bluuebunny/crossref_metadata_2025 huggingface dataset:
Transesophageal Echocardiography-Guided Ventriculoatrial Shunt Insertion
Authors: Isaacs Albert McAnsah , Krahn Danae , Walker Andrew M , Hurdle Heather , Hamilton Mark G
Published: December 2019

BACKGROUND

Determining an optimal location within the right atrium (RA) for placement of the distal ventriculoatrial (VA) shunt catheter offer several operative challenges that place patients at risk for perioperative complications and downstream VA shunt failure. Utilizing transesophageal echocardiography (TEE) guidance to place distal VA shunt catheters may help to circumvent these risks.

OBJECTIVE

To review our current practice of VA shunt insertion using TEE guidance.

METHODS

A retrospective review of all consecutive patients who underwent VA shunt procedures between December 19, 2016 and January 22, 2019, during which time intraoperative TEE was used for shunt placement was performed. Data on the time required for shunt placement and total procedure time, baseline echocardiography findings, and short- and long-term complications of shunt placement were assessed.

RESULTS

A total of 33 patients underwent VA shunt procedures, with a median follow-up time of 250 (88-412) d. The only immediate complication related to shunt placement or TEE use was transient ectopy in 1 patient. The mean time for atrial catheter insertion was 12.6 ± 4.8 min. Right-heart catheters were inserted between the RA-superior vena cava junction and 22 mm within the RA in all but 3 procedures. A total of 7/33 patients (21%) underwent shunt revision. Indications for revisions included distal clots, proximal obstruction, positive blood culture, and shunt valve revision. No other complications of VA shunt insertion were reported.

CONCLUSION

VA shunt insertion using TEE allows for precise distal catheter placement. Early patient experience confirms this technique has a low complication rate.
Microsurgical Resection of the IV Ventricle Subependymoma: 2-Dimensional Operative Video
Authors: Pojskić Mirza , Nguyen Vincent N , Boop Frederick A , Arnautović Kenan I
Published: December 2019

In this video, we demonstrate microsurgical resection of IV ventricle subependymoma. To the best of our knowledge, this is the first video case report of a microsurgical resection of subependymoma of the IV ventricle in the peer-reviewed English literature.

Subependymomas are benign central nervous system tumors, typically arising in ventricular spaces, mostly in the IV and lateral ventricles.
1-3
They are isointense on T1 and hyperintense on T2-weighted magnetic resonance imaging (MRI) with minimal or no enhancement.
4
Microsurgery remains the mainstay treatment. Complete tumor resection is possible and curative with excellent prognosis.
1,5-7
Although the clinical course appears benign, the inability to diagnose them radiographically with certainty and the possibility of an alternative malignant lesion support a low threshold for early and safe resection.
8

A 39-yr-old man presented with severe headache and balance problems. Pre- and postcontrast neuroaxis MRI revealed a centrally located IV ventricle lesion without hydrocephalus. The aim of the surgery was complete tumor resection. Surgery was performed in the prone position by the senior author (KIA) with intraoperative neurophysiology monitoring. A small suboccipital craniotomy and C1 posterior arch removal was done. After opening the dura and arachnoid membrane, the tumor was identified and meticulously dissected from the adjacent posterior inferior cerebellar artery and the floor of the fourth ventricle and from brain stem white matter at the tumor-neural tissue interface to avoid brainstem interference. Histological analysis revealed subependymoma (World Health Organization Grade I). Postoperative pre- and postcontrast MRI revealed complete resection. Headache and balance problems completely resolved; the patient was neurologically intact.

The patient provided written consent and permission to publish his image.
BOGOMOLOV MULTIPLIERS OF P-GROUPS OF MAXIMAL CLASS
Authors: FernÁndez-Alcober Gustavo A , Jezernik Urban
Published: December 2019

Let $G$ be a $p$-group of maximal class and order $p^n$. We determine whether or not the Bogomolov multiplier ${\operatorname{B}}_0(G)$ is trivial in terms of the lower central series of $G$ and $P_1 = C_G(\gamma _2(G) / \gamma _4(G))$. If in addition $G$ has positive degree of commutativity and $P_1$ is metabelian, we show how understanding ${\operatorname{B}}_0(G)$ reduces to the simpler commutator structure of $P_1$. This result covers all $p$-groups of maximal class of large-enough order, and, furthermore, it allows us to give the first natural family of $p$-groups containing an abundance of groups with non-trivial Bogomolov multipliers. We also provide more general results on Bogomolov multipliers of $p$-groups of arbitrary coclass $r$.
Community-based prevention of epidemic Rocky Mountain spotted fever among minority populations in Sonora, Mexico, using a One Health approach
Authors: Alvarez-Hernandez Gerardo , Drexler Naomi , Paddock Christopher D , Licona-Enriquez Jesus D , la Mora Jesus Delgado-de , Straily Anne , del Carmen Candia-Plata Maria , Cruz-Loustaunau Denica I , Arteaga-Cardenas Vanessa A
Published: December 2019

Background

Rocky Mountain spotted fever (RMSF) is a significant public health problem in Sonora, Mexico, resulting in thousands of cases and hundreds of deaths. Outbreaks of RMSF are perpetuated by heavy brown dog tick infestations in and around homes. During 2009–2015, there were 61 RMSF cases and 23 deaths in a single community of Sonora (Community A).

Methods

An integrated intervention was carried out from March–November 2016 aimed at reducing tick populations with long-acting acaricidal collars on dogs, environmental acaricides applied to peri-domestic areas and RMSF education. Tick levels were measured by inspection of community dogs to monitor efficacy of the intervention. A similar neighborhood (Community B) was selected for comparison and received standard care (acaricide treatment and education).

Results

The prevalence of tick-infested dogs in Community A declined from 32.5% to 8.8% (p<0.01). No new cases of RMSF were identified in this area during the subsequent 18 mo. By comparison, the percentage of tick-infested dogs in Community B decreased from 19% to 13.4% (p=0.36) and two cases were reported, including one death.

Conclusions

Community-based interventions using an integrated approach to control brown dog ticks can diminish the morbidity and mortality attributable to RMSF.
Seroprevalence and associated risk factors of toxocariasis among nomads in Boyer-Ahmad County, southwest Iran
Authors: Arefkhah Nasir , Shadzi Mohammad Reza , Mikaeili Fattaneh , Sarkari Bahador , Esfandiari Farideh , Goudarzi Fatemeh
Published: December 2019

Background

Human toxocariasis is caused by the larval stage of Toxocara canis and Toxocara cati. This cross-sectional study was conducted to evaluate the seroprevalence and the risk factors associated with Toxocara infection in nomads of Boyer-Ahmad County in the southwest of Iran.

Methods

A total of 968 blood samples were collected from nomads. A structured questionnaire, containing sociodemographic data, was completed for each participant. Sera were evaluated for anti-Toxocara antibodies, using the T. canis excretory-secretory antigens prepared from the second stage larvae, in an ELISA system.

Results

Among the 968 participants, 220 (22.7%) were males and 748 (77.3%) were females; the mean age was 40.71 y. Anti-Toxocara IgG antibodies were detected in 14 (1.4%) of the 968 nomads. The association between Toxocara infection and gender, age, contact with dogs, residential area and level of education were not statistically significant (p>0.05).

Conclusions

The findings of the study revealed a low prevalence rate of toxocariasis in nomadic communities in southwest Iran. Geographic location and climatic conditions as well as the lifestyle and sociodemographic features of the participants may contribute to the low prevalence rate of Toxocara infection.
Serological assays for the diagnosis of Strongyloides stercoralis infection: a systematic review and meta-analysis of diagnostic test accuracy
Authors: Kalantari Narges , Chehrazi Mohammad , Ghaffari Salman , Gorgani-Firouzjaee Tahmineh
Published: December 2019

The standard method for the diagnosis of Strongyloides stercoralis, stool examinations, is inconvenient and, therefore, serological methods have been proposed. This study aimed to evaluate the accuracy of serological assays for the diagnosis of strongyloidiasis using a systematic review and meta-analysis model.

Four electronic databases were reviewed. We used a random effects model and 95% CIs to determine the overall sensitivity, specificity and diagnostic odds ratio (DOR). Heterogeneity was intended with Cochran Q χ2 test and I2 statistic.

The accuracy of serological assays resulted in a sensitivity of 71.7% (95% CI: 56.07 to 83.4%), a specificity of 89.9% (95% CI: 80.8 to 94.9%) and a DOR of 22.5 (95% CI: 10.8 to 46.9). The forest plot showed high heterogeneity regarding sensitivity (I2=90.4%, 95% CI: 87.4 to 93.3%; Q=228.1, p=0.000) and specificity (I2=98.9%, 95% CI: 98.8 to 99.1%; Q=2066.4, p=0.000). Fagan's nomogram showed that the probability of someone having the infection and with a positive test result was 49%. Deeks' funnel plots showed no evidence of potential publication bias for the studies (p=0.26).

The current review suggests that serological techniques have acceptable sensitivity and specificity and therefore can be recommended for the screening of S. stercoralis infection.
IL‐18R‐dependent and independent pathways account for IL‐18‐enhanced antitumor ability of CAR‐T cells
Authors: Huang Yong , Li Dan , Zhang Peng‐Fei , Liu Mei , Liang Xiao , Yang Xiao , Jiang Lin , Zhang Li‐Feng , Zhou Wei‐Lin , Su Jin‐Hua , Gong You‐Ling , Gou Hong‐Feng , Wei Yu‐Quan , Wang Wei
Published: December 2019

Interleukin‐18 (IL‐18) has been demonstrated to augment the antitumor capacity of chimeric antigen receptor‐T cells (CAR‐T) but the underlying mechanisms are largely unknown. Here we explored the effects and mechanisms of exogenous IL‐18 on the antitumor response of CAR‐T cells. IL‐18 boosted the cytotoxicity of human epidermal growth factor receptor‐2 (HER2)‐specific CAR‐T cells ex vivo and enhanced the antitumor efficacy of the CAR‐T cells in immunodeficient mice, moreover, IL‐18 improved the antitumor capacity of OVA‐specific T cells in immunocompetent mice, indicating the universal enhancing function of IL‐18 for adoptive cell therapy. To address the roles of IL‐18 receptor (IL‐18R) in the enhancing function, we evaluated the effects of IL‐18R knockout (IL‐18R−/−) condition in immunocompetent host and CAR‐T cells on the IL‐18‐enhanced antitumor activities. Interestingly, IL‐18 persisted to improve the antitumor ability of IL‐18R intact CAR‐T cells in IL‐18R−/− mice. For IL‐18R−/− CAR‐T cells, however, IL‐18 still holds the enhancing ability to boost the antitumor efficacy in IL‐18R−/− mice, albeit the ex vivo tumor‐killing ability was lower than that of IL‐18R intact CAR‐T cells, indicating that IL‐18R‐independent pathway is involved in the enhancement. Furthermore, tagged IL‐18 binded to the membrane of IL‐18R−/− splenic and lymph node cells and IL‐18R intact and IL‐18R−/− CAR‐T cells showed distinct transcriptomic profiles when stimulated by IL-18. These data demonstrate that IL‐18R‐independent pathways contribute to functions of IL‐18.
Icariin and its phosphorylated derivatives alleviate intestinal epithelial barrier disruption caused by enterotoxigenic Escherichia coli through modulate p38 MAPK in vivo and in vitro
Authors: Xiong Wen , Huang Jing , Li Xueying , Zhang Zhu , Jin Meilan , Wang Jian , Xu Yuwei , Wang Zili
Published: December 2019

The natural product icariin (ICA) and its phosphorylated derivatives (pICA) have been shown to have outstanding anti‐inflammatory and antioxidant properties. This study was to explore the protective effects of ICA and pICA on the intestinal epithelium of enterotoxigenic Escherichia coli (ETEC)‐induced piglet diarrhea and its underlying mechanisms in vivo and in vitro. ETEC K88 increased pro‐inflammatory cytokine expression, activated oxidative stress and inhibited antioxidant enzyme activity, induced phosphorylated p38 MAPK gene and protein expression, disrupted intestinal barrier function, and led to diarrhea in piglets. Pretreatment with ICA and pICA effectively alleviated ETEC‐induced intestinal barrier dysfunction in vivo and in vitro. Pretreatment with p38 MAPK inhibitor (SB203580) significantly rescued the IPEC‐J2 cells barrier function damaged by ETEC challenge. However, pretreatment with p38 MAPK activator (anisomycin) did not alleviated the IPEC‐J2 cells barrier function damaged by ETEC challenge. Our data demonstrated that ICA and pICA regulate the inflammatory response and oxidative stress of intestinal epithelial cells by inhibiting the expression of p38 MAPK, thereby alleviating ETEC K88‐induced disruption of intestinal barrier function and intestinal permeability. These findings provide new insights into the prevention and treatment of intestinal barrier dysfunction induced by ETEC K88.
Local nucleosome dynamics and eviction following a double-strand break are reversible by NHEJ-mediated repair in the absence of DNA replication
Authors: Tripuraneni Vinay , Memisoglu Gonen , Zhu Wei , Tran Trung , Hartemink Alexander J , Haber James E , MacAlpine David M
Published: December 2019

Although the molecular events required for the repair of double-strand breaks (DSB) have been well characterized, the role of epigenetic processes in the recognition and repair of DSBs has only been investigated at low resolution. We rapidly and synchronously induced a site-specific DSB inSaccharomyces cerevisiaeupstream of thePHO5locus, which has well-positioned nucleosomes. Utilizing MNase-seq epigenome mapping we interrogated the order of chromatin changes that occur immediately following a DSB by generating a base-pair resolution map of the chromatin landscape. In wild type cells, the first nucleosome left of the break was rapidly evicted. The eviction of this flanking nucleosome was dynamic and proceeded through an early intermediate chromatin structure where the nucleosome was repositioned in the adjacent linker DNA. Other nucleosomes bordering both sides of the break were also shifted away from the break; however, their loss was more gradual. These local changes preceded a broader loss of chromatin organization and nucleosome eviction that was marked by increased MNase sensitivity in the regions ∼8 kb on each side of the break. While the broad loss of chromatin organization was dependent on the end-processing complex, Mre11-Rad50-Xrs2 (MRX), the early remodeling and repositioning of the nucleosome adjacent to the break was independent of the MRX and YKU70/80 complexes. We also examined the temporal dynamics of NHEJ-mediated repair in a G1-arrested population, where 5’ to 3’ end-resection of DSB ends is blocked. Concomitant with DSB repair, we observed the re-deposition and precise re-positioning of nucleosomes at the originally-occupied positions. This re-establishment of the pre-lesion chromatin landscape suggests that a DNA replication-independent mechanism exists in G1 cells to preserve epigenome organization following DSB repair.
HIV-DRLink: A tool for detecting linked HIV-1 drug resistance mutations in next generation sequencing data
Authors: Shao Wei , Boltz Valerie F. , Hattori Junko , Bale Michael J. , Maldarelli Frank , Coffin John M. , Kearney Mary F.
Published: December 2019

The prevalence of HIV-1 drug resistance is increasing worldwide and monitoring its emergence is important for the successful management of populations receiving combination antiretroviral therapy (cART). Using Ultrasensitive Single-Genome Sequencing (uSGS), a next-generation method that avoids PCR bias and PCR recombination, a recent report showed that pre-existing dual-class drug resistance mutations linked on the same viral genomes were predictive of treatment failure while unlinked mutations were not. Because of the large numbers of sequences generated by uSGS and other next-generation sequencing methods, it is difficult to assess each sequence individually for linked resistance mutations. Several software/programs exist to report the frequencies of individual mutations in large datasets but they provide no information on their linkage. Here, we report the HIV-DRLink program, a research tool that provides mutation frequencies in the total dataset as well as their linkage to other mutations conferring resistance to the same or different drug classes. The HIV-DRLink program should only be used on datasets generated by methods that eliminate artifacts due to PCR recombination, for example, standard Single-Genome Sequencing (SGS) or Ultrasensitive Single-Genome Sequencing (uSGS). HIV-DRLink is exclusively a research tool and is not intended to inform clinical decisions.
Distinct activities of Scrib module proteins organize epithelial polarity
Authors: Khoury Mark J. , Bilder David
Published: December 2019

A polarized architecture is central to both epithelial structure and function. In many cells, polarity involves mutual antagonism between the Par complex and the Scrib module. While molecular mechanisms underlying Par-mediated apical determination are well-understood, how Scrib module proteins specify the basolateral domain remains unknown. Here, we demonstrate dependent and independent activities of Scrib, Dlg and Lgl using the Drosophila follicle epithelium. Our data support a linear hierarchy for localization, but rule out previously proposed protein-protein interactions as essential for polarization. Membrane recruitment of Scrib does not require palmitoylation or polar phospholipid binding but instead an independent cortically-stabilizing activity of Dlg. Scrib and Dlg do not directly antagonize aPKC, but may instead restrict aPKC localization by enabling the aPKC-inhibiting activity of Lgl. Importantly, while Scrib, Dlg and Lgl are each required, all three together are not sufficient to antagonize the Par complex. Our data demonstrate previously unappreciated diversity of function within the Scrib module and begin to define the elusive molecular functions of Scrib and Dlg.

SIGNIFICANCE STATEMENT

To enable their physiological functions, cells must polarize their plasma membrane. In many epithelia, polarity is regulated by balanced activity of the apical Par complex and basolateral Scribble module. While the former is understood in molecular detail, little is known about how the latter works. We identify distinct functions of the three Scribble module proteins, separating independent roles in a localization hierarchy from cooperative roles in apical polarity antagonism and showing that they are not together sufficient to specify basolateral identity. This work establishes an essential basis for a mechanistic understanding of this core polarity machinery that controls processes ranging from stem cell divisions to organ morphogenesis across animal species.
An endoribonuclease-based feedforward controller for decoupling resource-limited genetic modules in mammalian cells
Authors: Jones Ross D. , Qian Yili , Siciliano Velia , DiAndreth Breanna , Huh Jin , Weiss Ron , Vecchio Domitilla Del
Published: December 2019

Synthetic biology has the potential to bring forth advanced genetic devices for applications in healthcare and biotechnology. However, accurately predicting the behavior of engineered genetic devices remains difficult due to lack of modularity, wherein a device’s output does not depend only on its intended inputs but also on its context. One contributor to lack of modularity is competition among genes for shared cellular resources, such as those required for transcription and translation, which can induce ‘coupling’ among otherwise independently-regulated genes. Here, we quantify the effects of resource sharing on engineered genetic systems in mammalian cells and develop an endoribonuclease-based incoherent feedforward loop (iFFL) to make gene expression levels robust to changes in resource availability. Our iFFL accurately controls gene expression levels in various cell lines and in the presence of significant resource sequestration by transcriptional activators. In addition to mitigating resource sharing, our iFFL also adapts gene expression to multiple log decades of DNA copy number variation, substantially improving upon previously-described miRNA-based iFFLs. Ultimately, our iFFL device will enable predictable, robust, and context-independent control of gene expression in mammalian cells.
Adaptation to transients disrupts spatial coherence in binocular rivalry
Authors: Naber Marnix , Stuit Sjoerd , de Kloe Yentl , Van der Stigchel Stefan , Paffen Chris L.E.
Published: December 2019

When the two eyes are presented with incompatible images, the visual system fails to create a single, fused, coherent percept. Instead, it creates an ongoing alternation between each eye’s image; a phenomenon dubbed binocular rivalry (BR). Such alternations in awareness are separated by brief, intermediate states during which a spatially mixed (incoherent) pattern of both images is perceived. A recent study proposed that the precedence of mixed percepts positively correlates with the degree of adaptation to conflict between the eyes. However, it neglected the role of visual transients, which covaried with the degree of conflict in the stimulus design. We here study whether the presence of visual transients drive adaptation to interocular conflict and explain incidence rates of spatially incoherent BR. Across three experiments we created several adaptation conditions in which we systematically varied the frequency of transients and the degree of conflict between the eyes. Transients consisted of grating orientation reversals, blanks, and plaids. The results showed that the pattern of variations in the fractions mixed percepts across conditions was best explained by variations in the frequency of visual transients, rather than the degree of conflict between the eyes. We propose that the prolonged presentation of transients to both eyes evokes a chain of events consisting of (1) the exogenous allocation of attention to both images, (2) the increase in perceptual dominance of both rivalling images, (3) the speed up of adaptation of interocular suppression, and eventually (4) the facilitation of mixed perception during BR after adaptation.

Author summary

When one eye is presented with an image that is distinct from the image presented to the other eye, the eyes start to rival and suppress each other’s image. Binocular rivalry leads to perceptual alternations between the images of each eye, during which only one of the images is perceived at a time. However, when the eyes exert weak and shallow mutual suppression, observers tend to perceive both images intermixed more often. Here we designed an experiment and a model to investigate how stereoscopic stimuli can be designed to alter the degree of interocular suppression. We find that prolonged and repeated observations of strong visual transients, such as sudden changes in contrast, can facilitate the adaptation to suppression between the eyes, resulting in that observers report more mixed percepts. This novel finding is relevant to virtual- and augmented reality for which it is crucial to design stereoscopic environments in which binocular rivalry is limited.
The evolutionary origin of the universal distribution of mutation fitness effect
Authors: Barlukova Ayuna , Rouzine Igor M.
Published: December 2019

An intriguing fact long defying explanation is the observation of a universal exponential distribution of beneficial mutations in fitness effect for different microorganisms. Here we use a general and straightforward analytic model to demonstrate that, regardless of the inherent distribution of mutation fitness effect across genomic sites, an observed exponential distribution of fitness effects emerges naturally in the long term, as a consequence of the evolutionary process. This result follows from the exponential statistics of the frequency of the less-fit alleles f predicted to evolve, in the long term, for both polymorphic and monomorphic sites. The exponential distribution disappears when the system arrives at the steady state, when it is replaced with the classical mutation-selection result, f = μ/s. Based on these findings, we develop a technique to measure selection coefficients for specific genomic sites from two single-time sequence sets. Our results demonstrate the striking difference between the distribution of fitness effects observed experimentally, for naturally occurring mutations, and the “inherent” distribution obtained in a directed-mutagenesis experiment, which can have any shape depending on organism. Based on these results, we develop a new method to measure fitness effects of mutations for each variable residue based on DNA sequences isolated from an adapting population at two time points. This new method is not sensitive to linkage effects and does not require one-site model assumptions.
HBV DNA is a substrate for the cGAS/STING pathway but is not sensed in infected hepatocytes
Authors: Lauterbach-Rivière Lise , Bergez Maïwenn , Mönch Saskia , Qu Bingqian , Riess Maximilian , Vondran Florian W. R. , Liese Juliane , Hornung Veit , Urban Stephan , König Renate
Published: December 2019

HBV chronic infection is a critical risk factor for hepatocellular carcinoma. Although debated, the absence of innate immune response to HBV infection in hepatocytes is becoming the current view. However the underlying reasons are poorly understood. This study aims to define potential viral pathogen-associated molecular patterns (PAMPs) and the pattern recognition receptors (PRRs), and to elucidate whether HBV counteracts the innate pathways.

The innate immune response to HBV infection was monitored by interferon-stimulated gene 54 (ISG54) mRNA, a direct downstream transcriptional target of Interferon Regulatory Factor 3 (IRF3), or IRF3 phosphorylation. The immunostimulatory potential of naked HBV DNAs or RNAs and the respective PRRs were determined upon viral nucleic acid transfection in immunocompetent cells including knockout cells lacking key molecules of innate pathways. The expression and functionality of DNA and RNA sensing pathways in primary human hepatocytes (PHH) were assessed. The inhibition of the DNA-sensing pathway by HBV was tested using IRF3 nuclear translocation assay.

Our study revealed that HBV infection does not induce an innate response in infected hepatocytes, even in absence of HBV X protein. HBV relaxed-circular DNA (rcDNA) and DNA replication intermediates, but not HBV RNAs, are immunostimulatory and sensed by Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase (cGAS) and Stimulator of Interferon Genes (STING). Although PHH express DNA sensors to reduced levels compared to myeloid cells, they can respond to naked HBV rcDNA. However, we show that the absence of innate response to HBV infection in hepatocytes is not due to an active inhibition of the DNA sensing pathway by the virus.

HBV passively evades the innate immune response in infected hepatocytes by (i) producing non-immunostimulatory RNAs, (ii) avoiding sensing of its DNAs by cGAS/STING without active inhibition of the pathway, possibly through shielding of the viral DNAs by the capsid.

Author summary

Innate immune responses are the first line of defense against viral infections. They lead to the production of antiviral factors after recognition of specific viral features by the infected cells. Here we show that HBV, a major cause of liver cirrhosis and cancer, avoids recognition by infected hepatocytes through different means. First, HBV RNAs, contrarily to other viral RNAs, are not immunostimulatory. Second, we show that naked HBV DNAs are recognized by cGAS/STING and induce an innate immune response. Furthermore, we demonstrate that this pathway is active in hepatocytes and is not inhibited by the virus. Instead, we propose that HBV DNAs are not accessible to cGAS/STING in the context of an infection. This might be due to shielding of the viral DNA by the viral capsid.
Bacterial and plant produced lipids can exacerbate the Olive Quick Decline Syndrome caused byXylella
Authors: Scala Valeria , Pucci Nicoletta , Salustri Manuel , Modesti Vanessa , L’Aurora Alessia , Scortichini Marco , Zaccaria Marco , Momeni Babak , Reverberi Massimo , Loreti Stefania
Published: December 2019

Xylella fastidiosais an insect vector-transmitted bacterial plant pathogen associated with severe diseases in a wide range of plants. In last decades,X. fastidiosawas detected in several European countries. AmongX. fastidiosasubspecies, here we studyX. fastidiosasubsp.paucaassociated with the Olive Quick Decline Syndrome (OQDS) causing severe losses in Southern Italy. First, we collectedOlea europaeaL. (cv. Ogliarola salentina) samples in groves located in infected zones and uninfected zones. Secondly, the untargeted LC-TOF analysis of the lipid profiles of OQDS positive (+) and negative (-) plants showed a significant clustering of OQDS+ samples apart from OQDS-ones. Thirdly, using HPLC-MS/MS targeted methods and chemometric analysis, we identified a shortlist of 10 lipids significantly different in the infected versus healthy samples. Last, we observed a clear impact onX. fastidiosasubsp.paucagrowth and biofilm formationin vitroliquid cultures supplemented with these compounds.

Considering that growth and biofilm formation are primary ways by whichX. fastidiosacauses disease, our results demonstrate that lipids produced as part of the plant’s immune response can exacerbate the disease. This is reminiscent of an allergic reaction in animal systems, offering the depression of plant immune response as a potential strategy for OQDS treatment.

Author summary

Global trade and climate change are re-shaping the distribution map of pandemic pathogens. One major emerging concern isXylella fastidiosa, a tropical bacterium recently introduced into Europe from America. Its impact has been dramatic: in the last 5-years only, Olive Quick Decline Syndrome (OQDS) has caused thousands of 200 years old olive trees to be felled in the southern Italy.Xylella fastidiosathrough a tight coordination of the adherent biofilm and the planktonic states, invades the host systemically. The planktonic phase is correlated to low cell density and vessel colonization. Increase in cell density triggers a quorum sensing system based on cis 2-enoic fatty acids—diffusible signalling factors (DSF) that promote stickiness and biofilm. Xylem vessels are occluded by the combined effect of bacterial biofilm and plant defences (e.g. tyloses). This study provides novel insight on howX. fastidiosasubsp.paucabiology relates to the Olive Quick Decline Syndrome. We found that some class of lipids increase their amount in the infected olive tree. These lipid entities, provided toX. fastidiosasubsp.paucabehave as hormone-like molecules: modulating the dual phase, e.g. planktonicversusbiofilm. Probably, part of these lipids represents a reaction of the plant to the bacterial contamination.
Characterization, modelling and mitigation of gene expression burden in mammalian cells
Authors: Frei T , Cella F , Tedeschi F , Gutierrez J , Stan GB , Khammash M , Siciliano V
Published: December 2019

Despite recent advances in genome engineering, the design of genetic circuits in mammalian cells is still painstakingly slow and fraught with inexplicable failures. Here we demonstrate that competition for limited transcriptional and translational resources dynamically couples otherwise independent co-expressed exogenous genes, leading to diminished performance and contributing to the divergence between intended and actual function. We also show that the expression of endogenous genes is likewise impacted when genetic payloads are expressed in the host cells. Guided by a resource-aware mathematical model and our experimental finding that post-transcriptional regulators have a large capacity for resource redistribution, we identify and engineer natural and synthetic miRNA-based incoherent feedforward loop (iFFL) circuits that mitigate gene expression burden. The implementation of these circuits features the novel use of endogenous miRNAs as integral components of the engineered iFFL device, a versatile hybrid design that allows burden mitigation to be achieved across different cell-lines with minimal resource requirements. This study establishes the foundations for context-aware prediction and improvement ofin vivosynthetic circuit performance, paving the way towards more rational synthetic construct design in mammalian cells.
Variation in cell surface hydrophobicity amongCryptococcus neoformansstrains influences interactions with amoeba
Authors: Vij Raghav , Crawford Conor J. , Casadevall Arturo
Published: December 2019

Cryptococcus neoformansandCryptococcus gattiiare pathogenic fungi that cause significant morbidity and mortality. Cell surface hydrophobicity (CSH) is a biophysical parameter that influences the adhesion of fungal cells or spores to biotic and abiotic surfaces.C. neoformansis encased by polysaccharide capsule that is highly hydrophilic and is a critical determinant of virulence. In this study, we report large differences in the CSH of someC. neoformansandC. gattiistrains. The capsular polysaccharides ofC. neoformansstrains differ in repeating motifs, and therefore vary in the number of hydroxyl groups, which along with higher-order structure of the capsule, may contribute to the variation in hydrophobicity that we observed. ForC. neoformans, CSH correlated with phagocytosis by natural soil predatorAcanthamoeba castellani. Furthermore, capsular binding of the protective antibody (18B7), but not the non-protective (13F1) antibody altered the CSH ofC. neoformansstrains. Variability in CSH could be an important characteristic when comparing the biological properties of cryptococcal strains.

IMPORTANCE

The interaction of a microbial cell with its environment is influenced by the biophysical properties of a cell. The affinity of the cell surface for water, defined by the Cell Surface Hydrophobicity (CSH), is a biophysical parameter that varied amongst different strains ofCryptococcus neoformans. The CSH influenced the phagocytosis of the yeast by its natural predator in the soil, Amoeba. Studying variation in biophysical properties like CSH gives us insight into the dynamic host-predator interaction, and host-pathogen interaction in a damage-response framework.
BAX and SMAC Regulate Bistable Properties of the Apoptotic Caspase System
Authors: McKenna Stephanie , García-Gutiérrez Lucía , Matallanas David , Fey Dirk
Published: December 2019

The initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that the process is tightly regulated by positive feedback and a bistable switch. BAX and SMAC are often dysregulated in diseases such as cancer or neurodegeneration and are two key regulators that interact with the caspase system generating the apoptotic switch. Here we present a mathematical model of how BAX and SMAC control the apoptotic switch. Formulated as a system of ordinary differential equations, the model summarises experimental and computational evidence form the literature and incorporates the biochemical mechanisms of how BAX and SMAC interact with the components of the caspase system. Using simulations and bifurcation analysis, we find that both BAX and SMAC regulate the time-delay and activation threshold of the apoptotic switch. Interestingly, the model predicted that BAX (not SMAC) controls the amplitude of the apoptotic switch. Cell culture experiments using siRNA mediated BAX and SMAC knockdowns this model prediction. We further validated the model on data of the NCI-60 cell line panel using BAX protein expression as cell-line specific parameter and show that model simulations correlated with the cellular response to DNA damaging drugs and established a defined threshold for caspase activation that could distinguish between sensitive and resistant melanoma cells. In summary, we present an experimentally validated dynamic model that summarises our current knowledge of how BAX and SMAC regulate the bistable properties of irreversible caspase activation during apoptosis.
A genome-wide loss-of-function screen identifiesToxoplasma gondiigenes that determine fitness in interferon gamma-activated murine macrophages
Authors: Wang Yifan , Sangaré Lamba Omar , Paredes-Santos Tatiana C. , Krishnamurthy Shruthi , Hassan Musa A. , Furuta Anna M. , Markus Benedikt M. , Lourido Sebastian , Saeij Jeroen P.J.
Published: December 2019

Macrophages play an essential role in the early immune response againstToxoplasmaand are the cell type preferentially infected by the parasitein vivo. Interferon gamma (IFNγ) elicits a variety of anti-Toxoplasmaactivities in macrophages. Using a genome-wide CRISPR screen we identified ∼130Toxoplasmagenes that determine parasite fitness in naїve macrophages and ∼466 genes that determine fitness in IFNγ-stimulated murine macrophages, seven of which we investigated and confirmed. We show that one of these genes encodes dense granule protein GRA45, which contains a putative chaperone-like domain, and which we show is critical in preventing other GRA effectors from aggregating. Parasites lackingGRA45mislocalize GRA effectors upon secretion, are more susceptible to IFNγ-mediated growth inhibition, and have reduced virulence in mice. Our results provide a resource for the community to further explore the function ofToxoplasmagenes that determine fitness in IFNγ-stimulated macrophages.

IMPORTANCE

The intracellular parasiteToxoplasma gondiican cause congenital infections and severe disease in immunocompromised patients. The cytokine IFNγ can block parasite replication by upregulating a variety of toxoplasmacidal mechanisms in many cells, including macrophages.Toxoplasmapreferentially infects macrophages. Therefore, the parasite has evolved mechanisms to survive in these cells in the presence of IFNγ. Here, we generated pools ofToxoplasmamutants for every gene and determined which mutants were specifically depleted in IFNγ-stimulated macrophages, thus identifying parasite genes determining fitness in these cells. We show that one of these genes encodes for a dense granule protein (GRA45) that plays an important role in preventing other GRA effectors from aggregating. Parasites without GRA45 mislocalize GRA effectors upon secretion, have enhanced susceptibility to IFNγ-mediated growth inhibition, and are avirulent in mice. Thus, our screen provides a resource to theToxoplasmacommunity to determine the function ofToxoplasmagenes that affect its fitness in IFNγ-stimulated macrophages.
Phylogeography of equine infectious anemia virus
Authors: Jara Manuel , Frias-De-Diego Alba , Machado Gustavo
Published: December 2019

Equine Infectious Anemia virus (EIAV) is the causative agent of one of the most impacting infectious diseases affecting equids. EIAV is genetically diverse with several lineages circulating globally. To elucidate EIAV global spread patterns, we studied its spatiotemporal dynamics applying Bayesian phylodynamic analyses, using a worldwide compiled dataset composed of unique sequences of the gag gene. In addition, we performed a scoping review of 1.470 publications on EIAV to characterize the spatiotemporal trends in EAIV research. Phylogeographic reconstruction suggested Hungary as the most likely country of origin for current EIAV circulation (root state posterior probability = 0.21), and one of the most important centers of diversification for the disease. Historical EIAV spread was predominantly characterized by long-distance spread across continents. As a result, we found that the American and Asian circulating EIAV (i.e., Mongolia) are more related to European lineages than to other Asian countries, being Europe the continent with the highest EIAV phylogenetic diversity. Our bibliometric analysis showed a continuous increment in the number of publications per year, where the United States and China appeared as the countries with highest EIAV-related scientific production. This study provides a historical geographic mapping of the EIAV linages’ spread patterns. In addition, we identified important asymmetry between the current research effort and the availability of genetic data which restricted our abilities to quantify for example the time frame of virus dispersal.
Functional randomness despite high taxonomic turnover across an elevational gradient in a global biodiversity hotspot: A case study of hawkmoths and birds
Authors: Mungee Mansi , Athreya Ramana
Published: December 2019

Aim

We examined the patterns and processes of taxonomic and functional dissimilarities for two disparate organismal groups (ectothermic hawkmoths and endothermic birds) across a broad tropical elevational gradient.

Location

Eaglenest Wildlife Sanctuary (northeast India), eastern Himalayan global biodiversity hotspot.

Taxon

4,731 hawkmoths; 15,387 birds

Methods

Turnover and nestedness components for taxonomic and functional dissimilarities were obtained using the methods developed by Baselga (2013) and Leprieur et al., 2012. We used Generalized Dissimilarity Modeling (GDM) with geographic distance, contemporary and historic climatic variables to assess the relative importance of dispersal and environmental processes in determining the beta diversity. Functional redundancy (FRed) was calculated for both organismal groups using the Simpson’s diversity indices. Null modeling was used to determine randomness in species and trait distributions.

Results

Turnover dominated taxonomic and functional dissimilarities, however the contribution of nestedness was considerably higher to the latter. Overall, the rate of dissimilarity with distance, for both facets of diversity, was significantly higher for birds, with stronger contributions of geographic distance and historic climate; whereas the hawkmoth dissimilarities were strongly correlated with only contemporary climate. Taxonomic dissimilarities deviated significantly from null, whereas functional dissimilarities exhibited high redundancy and randomness.

Main Conclusions

Overall, our results suggest that while the drivers of beta-diversity exhibit idiosyncrasy and taxon-specificity; for a given taxa, they are consistent across the two facets of dissimilarity. More importantly, regardless of the principal predictor, the net result was that of high taxonomic turnover, which is de-coupled to a high degree from functional turnover in these tropical ecosystems. The large redundancy in trait values, despite high species turnover, indicates functional resilience of these tropical communities. The consistency of this pattern, across two disparate organismal groups, is suggestive of a key mechanism in which tropical communities may retain functionality of ecosystems in a changing environment.
Disentangling the contribution of each descriptive characteristic of every single mutation to its functional effects
Authors: Sruthi C. K. , Prakash Meher K.
Published: December 2019

Mutational effects predictions continue to improve in accuracy as advanced artificial intelligence (AI) algorithms are trained on exhaustive experimental data. The next natural questions to ask are if it is now possible to gain insights into which attribute of the mutation contributes how much to the mutational effects, and if one can develop universal rules for mapping the descriptors to mutational effects. In this work, we mainly address the former aspect using a framework of interpretable AI. Relations between the physico-chemical descriptors and their contributions to the mutational effects are extracted by analyzing the data on 29,832 variants from 8 systematic deep-mutational scan studies. It is found that the intuitive dependences of fitness and solubility on the distance of the amino acid from active site could be extracted and quantified. The dependence of the mutational effect contributions on the number of contacts an amino acid has or the BLOSUM score descriptor of the change showed universal trends. Our attempts in the present work to explain the quantitative differences in the dependence on conservation and SASA across proteins were not successful. The work nevertheless brings transparency into the predictions, development of rules, and will hopefully lead to uncovering the universalities among these rules.
Transposable element landscape inDrosophilapopulations selected for longevity
Authors: Fabian Daniel K. , Dönertaş Handan Melike , Fuentealba Matías , Partridge Linda , Thornton Janet M.
Published: December 2019

Transposable elements (TEs) inflict numerous negative effects on health and fitness as they replicate by integrating into new regions of the host genome. Even though organisms employ powerful mechanisms to demobilize TEs, transposons gradually lose repression during aging. The rising TE activity causes genomic instability and was implicated in age-dependent neurodegenerative diseases, inflammation and the determination of lifespan. It is therefore conceivable that long-lived individuals have improved TE silencing mechanisms resulting in reduced TE expression relative to their shorter-lived counterparts and fewer genomic insertions. Here, we test this hypothesis by performing the first genome-wide analysis of TE insertions and expression in populations ofDrosophila melanogasterselected for longevity through late-life reproduction for 50-170 generations from four independent studies. Contrary to our expectation, TE families were generally more abundant in long-lived populations compared to non-selected controls. Although simulations showed that this was not expected under neutrality, we found little evidence for selection driving TE abundance differences. Additional RNA-seq analysis revealed a tendency for reducing TE expression in selected populations, which might be more important for lifespan than regulating genomic insertions. We further find limited evidence of parallel selection on genes related to TE regulation and transposition. However, telomeric TEs were genomically and transcriptionally more abundant in long-lived flies, suggesting improved telomere maintenance as a promising TE-mediated mechanism for prolonging lifespan. Our results provide a novel viewpoint indicating that reproduction at old age increases the opportunity of TEs to be passed on to the next generation with little impact on longevity.
RADAR: Differential analysis of MeRIP-seq data with a random effect model
Authors: Zhang Zijie , Zhan Qi , Eckert Mark , Zhu Allen , Chryplewicz Agnieszka , De Jesus Dario F , Ren Decheng , Kulkarni Rohit N , Lengyel Ernst , He Chuan , Chen Mengjie
Published: December 2019

Epitranscriptome profiling using MeRIP-seq is a powerful technique for in vivo functional studies of reversible RNA modifications. We develop RADAR, a comprehensive analytical tool for detecting differentially methylated loci in MeRIP-seq data. RADAR enables accurate identification of altered methylation sites by accommodating variability of pre-immunoprecipitation expression level and post-immunoprecipitation count using different strategies. In addition, it is compatible with complex study design when covariates need to be incorporated in the analysis. Through simulation and real datasets analyses, we show that RADAR leads to more accurate and reproducible differential methylation analysis results than alternatives, which is available at https://github.com/scottzijiezhang/RADAR.