bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic Approach to Monogenic Inflammatory Bowel Disease in Clinical Practice: A Ten-Year Multicentric Experience
Authors: Lega Sara , Pin Alessia , Arrigo Serena , Cifaldi Cristina , Girardelli Martina , Bianco Anna Monica , Malamisura Monica , Angelino Giulia , Faraci Simona , Rea Francesca , Romeo Erminia Francesca , Aloi Marina , Romano Claudio , Barabino Arrigo , Martelossi Stefano , Tommasini Alberto , Di Matteo Gigliola , Cancrini Caterina , De Angelis Paola , Finocchi Andrea , Bramuzzo Matteo
Published: August 2019

Background and aims

Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients’ management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis.

Methods

Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008–2017 who underwent a genetic workup were collected.

Results

Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT.

Conclusion

A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients’ management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.
Asymptotics of the eigenmodes and stability of an elastic structure with general feedback matrix
Authors: Shubov Marianna A , Kindrat Laszlo P
Published: August 2019

The distribution of natural frequencies of the Euler–Bernoulli beam subject to fully non-dissipative boundary conditions is investigated. The beam is clamped at the left end and equipped with a 4-parameter ($\alpha ,\beta ,k_1,k_2$) linear boundary feedback law at the right end. The $2 \times 2$ boundary feedback matrix relates the control input (a vector of velocity and its spatial derivative at the right end), to the output (a vector of shear and moment at the right end). The initial boundary value problem describing the dynamics of the beam has been reduced to the first order in time evolution equation in the state Hilbert space equipped with the energy norm. The dynamics generator has a purely discrete spectrum (the vibrational modes) denoted by $\{\nu _n\}_{n\in \mathbb {Z}^{\prime}}$. The role of the control parameters is examined and the following results have been proven: (i) when $\beta \neq 0$, the set of vibrational modes is asymptotically close to the vertical line on the complex $\nu$-plane given by the equation $\Re \nu = \alpha + (1-k_1k_2)/\beta$; (ii) when $\beta = 0$ and the parameter $K = (1-k_1 k_2)/(k_1+k_2)$ is such that $\left |K\right |\neq 1$ then the following relations are valid: $\Re (\nu _n/n) = O\left (1\right )$ and $\Im (\nu _n/n^2) = O\left (1\right )$ as $\left |n\right |\to \infty$; (iii) when $\beta =0$, $|K| = 1$, and $\alpha = 0$, then the following relations are valid: $\Re (\nu _n/n^2) = O\left (1\right )$ and $\Im (\nu _n/n) = O\left (1\right )$ as $\left |n\right |\to \infty$; (iv) when $\beta =0$, $|K| = 1$, and $\alpha>0$, then the following relations are valid: $\Re (\nu _n/\ln \left |n\right |) = O\left (1\right )$ and $\Im (\nu _n/n^2) = O\left (1\right )$ as $\left |n\right |\to \infty$.
Virtual element method for quasilinear elliptic problems
Authors: Cangiani A , Chatzipantelidis P , Diwan G , Georgoulis E H
Published: August 2019

A virtual element method for the quasilinear equation $-\textrm{div} ({\boldsymbol \kappa }(u)\operatorname{grad} u)=f$ using general polygonal and polyhedral meshes is presented and analysed. The nonlinear coefficient is evaluated with the piecewise polynomial projection of the virtual element ansatz. Well posedness of the discrete problem and optimal-order a priori error estimates in the $H^1$- and $L^2$-norm are proven. In addition, the convergence of fixed-point iterations for the resulting nonlinear system is established. Numerical tests confirm the optimal convergence properties of the method on general meshes.
Standardized total tract digestible phosphorus requirement of 24- to 130-kg pigs1,2
Authors: Vier Carine M , Dritz Steve S , Wu Fangzhou , Tokach Mike D , DeRouchey Joel M , Goodband Robert D , Gonçalves Márcio A D , Orlando Uislei A D , Chitakasempornkul Kessinee , Woodworth Jason C
Published: August 2019

A study was conducted to determine the standardized total tract digestible phosphorus (STTD P) requirement for 24- to 130-kg finishing pigs housed under commercial conditions. A total of 1,130 barrows and gilts (PIC 359 × 1050, Hendersonville, TN; initially 24.2 kg) were used, with 26 to 27 pigs per pen with 7 replicates per treatment. Pens of pigs were allotted to treatments in a randomized complete block design with body weight (BW) as the blocking factor. The dietary treatments were fed in 4 phases and were formulated to contain 80%, 90%, 100%, 115%, 130%, and 150% of the National Research Council (NRC) requirement estimate for finishing pigs within each phase. Weight ranges for each phase were: 27 to 49, 49 to 76, 76 to 90, and 90 to 130 kg. Treatments were achieved by increasing the amount of monocalcium phosphate at the expense of corn in the diet with no added phytase. All diets were formulated to contain a similar 1.14:1 to 1.16:1 total Ca:P ratio across treatments in all phases. Increasing STTD P resulted in a quadratic response (P < 0.05) in average daily gain (ADG), gain-to-feed ratio (G:F), and final BW. The greatest improvement was observed with STTD P at 130% of NRC for ADG and final BW and at 115% STTD P for G:F. Average daily feed intake increased linearly (linear, P < 0.05) with the inclusion of STTD P. Increasing STTD P resulted in an increase (quadratic, P < 0.05) in hot carcass weight (HCW) and carcass ADG with the greatest response observed with STTD P at 130% of NRC. There was a marginally significant response (quadratic, P < 0.10) in carcass G:F, with the greatest improvement with STTD P at 115% of NRC. Carcass yield decreased (linear, P < 0.05) with increasing STTD P, while there was a marginally significant (linear, P < 0.10) decrease in backfat and increase in fat-free lean. At the end of the study, a metacarpal was collected and analyzed for bone ash. Increasing STTD P resulted in an increase (linear, P < 0.05) in bone ash weight and percentage ash. For ADG and G:F, the quadratic model demonstrated the best fit. The maximum response in ADG and G:F was estimated at 122% and 116% of NRC STTD P, respectively. The broken-line linear model best fit the data for percentage bone ash, with a plateau achieved at 131% of the NRC STTD P. In conclusion, the estimated STTD P requirement of 24 to 130 kg ranged from 116% to 131% of the NRC publication (2012) requirement estimate.
Deciphering the anti-Parkinson’s activity of sulphated polysaccharides from Chlamydomonas reinhardtii on the α-Synuclein mutants A30P, A53T, E46K, E57K and E35K
Authors: Panigrahi Gitanjali P , Rane Ankita R , Vavilala Sirisha L , Choudhary Sinjan
Published: August 2019

Parkinsonism-linked mutations in alanine and glutamic acid residues of the pre-synaptic protein α-Synuclein (α-Syn) affect specific tertiary interactions essential for stability of the native state and make it prone to more aggregation. Many of the currently available drugs used for the treatment of Parkinson’s disease (PD) are not very effective and are associated with multiple side effects. Recently, marine algae have been reported to have sulphated polysaccharides which offers multiple pharmaceutical properties. With this background, we have isolated sulphated polysaccharides from Chlamydomonas reinhardtii (Cr-SPs) and investigated their effects on inhibition of fibrillation/aggregation of α-Syn mutants through a combination of spectroscopic and microscopic techniques. The kinetics of α-Syn fibrillation establishes that Cr-SPs are very effective in inhibiting fibrillation of α-Syn mutants. The morphological changes associated with the fibrillation/aggregation process have been monitored by transmission electron microscopy. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis gel image suggests that Cr-SPs increase the amount of soluble protein after completion of the fibrillation/aggregation process. The circular dichroism results showed that Cr-SPs efficiently delay the conversion of native protein into β-sheet-rich structures. Thus, the current work has considerable therapeutic implications towards deciphering the potential of Cr-SPs to act against PD and other protein aggregation-related disorders.
Host providers may be subject to obligations resulting in content removal on a worldwide basis, says AG Szpunar
Authors: Harvey Riana E
Published: August 2019

Opinion of Advocate General Maciej Szpunar in Case C-18/18 Eva Glawischnig-Piesczek v Facebook Ireland Limited, EU:C:2019:458

Advocate General (AG) Szpunar advised the Court of Justice of the European Union (CJEU) to rule that Facebook can be ordered to seek and identify: (i) identical information found to be illegal in relation to all content disseminated on its platform and (ii) equivalent information where this originate from the same user; such order can result in a hosting provider being required to remove information worldwide in certain situations.
Medication-Related Osteonecrosis of the Jaws
Authors: Migliorati Cesar A , Brennan Michael T , Peterson Douglas E
Published: August 2019

Medication-related osteonecrosis of the jaw is an oral complication in cancer patients being treated with either antiresorptive or antiangiogenic drugs. The first reports of MRONJ were published in 2003. Hundreds of manuscripts have been published in the medical and dental literature describing the complication, clinical and radiographic signs and symptoms, possible pathophysiology, and management. Despite this extensive literature, the pathobiological mechanisms by which medication-related osteonecrosis of the jaw develops have not yet been fully delineated. The aim of this manuscript is to present current knowledge about the complication ragarding to the definition, known risk factors, and clinical management recommendations. Based on this current state of the science, we also propose research directions that have potential to enhance the management of future oncology patients who are receiving these agents.
Gas in gallbladder—gallstone ileus?
Authors: Gan Siang Wei , Rosli Reizal Mohd , Kiroff George , Rana Abdullah Muhammad , Tonkin Darren
Published: August 2019

Gallstone ileus is an uncommon presentation among acute surgical patients. Its diagnosis is often delayed due to its non-specific clinical presentation. We report the case of an 81-year-old gentleman with a 2-day history of small bowel obstruction (SBO). He had a history of gallstone disease and no past surgical history. Plain abdominal radiography was consistent with SBO. A computed tomography (CT) abdomen scan would be warranted given the presentation of SBO in a virgin abdomen. However, this case emphasizes the importance of early CT imaging in a case of suspected gallstone ileus given that the diagnosis could not be made on plain abdominal radiography. CT abdomen is superior in detecting small amounts of gas and at discriminating soft tissue density.
Adrenalectomy for huge solid pheochromocytoma: a challenging surgery or piece of cake?
Authors: Labib Mahmoud , Ismail Asmaa , Elmansy Hazem , Shahrour Walid , Prowse Owen , Kotb Ahmed
Published: August 2019

Pheochromocytoma (PCC) is an uncommon adrenal tumor that is occasionally diagnosed during the work up for patients with uncontrolled hypertension. Treatment of PCC is mainly surgical. This case represents the largest PCC reported to date, which was safely removed.
NGC 300 ULX1: spin evolution, super-Eddington accretion, and outflows
Authors: Vasilopoulos G , Petropoulou M , Koliopanos F , Ray P S , Bailyn C B , Haberl F , Gendreau K
Published: August 2019

NGC 300 ULX1 is an ultraluminous X-ray pulsar, showing an unprecedented spin evolution, from about 126 s to less than 20 s in only 4 yr, consistent with steady mass accretion rate. Following its discovery we have been monitoring the system with Swift and NICER to further study its properties. We found that even though the observed flux of the system dropped by a factor of ≳20, the spin-up rate remained almost constant. A possible explanation is that the decrease in the observed flux is a result of increased absorption of obscuring material due to outflows or a precessing accretion disc.
Narrow, intrinsic C iv absorption in quasars as it relates to outflows, orientation, and radio properties
Authors: Stone Robert B , Richards Gordon T
Published: August 2019

This work provides evidence that a large fraction of C iv narrow absorption lines (NALs) seen along the line of sight to distant quasars are due to accretion disc winds, while also seeking to understand the relationship between NALs and certain quasar-intrinsic properties. We extend the results from past work in the literature using ${\sim}105\, 000$ NALs from a sample of ${\sim}58\, 000$ SDSS quasars. The primary results of this work are summarized as follows: (1) the velocity distribution (dN/dβ) of NALs is not a function of radio loudness (or even detection) once marginalized by optical/UV luminosity; (2) there are significant differences in the number and distribution of NALs as a function of both radio spectral index and optical/UV luminosity, and these two findings are not entirely interdependent; (3) improvements in quasar systemic redshift measurements and differences in the NAL distribution as a combined function of optical luminosity and radio spectral index together provide evidence that a significant portion of NALs are due to outflows; (4) the results are consistent with standard models of accretion disc winds governed by the LUV–αox relationship and line-of-sight orientation indicated by radio spectral index, and (5) possibly support a magnetically arrested disc model as an explanation for the semistochastic nature of strong radio emission in a fraction of quasars.
Constraints on chameleon f(R)-gravity from galaxy rotation curves of the SPARC sample
Authors: Naik Aneesh P , Puchwein Ewald , Davis Anne-Christine , Sijacki Debora , Desmond Harry
Published: August 2019

In chameleon f(R)-gravity, the fifth force will lead to ‘upturns’ in galaxy rotation curves near the screening radius. The location of the upturn depends on the cosmic background value of the scalar field $\bar{f}_\mathrm{R0}$, as well as the mass, size, and environment of the galaxy. We search for this signature of modified gravity in the SPARC sample of measured rotation curves, using an MCMC technique to derive constraints on $\bar{f}_\mathrm{R0}$. Assuming NFW dark matter haloes and with $\bar{f}_\mathrm{R0}$ freely varying for each galaxy, most galaxies prefer f(R) gravity to ΛCDM, but there is a large spread of inferred $\bar{f}_\mathrm{R0}$ values, inconsistent with a single global value. Requiring instead a consistent $\bar{f}_\mathrm{R0}$ value for the whole sample, models with $\log _{10}|\bar{f}_\mathrm{R0}|\gt -6.1$ are excluded. On the other hand, models in the range $-7.5\lt \log _{10}|\bar{f}_\mathrm{R0}|\lt -6.5$ seem to be favoured with respect to ΛCDM, with a significant peak at −7. However, this signal is largely a result of galaxies for which the f(R) signal is degenerate with the core/cusp problem, and when the NFW profile is replaced with a cored halo profile, ΛCDM gives better fits than any given f(R) model. Thus, we find no convincing evidence of f(R) gravity down to the level of $|\bar{f}_\mathrm{R0}|\sim 6 \times 10^{-8}$, with the caveat that if cored halo density profiles cannot ultimately be explained within ΛCDM, a screened modified gravity theory could possibly provide an alternative solution for the core/cusp problem. However, the f(R) models studied here fall short of achieving this.
Power spectrum modelling of galaxy and radio intensity maps including observational effects
Authors: Blake Chris
Published: August 2019

Fluctuations in the large-scale structure of the Universe contain significant information about cosmological physics, but are modulated in survey data sets by various observational effects. Building on existing literature, we provide a general treatment of how fluctuation power spectra are modified by a position-dependent selection function, noise, weighting, smoothing, pixelization, and discretization. Our work has relevance for the spatial power spectrum analysis of galaxy surveys with spectroscopic or accurate photometric redshifts, and radio intensity-mapping surveys of the sky brightness temperature including generic noise, telescope beams, and pixelization. We consider the autopower spectrum of a field, the cross-power spectrum between two fields and the multipoles of these power spectra with respect to a curved sky, deriving the corresponding power spectrum models, estimators, errors, and optimal weights. We note that ‘FKP weights’ for individual tracers do not in general provide the optimal weights when measuring the cross-power spectrum. We validate our models using mock data sets drawn fromN-body simulations.1 Our treatment should be useful for modelling and studying cosmological fluctuation fields in observed and simulated data sets.
Laser-driven programmable non-contact transfer printing of objects onto arbitrary receivers via an active elastomeric microstructured stamp
Authors: Luo Hongyu , Wang Chengjun , Linghu Changhong , Yu Kaixin , Wang Chao , Song Jizhou
Published: August 2019

Transfer printing, as an important assembly technique, has attracted much attention due to its valuable merits to develop novel forms of electronics such as stretchable inorganic electronics requiring the heterogeneous integration of inorganic materials with soft elastomers. Here, we report on a laser-driven programmable non-contact transfer printing technique via a simple yet robust design of active elastomeric microstructured stamp that features cavities filled with air and embedded under the contacting surface, a micro-patterned surface membrane that encapsulates the air cavities and a metal layer on the inner-cavity surfaces serving as the laser-absorbing layer. The micro-patterned surface membrane can be inflated dynamically to control the interfacial adhesion, which can be switched from strong state to weak state by more than three orders of magnitude by local laser heating of the air in the cavity with a temperature increase below 100°C. Theoretical and experimental studies reveal the fundamental aspects of the design and fabrication of the active elastomeric microstructured stamp and the operation of non-contact transfer printing. Demonstrations in the programmable transfer printing of micro-scale silicon platelets and micro-scale LED chips onto various challenging receivers illustrate the extraordinary capabilities for deterministic assembly that are difficult to address by existing printing schemes, thereby creating engineering opportunities in areas requiring the heterogeneous integration of diverse materials such as curvilinear electronics and MicroLED displays.
Flow Diversion of an Incompletely-Treated Fusiform Middle Cerebral Artery Aneurysm: 2-Dimensional Operative Video
Authors: Sorenson Thomas J , Klein Jon P , Rangel-Castilla Leonardo , Lanzino Giuseppe
Published: August 2019

Fusiform aneurysms involving the M2 branches of the middle cerebral artery are often dissecting, identified by a characteristic diseased adjacent segment, and location not at a branch point. Herein, we present the case of a 38-yr-old man with a symptomatic, dissecting M2 aneurysm that was previously incompletely treated with stent-assisted coiling. In our experience, symptomatic fusiform aneurysms in this location tend to recur unless the involved segment is completely trapped or reconstructed with flow diversion. We successfully treated this patient with a vessel reconstruction using a Pipeline Flex Embolization Device (Medtronic). Deployment of a flow diverter inside a previously placed stent can pose potential challenges, as the original stent may constrain complete expansion of the flow diverter and prevent perfect apposition against the parent vessel wall. In this operative video, we demonstrate this technique and provide a brief discussion of the potential pitfalls.
Order Cancellations, Fees, and Execution Quality in U.S. Equity Options
Authors: Griffith Todd G , Van Ness Robert A
Published: August 2019

We examine the effects of an order cancellation fee on limit order flow and execution quality in the PHLX options market. The cancellation fee on professional order flow effectively reduces the rate at which limit orders are canceled. Whereas the cancellation fee discourages the submission of nonmarketable orders, it encourages the submission of marketable orders. Consequently, nonmarketable order fill rates increase; marketable order fill speeds decrease; and bid-ask spreads widen. We also find slight increases in both dollar volume and market share. (JEL G11, G14, G18)

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Equity as a nest: the principle-based secret trusts
Authors: Leung Samuel Yee Ching
Published: August 2019

The fraud theory and the dehors the will theory are generally considered as the starting points for analysing secret trusts. However, both theories have been severely criticised. This article argues that the fraud theory is defensible from a jurisprudential perspective and should be preferred. Had a ‘principle-based’ approach been adopted in the analysis, secret trusts can indeed be justified on the basis of a legal principle—‘the prevention of fraud’—so that the dehors the will theory is unnecessary. The ‘principle-based’ approach should be distinguished from the ‘rule-based’ approach which is suitable for the analysis of statutes. The ‘principle-based’ approach can also reconcile fully-secret trusts and half-secret trusts.
Suramin could block the activity of Arabinono-1, 4-lactone oxidase enzyme from Leishmania donovani: structure-based screening and molecular dynamics analyses
Authors: Adinehbeigi Keivan , Shaddel Minoo , Khalili Saeed , Zakeri Alireza
Published: August 2019

Background

Leishmania donovani, a parasitic protozoan causing visceral leishmaniasis, can lead to a dangerous and often fatal disease in humans. Current treatment for leishmaniasis may have severe side effects, low efficacy and high cost, hence an immediate need for new efficient drugs is essential. Arabinono-1, 4-lactone oxidase enzyme from Leishmania donovani (LdALO), which catalyzes the last step of the ascorbate biosynthesis pathway, has been considered as a potential target for antileishmanial drugs design.

Methods

The current study was performed with an in silico approach to predict novel inhibitory molecules against the LdALO enzyme. Various modeling and refinement processes were employed to obtain a reliable 3D structure.

Results

The best LdALO model with the highest qualitative model energy analysis score was predicted by the Robetta server and subsequently refined by 3D refine and ModLoop servers. The high quality of the final LdALO model was confirmed using model assessment software. Based on docking analysis results, we predicted 10 inhibitory molecules of a US Food and Drug Administration-approved library, with appropriate criteria regarding energy binding and interaction with the main functionally active sites of LdALO, indicating that they could be significant targets for further drug design investigations against L. donovani.

Conclusion

Suramin is used to treat the first stage of African sleeping sickness and its mechanism of action is unknown. Our results showed that suramin was the best-predicted inhibitor compound for LdALO enzyme activity.
Validation of Serum Neurofilaments as Prognostic & Potential Pharmacodynamic Biomarkers for ALS
Authors: Benatar Michael , Zhang Lanyu , Wang Lily , Granit Volkan , Statland Jeffrey , Barohn Richard , Swenson Andrea , Ravits John , Jackson Carlayne , Burns Ted M , Trivedi Jaya , Pioro Erik P , Caress James , Katz Jonathan , McCauley Jacob L , Rademakers Rosa , Malaspina Andrea , Ostrow Lyle W , Wuu Joanne
Published: August 2019

Objective

Identify preferred neurofilament assays, and clinically validate serum NfL and pNfH as prognostic and potential pharmacodynamic biomarkers relevant to ALS therapy development.

Methods

Prospective, multi-center, longitudinal observational study of patients with ALS (n=229), primary lateral sclerosis (PLS, n=20) and progressive muscular atrophy (PMA, n=11). Biological specimens were collected, processed and stored according to strict standard operating procedures (SOPs)1. Neurofilament assays were performed in a blinded manner by independent contract research organizations (CROs).

Results

For serum NfL and pNfH measured using the Simoa assay, missing data (i.e. both technical replicates below the lower limit of detection (LLD) was not encountered. For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples respectively. Mean coefficients of variation (CVs) for pNfH in serum and CSF were ∼4-5% and ∼2-3% respectively in all assays. Baseline NfL concentration, but not pNfH, predicted the future ALSFRS-R slope and survival.

Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.

Conclusions

Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, have potential utility as pharmacodynamic biomarkers of treatment effect.
A phenome-wide analysis of short- and long-run disease incidence following Recurrent Pregnancy Loss using data from a 39-year period
Authors: Westergaard David , Nielsen Anna Pors , Mortensen Laust Hvas , Nielsen Henriette Svarre , Brunak Søren
Published: August 2019

Background

Pregnancy loss is one of the most frequent pregnancy complications. It is unclear how recurrent pregnancy loss (RPL) impacts disease risk later in life and if later disease risk is different in women with or without a live birth prior to RPL (primary vs. secondary RPL). We sought to investigate if women have an increased risk of disease following RPL, and if there was a difference between primary and secondary RPL.

Methods

Using population-wide health care registry databases from Denmark we identified a cohort of 1,370,896 women between 12 and 40 years in the period January 1, 1977, to October 5, 2016 who had been pregnant. Each woman was followed on average for 15.8 years. Of these, 10,691 (0.77%) women fulfilled the criteria for RPL (50.0% had primary RPL). Relative Risk Ratios (RR) were calculated in a phenome-wide manner for diagnoses with a cumulative incidence proportion >0.1% in women with RPL. Diagnoses related to assessment and diagnosis of RPL and those appearing later in life were separated using a Mixture Model.

Results

In the full cohort of pregnant women, 0.77% (10,691) fulfilled the criteria for RPL (50.0% primary RPL). Compared to women without RPL, primary RPL increased the risk of subsequent cardiovascular disorders, including atherosclerosis (RR=2.45, 1.65-3.51 95% Uncertainty Interval (UI)), cerebral infarction (RR=1.87, 1.43-2.4 95% UI), heart failure (RR=1.97, 1.44-2.63 95% UI), and pulmonary embolism (RR=1.82, 1.32-2.46 95% UI). Women with secondary RPL had an increased risk of obstetric complications, e.g. placenta previa (RR=3.76, 2.9-4.8 95% UI), premature rupture of membrane (RR=2.55, 2.21-2.91 95% UI), intrapartum hemorrhage (RR=2.8, 1.77-4.31 95% UI), gestational hypertension (RR=2.2, 1.67-2.87 95% UI), and puerperal sepsis (RR=2.54, 1.8-3.5 95% UI). We also noticed associations to autoimmune, respiratory, gastro-intestinal and mental disorders in both subtypes.

Conclusion

Our findings show that RPL is a risk factor for a spectrum of disorders. This can in part be due to increased screening following RPL, but it also suggests that RPL may directly influence or share etiology with a number of diseases later in life. Research into the pathophysiology of both pregnancy loss and later diseases merits further investigation.
Role of miRNAs induced by oxidized low-density lipoproteins in coronary artery disease: the REGICOR Study
Authors: Dégano IR , Subirana I , García-Mateo N , Cidad P , Muñoz-Aguado D , Puigdecanet E , Nonell L , Vila J , Camps A , Crepaldi F , de Gonzalo-Calvo D , Llorente-Cortés Vc , Pérez-García MT , Elosua R , Fitó M , Marrugat J
Published: August 2019

Aims

Current risk prediction tools are not accurate enough to identify most individuals at high coronary risk. On the other hand, oxidized low-density lipoproteins (ox-LDLs) and miRNAs are actively involved in atherosclerosis. Our aim was to examine the association of ox-LDL-induced miRNAs with coronary artery disease (CAD), and to assess their predictive capacity of future CAD.

Methods and results

Human endothelial and vascular smooth muscle cells were treated with oxidized or native LDLs (nLDL), and their miRNA expression was measured with the miRNA 4.0 array, and analyzed with moderated t-tests. Differently expressed miRNAs and others known to be associated with CAD, were examined in serum samples of 500 acute myocardial infarction (AMI) patients and 500 healthy controls, and baseline serum of 117 incident CAD cases and c 485 randomly-selected cohort participants (case-cohort). Both were developed within the REGICOR AMI Registry and population cohorts from Girona. miRNAs expression in serum was measured with custom OpenArray plates, and analyzed with fold change (age and sex-paired case-control) and survival models (case-cohort). Improvement in discrimination and reclassification by miRNAs was assessed. Twenty-one miRNAs were up- or down-regulated with ox-LDL in cell cultures. One of them, 1 (has-miR-122-5p, fold change=4.85) was upregulated in AMI cases. Of the 28 known CAD-associated miRNAs, 11 were upregulated in AMI cases, and 1 (hsa-miR-143-3p, hazard ratio=0.56 [0.38-0.82]) was associated with CAD incidence and improved reclassification.

Conclusion

We identified 2 novel miRNAs associated with ox-LDLs (hsa-miR-193b-5p and hsa-miR-1229-5p), and 1 miRNA that improved reclassification of healthy individuals (hsa-miR-143-3p).
Meat intake and cancer risk: prospective analyses in UK Biobank
Authors: Knuppel Anika , Papier Keren , Fensom Georgina K. , Appleby Paul N. , Schmidt Julie A. , Tong Tammy Y. N. , Travis Ruth C. , Key Timothy J. , Perez-Cornago Aurora
Published: August 2019

Background

Red and processed meat has been consistently associated with risk for colorectal cancer, but evidence for other cancer sites is limited and few studies have examined the association between poultry intake and cancer risk. We examined associations between total meat, red meat, processed meat and poultry intake and incidence for 20 common cancer sites.

Methods and Findings

We analysed data from 475,023 participants (54% women) in UK Biobank. Participants were aged 37-73 years and cancer free at baseline. Information on meat consumption was based on a touchscreen questionnaire completed at baseline covering type and frequency of meat intake. Diet intake was re-measured a minimum of three times in a subsample (15%) using a web-based 24h dietary recall questionnaire. Multivariable-adjusted Cox proportional hazards models were used to determine the association between baseline meat intake and cancer incidence. Trends in risk across baseline meat intake categories were calculated by assigning a mean value to each category using estimates from the re-measured meat intakes. During a mean follow-up of 6.9 years, 28,955 participants were diagnosed with a malignant cancer. Total, red and processed meat intakes were each positively associated with risk of colorectal cancer (e.g. hazard ratio (HR) per 70 g/day higher intake of red and processed meat combined 1.31, 95%-confidence interval (CI) 1.14-1.52).

Red meat intake was positively associated with breast cancer (HR per 50 g/day higher intake 1.12, 1.01-1.24) and prostate cancer (1.15, 1.03-1.29). Poultry intake was positively associated with risk for cancers of the lymphatic and hematopoietic tissues (HR per 30g/day higher intake 1.16, 1.03-1.32). Only the associations with colorectal cancer were robust to Bonferroni correction for multiple comparisons. Study limitations include unrepresentativeness of the study sample for the UK population, low case numbers for less common cancers and the possibility of residual confounding.

Conclusions

Higher intakes of red and processed meat were associated with a higher risk of colorectal cancer. The observed positive associations of red meat consumption with breast and prostate cancer, and poultry intake with cancers of the lymphatic and hematopoietic tissues, require further investigation.
Enhance genome editing efficiency and specificity by a quick CRISPR/Cas9 system
Authors: Hu Yingying , Luo Zhou , Li Jing , Wang Dan , Sun Hai-Xi , Xiao An , Liu Da , Cheng Zhenchao , Wu Jun , Shen Yue , Xu Xun , Zhang Bo , Wang Jian , Gu Ying , Yang Huanming
Published: August 2019

CRISPR/Cas9 is a powerful genome editing tool that has been successfully applied to a variety of species, including zebrafish. However, targeting efficiencies vary greatly at different genomic loci, the underlying causes of which were still elusive. Here we report a quick CRISPR/Cas9 system, designated as qCas9, which exhibits accelerated turnover of Cas9 protein in zebrafish. Our data showed that qCas9 significantly improved targeting efficiency, including both knock-out and knock-in in F0embryos, and yielded higher germline transmission rate in founder screen. Importantly, qCas9 showed little to no off-target editing in zebrafish and profoundly reduced off-target effect in HEK293T cell line. In summary, our findings demonstrate that qCas9 is a simple, economic and highly effective method to improve genome editing efficiency in zebrafish embryos and also holds great potential in reducing off-target effect in mammalian cell lines.
A visualizable hepatitis A virus and hepatitis C virus coinfection model in vitro: coexistence of two hepatic viruses under limited competition in viral RNA synthesis
Authors: Jiang Wang , Ma Pengjuan , Long Gang
Published: August 2019

Hepatitis A virus (HAV) and hepatitis C virus (HCV) coinfection in patients usually leads to HCV suppression or clearance. Whether this suppression/clearance is caused by direct virus-virus interaction or indirect interactions is still unknown. Here, we present a robust and visualizable HAV/HCV coinfection model for investigating their interactions in vitro. We find that HAV super infects HCV-persistently-infected Huh-7.5.1 cells without obvious virus-virus exclusion and vice versa, while there is a mild reciprocal viral interference in coinfection. Through single-cell scale confocal microscopy analysis and treating co-infected cells with rNTPs or antivirals e.g. Sofosbuvir, Simeprevir, and Ledipasvir, we find that HAV and HCV exploit cellular machinery in a compatible manner, but with reciprocal competition for rNTPs in their RNA synthesis. In conclusion, our findings reveal the absence of direct HAV-HCV interaction but the presence of indirect interaction, which may be due to limited competition in viral RNA synthesis. Therefore, we propose that suppression/clearance of HCV in HAV/HCV coinfected patients is probably due to indirect interactions e.g. viral competition or immunological interactions.

Author summary

Virus-virus interactions could usually be categorized in three aspects: (1) direct interaction induced by interaction of viral gene or gene products; (2) indirect interaction mediated by immune response or (3) host environmental alteration. Hepatitis A virus (HAV) and hepatitis C virus (HCV) are two important causatives of human hepatitis. In patients, their coinfection often induces HCV suppression/clearance, and sometimes may lead to fulminant hepatitis. In this study, we find that a limited reciprocal viral interference occurs in HAV/HCV coinfection in vitro, which results from a viral competition of rNTPs in viral RNA synthesis. Our study provides a new paradigm of studying virus-virus interactions in single-cell scale. To our knowledge, we identify the rNTPs competition in virus coinfection for the first time by experiment, though several mathematical modelings have predicted the resource competition in virus coinfection.
ALS Motor Neurons Exhibit Hallmark Metabolic Defects That Are Rescued by Nicotinamide and SIRT3 Activation
Authors: Hor Jin-Hui , Santosa Munirah Mohamad , Lim Valerie Jing Wen , Xuan Ho Beatrice , Taylor Amy , Khong Zi Jian , Ravits John , Fan Yong , Liou Yih-Cherng , Soh Boon-Seng , Ng Shi-Yan
Published: August 2019

Motor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in Amyotrophic Lateral Sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells (iPSCs) from healthy controls, familial ALS and sporadic ALS patients were differentiated towards spinal MNs, cortical neurons and cardiomyocytes. Metabolic flux analyses reveal a MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, SIRT3 functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.
Chemotaxis and swarming in differentiated HL60 neutrophil-like cells
Authors: Babatunde Kehinde Adebayo , Wang Xiao , Hopke Alex , Mantel Pierre-Yves , Irimia Daniel
Published: August 2019

Human leukemia cell line (HL-60) is an alternative to primary neutrophils in research studies. However, because HL-60 cells proliferate in an incompletely differentiated state, they must undergo differentiation before they acquire the functional properties of neutrophils. Here we provide evidence of swarming and chemotaxis in HL-60 neutrophil-like cells using precision microfluidic assays. We found that dimethyl sulfoxide (DMSO) differentiated HL-60 cells have larger size, increased length, and lower ability to squeeze through narrow channels compared to primary neutrophils. They migrate through tapered microfluidic channels slower than primary neutrophils, but faster than HL60s differentiated by other protocols, e.g. using all-trans retinoic acid. We found that differentiated HL-60 can swarm toward zymosan particle clusters, though they display disorganized migratory patterns and produce swarms of smaller size compared to primary neutrophils.
Impact of second-generation antipsychotics on white matter microstructure in adolescent-onset psychosis
Authors: Barth Claudia , Lonning Vera , Gurholt Tiril Pedersen , Andreassen Ole A. , Myhre Anne M. , Agartz Ingrid
Published: August 2019

White matter abnormalities are well-established in adult patients with psychosis. Yet less is known about changes in early onset psychosis (EOP) during adolescence, especially whether antipsychotic medication might impact white matter microstructure in this sensitive phase. Here, we utilized Magnetic Resonance Imaging (MRI) in unmedicated and medicated adolescent EOP patients in comparison to healthy controls to examine the impact of antipsychotic medication status on indices of white matter microstructure. Twenty-two EOP patients (11 unmedicated) and 33 healthy controls, aged between 12-18 years, underwent 3T diffusion-weighted MRI. Using Tract-based Spatial Statistics, we calculate case-control differences in scalar diffusion measures, i.e. fractional anisotropy (FA), axial diffusion (AD) and radial diffusion (RD), and investigated their association with antipsychotic medication. We found significantly lower mean FA and AD in largely overlapping areas, particularly in left anterior corona radiata (ACR), in EOP patients relative to healthy controls. Mean FA in the left ACR was significantly associated with antipsychotic medication status (t = 2.991, p = 0.008, R2 = 0.298), showing higher FA values in medicated compared to unmedicated EOP patients. The present study is the first to link antipsychotic medication status to altered regional FA in the left ACR, a region being discussed to contribute to the etiology of psychosis. Yet, further work with larger samples is needed to draw firm conclusions about putatively enhancing effects of antipsychotic medication on white matter microstructure early in the disease process.
Heterogeneity in human hippocampal CaMKII transcripts reveals allosteric hub-dependent regulation
Authors: Sloutsky Roman , Dziedzic Noelle , Dunn Matthew J. , Bates Rachel M. , Torres-Ocampo Ana P. , Boopathy Sivakumar , Page Brendan , Weeks John G. , Chao Luke H. , Stratton Margaret M.
Published: August 2019

Ca2+-calmodulin dependent protein kinase II (CaMKII) plays a central role in Ca2+signaling throughout the body. Specifically in the hippocampus, CaMKII is required for learning and memory. CaMKII is encoded by four highly conserved genes in vertebrates: α, β, γ, and δ. AllCaMKIIs are comprised of a kinase domain, regulatory segment, variable linker region, and hub domain responsible for oligomerization. The four genes differ primarily in linker length and composition due to extensive alternative splicing. Here, we unambiguously report the heterogeneity of CaMKII transcripts in 3 complex samples of human hippocampus using Illumina sequencing. Our results show that hippocampal cells contain a diverse collection of 70 CaMKII transcripts from all four CaMKII genes. We characterized the Ca2+/CaM sensitivity of hippocampal CaMKII variants spanning a broad range of linker lengths and compositions. We demonstrate that the effect of the variable linker on Ca2+/CaM sensitivity is conditional on kinase and hub domains. Moreover, we reveal a novel role for the hub domain as an allosteric regulator of kinase activity, which may provide a new pharmacological target for modulating CaMKII activity. Using small angle X-ray scattering and single-particle electron cryo-microscopy, we present evidence for extensive interaction between the kinase and the hub domain, even in the presence of a 30-residue linker. Taken together, we propose that Ca2+/CaM sensitivity in CaMKII is gene-dependent and includes significant contributions from the hub. Our sequencing approach combined with biochemistry provides new insights into understanding the complex pool of endogenous CaMKII.

One Sentence Summary

CaMKII is a well-conserved protein that is essential for learning and memory. When CaMKII is mutated in a mouse, this mouse has difficulty learning and remembering how to get through a maze. The hippocampus is the part of the brain required for memory. Here, we used a specific experiment to determine every type of CaMKII that is in a human hippocampus. We found 70 different types and then asked how these differences affect CaMKII function. These data provide evidence that an assembly domain of CaMKII plays an unexpected role regulating its activity. This new finding helps us better understand endogenous CaMKII in the brain and provides a new mechanism for modulating CaMKII activity.
Immune Profiling of Atherosclerotic Plaques Identifies Innate and Adaptive Dysregulations Associated with Ischemic Cerebrovascular Events
Authors: Fernandez Dawn M. , Rahman Adeeb H. , Fernandez Nicolas , Chudnovskiy Aleksey , Amir El-ad David , Amadori Letizia , Khan Nayaab S. , Wong Christine , Shamailova Roza , Hill Christopher , Wang Zichen , Remark Romain , Li Jennifer R. , Pina Christian , Faries Christopher , Awad Ahmed J. , Moss Noah , Bjorkegren Johan L.M. , Kim-Schulze Seunghee , Gnjatic Sacha , Ma’ayan Avi , Mocco J. , Faries Peter , Merad Miriam , Giannarelli Chiara
Published: August 2019

Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. Yet the specific immune dysregulations within the atherosclerotic lesions that lead to clinical cerebro- and cardiovascular complications (i.e. ischemic stroke and myocardial infarction) are poorly understood. Here, using single-cell mass cytometry with Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) we found that atherosclerotic plaques were enriched in activated, differentiated, and exhausted subsets of T cells vs. blood. Next, using single-cell proteomic, transcriptomic, and cell-to-cell interaction analyses we found unique functional dysregulations of both T cells and macrophages in plaques of patients with clinically symptomatic (SYM; recent stroke of TIA) or asymptomatic (ASYM, no recent stroke) carotid artery disease. SYM plaques were enriched with a distinct CD4+T cell subset, and T cells were activated, differentiated and presented subset specific exhaustion. SYM macrophages presented alternatively activated phenotypes including subsets associated with plaque vulnerability. In ASYM plaques, T cells and macrophages were activated and displayed a strong IL-1β signaling across cell types, that was absent in SYM plaques. The identification of plaque-specific innate and adaptive immune dysregulations associated with cerebrovascular events provides the basis for the design of precisely tailored cardiovascular immunotherapies.
Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy
Authors: Pero Maria Elena , Meregalli Cristina , Qu Xiaoyi , Kumar Atul , Shorey Matthew , Rolls Melissa , Tanji Kurenai , Brannagan Thomas H. , Alberti Paola , Fumagalli Giulia , Monza Laura , Cavaletti Guido , Bartolini Francesca
Published: August 2019

The pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) is still poorly understood. Herein, we found that the CIPN-causing drug, bortezomib (Bort), induces delta 2 tubulin (D2) while affecting MT stability and dynamics in sensory neurons, and that accumulation of D2 is a hallmark of Bort-induced peripheral neuropathy in humans. Furthermore, while induction of D2 was sufficient to cause axonopathy and inhibit mitochondria motility, reducing D2 alleviated both axonal degeneration and loss of mitochondria motility promoted by Bort. Altogether, our data demonstrate that Bort, structurally unrelated to tubulin poisons, can affect the tubulin cytoskeleton in sensory neurons in vitro, in vivo and in humans, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. They further reveal a previously unrecognized pathogenic role for D2 in bortezomib-causing CIPN through its regulation of mitochondria dynamics.