary care hospital. Anesthesia providers (certified registered nurse anesthetists [CRNAs], residents, and fellows/attendings) were surveyed on their knowledge of the cost of commonly used therapies. Items were sorted into 12 categories: opioids, non-opioid analgesia, vasopressors, hypertension medications, antibiotics, neuromuscular blockers, reversals, anesthetics, supplies, kits, blood products, and blood-related products. Estimates were considered to be accurate if the median cost differed from the average wholesale price by < 25%, moderately inaccurate if between 25% and 50%, and severely inaccurate if by > 50%. RESULTS: A total of 107 surveys (CRNAs: 25, residents: 36, fellows/attendings: 46) were returned. The percentage of total items accurately estimated for cost was low (22% for all providers), and was not different between provider types (27% for CRNAs, 23% for residents, 20% for fellows/attendings; p = 0.69). The percentage of items with severe inaccuracies in cost estimation was high and was not different between provider types (56% for CRNAs, 60% for residents, 50% for fellows/attendings; p = 0.53). Rates of under- and overestimation varied widely, with greatest underestimation for vasopressors and blood-related products, and greatest overestimation for non-opioid analgesia and antibiotics. Low- and high-cost category items tended to be overestimated and underestimated, respectively (p < 0.0001). CONCLUSION: The majority of anesthesia providers have poor knowledge of cost. These findings suggest that cost awareness interventions may be necessary for promoting high-value health care.


Anesthesia , Nurse Anesthetists , Humans , Surveys and Questionnaires
10.
Transfusion ; 60(8): 1741-1746, 2020 08.
Article En | MEDLINE | ID: mdl-32579271

BACKGROUND: Transvenous lead extractions (TLEs) have increased in number due to an increased prevalence of cardiac implantable devices. Bleeding complications associated with TLEs can be catastrophic, and many institutions order blood components to be available in the procedure room. There are few studies supporting or refuting this practice. We evaluated transfusion rates for TLEs at a single, high-volume center to assess the need for having blood in the procedure room. STUDY DESIGN AND METHODS: Patients undergoing TLEs from April 2010 to February 2019 were identified from our institutional database. The percentage of patients transfused intraoperatively, the number of units transfused, and the reasons for transfusion were determined from the database and by manual chart review. RESULTS: A total of 473 patients underwent a TLE during this time frame. Of these, only 17 patients (3.6%) received a red blood cell (RBC) transfusion. Ten of the 17 patients received RBCs secondary to preoperative anemia. Of the remaining seven patients, only four patients received more than 2 RBC units, and only one received more than 10 RBC units. No patient received more than 2 RBC units or any plasma or platelets in the past 4 years. CONCLUSION: Due to improvements in procedural techniques, advent of accessible remote blood allocation systems, and changes in transfusion practice (e.g., electronic crossmatch), routinely having blood components in the procedure room for every TLE may be an outdated practice for high-volume centers.


Anemia , Continuous Renal Replacement Therapy , Databases, Factual , Defibrillators, Implantable , Erythrocyte Transfusion , Lead/blood , Preoperative Care , Adult , Aged , Aged, 80 and over , Anemia/blood , Anemia/therapy , Female , Humans , Male , Middle Aged
11.
Science ; 368(6497): 1367-1370, 2020 06 19.
Article En | MEDLINE | ID: mdl-32554594

Many infectious diseases are thought to have emerged in humans after the Neolithic revolution. Although it is broadly accepted that this also applies to measles, the exact date of emergence for this disease is controversial. We sequenced the genome of a 1912 measles virus and used selection-aware molecular clock modeling to determine the divergence date of measles virus and rinderpest virus. This divergence date represents the earliest possible date for the establishment of measles in human populations. Our analyses show that the measles virus potentially arose as early as the sixth century BCE, possibly coinciding with the rise of large cities.


Communicable Diseases, Emerging/history , Evolution, Molecular , Genetic Variation , Measles virus/genetics , Measles/history , Cities/history , Communicable Diseases, Emerging/virology , History, Ancient , Humans , Measles/virology , Rinderpest virus/genetics
12.
Emerg Infect Dis ; 26(6): 1283-1286, 2020 06.
Article En | MEDLINE | ID: mdl-32441635

Yaws-like lesions are widely reported in wild African great apes, yet the causative agent has not been confirmed in affected animals. We describe yaws-like lesions in a wild chimpanzee in Guinea for which we demonstrate infection with Treponema pallidum subsp. pertenue. Assessing the conservation implications of this pathogen requires further research.


Yaws , Animals , Guinea/epidemiology , Pan troglodytes , Treponema , Treponema pallidum/genetics , Yaws/epidemiology , Yaws/veterinary
13.
Anesth Analg ; 131(3): 901-908, 2020 09.
Article En | MEDLINE | ID: mdl-32304461

BACKGROUND: Patients requiring extracorporeal membrane oxygenation (ECMO) support are critically ill and have substantial transfusion requirements, which convey both risks and benefits. A retrospective analysis was conducted to assess the association between blood component administration and adverse outcomes in adult, pediatric, and neonatal ECMO patients. METHODS: We evaluated 217 ECMO patients at a single center hospitalized between January 2009 and June 2016. Three cohorts (88 adult, 57 pediatric, and 72 neonatal patients) were included for assessment of patient characteristics, blood utilization, and clinical outcomes. Univariable and multivariable analyses were used to assess the association between transfusions and clinical outcomes (primary outcome: mortality and secondary outcomes: morbid events). The analysis included the main exposure of interest (total number of blood component units transfused) and potential confounding variables (age group cohort, case mix index, sex, ECMO mode and duration, and primary ECMO indication). RESULTS: After adjustment for confounders, with each additional blood component unit transfused, there was an estimated increase in odds for mortality by 1% (odds ratio [OR] = 1.01; 95% confidence interval [CI], 1.00-1.02; P = .013) and an increase in odds for thrombotic events by 1% (OR = 1.01; 95% CI, 1.00-1.02; P = .007). Mortality was higher in the adult (57 of 88; 64.8%) and pediatric (37 of 57; 64.9%) than in the neonatal cohort (19 of 72; 26.4%) (P < .0001). Median total blood components transfused per day followed a similar pattern for the adult (2.3 units; interquartile range [IQR] = 0.8-7.0), pediatric (2.9 units; IQR = 1.1-10), and neonatal (1.0 units; IQR = 0.7-1.6) cohorts (P < .0001). Over the entire hospitalization, the total median blood components transfused was highest in the neonatal (41 units; IQR = 24-94) and pediatric (41 units; IQR = 17-113) compared to the adult (30 units; IQR = 9-58) cohort (P = .007). There was no significant interaction between total units transfused over the hospital stay and age cohort for mortality (P = .35). CONCLUSIONS: Given the association between transfusion and adverse outcomes, effective blood management strategies may be beneficial in ECMO patients.


Blood Transfusion , Critical Illness/therapy , Extracorporeal Membrane Oxygenation , Adolescent , Adult , Age Factors , Baltimore , Blood Transfusion/mortality , Child , Child, Preschool , Critical Illness/mortality , Databases, Factual , Extracorporeal Membrane Oxygenation/adverse effects , Extracorporeal Membrane Oxygenation/mortality , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Transfusion Reaction/mortality , Treatment Outcome , Young Adult
14.
J Neurosurg Spine ; : 1-9, 2020 Mar 20.
Article En | MEDLINE | ID: mdl-32197253

OBJECTIVE: Blood transfusions are given to approximately one-fifth of patients undergoing elective lumbar spine surgery, and previous studies have shown that transfusions are accompanied by increased complications and additional costs. One method for decreasing transfusions is administration of tranexamic acid (TXA). The authors sought to evaluate whether the cost of TXA is offset by the decrease in blood utilization in lumbar spine surgery patients. METHODS: The authors retrospectively reviewed patients who underwent elective lumbar or thoracolumbar surgery for degenerative conditions at a tertiary care center between 2016 and 2018. Patients who received intraoperative TXA (TXA patients) were matched with patients who did not receive TXA (non-TXA patients) by age, sex, BMI, ASA (American Society of Anesthesiologists) physical status class, and surgical invasiveness score. Primary endpoints were intraoperative blood loss, number of packed red blood cell (PRBC) units transfused, and total hemostasis costs, defined as the sum of TXA costs and blood transfusion costs throughout the hospital stay. A subanalysis was then performed by substratifying both cohorts into short-length (1-4 levels) and long-length (5-8 levels) spinal constructs. RESULTS: Of the 1353 patients who met inclusion criteria, 68 TXA patients were matched to 68 non-TXA patients. Patients in the TXA group had significantly decreased mean intraoperative blood loss (1039 vs 1437 mL, p = 0.01). There were no differences between the patient groups in the total costs of blood transfusion and TXA (p = 0.5). When the 2 patient groups were substratified by length of construct, the long-length construct group showed a significant net cost savings of $328.69 per patient in the TXA group (p = 0.027). This result was attributable to the finding that patients undergoing long-length construct surgeries who were given TXA received a lower amount of PRBC units throughout their hospital stay (2.4 vs 4.0, p = 0.007). CONCLUSIONS: TXA use was associated with decreased intraoperative blood loss and significant reductions in total hemostasis costs for patients undergoing surgery on more than 4 levels. Furthermore, the use of TXA in patients who received short constructs led to no additional net costs. With the increasing emphasis put on value-based care interventions, use of TXA may represent one mechanism for decreasing total care costs, particularly in the cases of larger spine constructs.

15.
Transfusion ; 59(12): 3639-3645, 2019 12.
Article En | MEDLINE | ID: mdl-31625178

BACKGROUND: Patient blood management (PBM) is especially applicable in major spine surgery, during which bleeding and transfusion are common. What remains unclear in this setting is the overall impact of bundled PBM measures on transfusion requirements and clinical outcomes. We compared these outcomes before and after implementing a PBM program. STUDY DESIGN AND METHODS: We conducted a retrospective review of 928 adult complex spine surgery patients performed by a single surgeon between January 2009 and June 2016. Although PBM measures were phased in over time, tranexamic acid (TXA) administration became standard protocol in July 2013, which defined our pre- and post-PBM periods. Transfusion rates for all blood components before and after PBM implementation were compared, as were morbid event rates and mortality. RESULTS: Baseline characteristics were similar before and after PBM. Before PBM, the mean number of units/patient decreased for red blood cells (RBCs; by 19.5%; p = 0.0057) and plasma (by 33%; p = 0.0008), but not for platelets (p = 0.15). After risk adjustment by multivariable analyses, the composite outcome of morbidity or mortality showed a nonsignificant trend toward improvement after PBM (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.39-1.01; p = 0.055), and the risk of thrombotic events was unchanged (OR, 1.12; 95% CI, 0.42-2.58; p = 0.80). CONCLUSION: In complex spine surgery, a multifaceted PBM program that includes TXA can be advantageous by reducing transfusion requirements without changing clinical outcomes.


Blood Transfusion/methods , Spine/surgery , Adult , Aged , Blood Loss, Surgical/prevention & control , Female , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Retrospective Studies , Tranexamic Acid/therapeutic use
16.
J Neurosci ; 38(42): 8922-8942, 2018 10 17.
Article En | MEDLINE | ID: mdl-30150361

Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α2A-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.SIGNIFICANCE STATEMENT Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.


Anxiety/physiopathology , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/physiology , Neurons/physiology , Receptors, Adrenergic, alpha-2/physiology , Septal Nuclei/physiology , Stress, Psychological/physiopathology , Adrenergic alpha-2 Receptor Agonists/administration & dosage , Animals , Catecholamines/metabolism , Female , Guanfacine/administration & dosage , Male , Mice, Inbred C57BL , Mice, Transgenic , Neurons/drug effects , Neurons/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Septal Nuclei/diagnostic imaging , Septal Nuclei/metabolism
17.
Mol Ecol Resour ; 18(3): 502-510, 2018 May.
Article En | MEDLINE | ID: mdl-29328547

Wildlife detection in urban areas is very challenging. Conventional monitoring techniques such as direct observation are faced with the limitation that urban wildlife is extremely elusive. It was recently shown that invertebrate-derived DNA (iDNA) can be used to assess wildlife diversity in tropical rainforests. Flies, which are ubiquitous and very abundant in most cities, may also be used to detect wildlife in urban areas. In urban ecosystems, however, overwhelming quantities of domestic mammal DNA could completely mask the presence of wild mammal DNA. To test whether urban wild mammals can be detected using fly iDNA, we performed DNA metabarcoding of pools of flies captured in Berlin, Germany, using three combinations of blocking primers. Our results show that domestic animal sequences are, as expected, very dominant in urban environments. Nevertheless, wild mammal sequences can often be retrieved, although they usually only represent a minor fraction of the sequence reads. Fly iDNA metabarcoding is therefore a viable approach for quick scans of urban wildlife diversity. Interestingly, our study also shows that blocking primers can interact with each other in ways that affect the outcome of metabarcoding. We conclude that the use of complex combinations of blocking primers, although potentially powerful, should be carefully planned when designing experiments.


Cities , Diptera/genetics , Mammals/genetics , Animals , Animals, Domestic/classification , Animals, Domestic/genetics , Biodiversity , Diptera/physiology , Ecosystem , Humans , Mammals/classification , Sequence Analysis, DNA
18.
Nature ; 548(7665): 82-86, 2017 08 02.
Article En | MEDLINE | ID: mdl-28770842

Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported. Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation.


Animal Diseases/mortality , Animals, Wild/microbiology , Anthrax/veterinary , Bacillus anthracis/pathogenicity , Mammals/microbiology , Rainforest , Tropical Climate , Africa South of the Sahara , Animal Diseases/microbiology , Animals , Anthrax/microbiology , Anthrax/mortality , Bacillus anthracis/isolation & purification , Diptera/microbiology , Extinction, Biological , Female , Male , Pan troglodytes/microbiology , Parks, Recreational , Phylogeny
19.
Mol Biol Evol ; 34(7): 1713-1721, 2017 07 01.
Article En | MEDLINE | ID: mdl-28369565

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are seen as close relatives but also unambiguously considered as evolutionary independent units. Here, we sequenced the genomes of 18 HSV-2 isolates characterized by divergent UL30 gene sequences to further elucidate the evolutionary history of this virus. Surprisingly, genome-wide recombination analyses showed that all HSV-2 genomes sequenced to date contain HSV-1 fragments. Using phylogenomic analyses, we could also show that two main HSV-2 lineages exist. One lineage is mostly restricted to subSaharan Africa whereas the other has reached a global distribution. Interestingly, only the worldwide lineage is characterized by ancient recombination events with HSV-1. Our findings highlight the complexity of HSV-2 evolution, a virus of putative zoonotic origin which later recombined with its human-adapted relative. They also suggest that coinfections with HSV-1 and 2 may have genomic and potentially functional consequences and should therefore be monitored more closely.


Simplexvirus/genetics , Base Sequence , Biological Evolution , DNA, Viral/genetics , Evolution, Molecular , Genetic Variation , Genome/genetics , Genome, Viral , Genomics , Herpesvirus 1, Human/genetics , Herpesvirus 2, Human/genetics , Phylogeny , Recombination, Genetic/genetics , Sequence Analysis, DNA/methods
20.
Sci Rep ; 6: 37952, 2016 11 30.
Article En | MEDLINE | ID: mdl-27901062

Monitoring wildlife infectious agents requires acquiring samples suitable for analyses, which is often logistically demanding. A possible alternative to invasive or non-invasive sampling of wild-living vertebrates is the use of vertebrate material contained in invertebrates feeding on them, their feces, or their remains. Carrion flies have been shown to contain vertebrate DNA; here we investigate whether they might also be suitable for wildlife pathogen detection. We collected 498 flies in Taï National Park, Côte d'Ivoire, a tropical rainforest and examined them for adenoviruses (family Adenoviridae), whose DNA is frequently shed in feces of local mammals. Adenoviral DNA was detected in 6/142 mammal-positive flies. Phylogenetic analyses revealed that five of these sequences were closely related to sequences obtained from local non-human primates, while the sixth sequence was closely related to a murine adenovirus. Next-generation sequencing-based DNA-profiling of the meals of the respective flies identified putative hosts that were a good fit to those suggested by adenoviral sequence affinities. We conclude that, while characterizing the genetic diversity of wildlife infectious agents through fly-based monitoring may not be cost-efficient, this method could probably be used to detect the genetic material of wildlife infectious agents causing wildlife mass mortality in pristine areas.


Adenoviridae Infections , Adenoviridae/genetics , DNA, Viral/genetics , Diptera/virology , Epidemiological Monitoring/veterinary , Haplorhini/virology , Insect Vectors/virology , Monkey Diseases , Adenoviridae Infections/epidemiology , Adenoviridae Infections/genetics , Animals , Feces/virology , Genetic Variation , Monkey Diseases/epidemiology , Monkey Diseases/virology , Rainforest
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