bluuebunny/crossref_metadata_2025 huggingface dataset:
Women in Law and Justice in Africa
Authors: Dancer Helen
Published: March 2020

African law and justice systems in the early 21st century are the result of over a thousand years of religious and cultural influences and political change on the continent. As customary and Islamic laws became reinterpreted and formalized by colonial states, women experienced the effects of successive periods of religious and political conquest as an entrenching of patriarchal control in the family and personal law sphere. The 20th century saw African women’s resistance rise from the grass roots as an important force for national liberation. African women’s legal activism grew after political independence and African women lawyers were part of global feminist movements. In the wake of dramatic political changes across Africa, Latin America, and Eastern Europe, the global sphere of rights post-1989 became an enabling frame for women’s legal activism. Political transitions to multiparty democracy, the liberalization of African economies, and a wave of constitutional reforms strengthened women’s rights and gender equality guarantees. The 1980s and 1990s saw the founding of regional and pan-African women’s legal activist organizations, including the Action Committee of Women Living Under Muslim Laws and Women in Law and Development in Africa as well as the adoption of the Maputo Protocol on the Rights of Women in Africa in 2003. In the 21st century, while social, economic, and legal inequalities persist in spite of many gains for women’s rights, some African women lawyers have risen to occupy the highest echelons of the judiciary in several countries and in international courts.
Gravity Models and Empirical Trade
Authors: Baier Scott , Standaert Samuel
Published: March 2020

The gravity model of international trade states that the volume of trade between two countries is proportional to their economic mass and a measure of their relative trade frictions. Perhaps because of its intuitive appeal, the gravity model has been the workhorse model of international trade for more than 50 years. While the initial empirical work using the gravity model lacked sound theoretical underpinnings, the theoretical developments have highlighted how a gravity-like specification can be derived from many models with varying assumptions about preferences, technology, and market structure. Along the strengthening of the theoretical roots of the gravity model, the way in which it is estimated has also evolved significantly since the start of the new millennium. Depending on the exact characteristics of regression, different estimation methods should be used to estimate the gravity model.
Mantle Convection in Terrestrial Planets
Authors: Mulyukova Elvira , Bercovici David
Published: March 2020

All the rocky planets in our solar system, including the Earth, initially formed much hotter than their surroundings and have since been cooling to space for billions of years. The resulting heat released from planetary interiors powers convective flow in the mantle. The mantle is often the most voluminous and/or stiffest part of a planet and therefore acts as the bottleneck for heat transport, thus dictating the rate at which a planet cools. Mantle flow drives geological activity that modifies planetary surfaces through processes such as volcanism, orogenesis, and rifting. On Earth, the major convective currents in the mantle are identified as hot upwellings such as mantle plumes, cold sinking slabs, and the motion of tectonic plates at the surface. On other terrestrial planets in our solar system, mantle flow is mostly concealed beneath a rocky surface that remains stagnant for relatively long periods. Even though such planetary surfaces do not participate in convective circulation, they deform in response to the underlying mantle currents, forming geological features such as coronae, volcanic lava flows, and wrinkle ridges. Moreover, the exchange of material between the interior and surface, for example through melting and volcanism, is a consequence of mantle circulation and continuously modifies the composition of the mantle and the overlying crust. Mantle convection governs the geological activity and the thermal and chemical evolution of terrestrial planets and understanding the physical processes of convection helps us reconstruct histories of planets over billions of years after their formation.
Causative/Inchoative in Morphology
Authors: Tubino-Blanco Mercedes
Published: March 2020

The Causative/Inchoative alternation involves pairs of verbs, one of which is causative and the other non-causative syntactically and semantically (e.g., John broke the window vs. The window broke). In its causative use, an alternating verb is used transitively and understood as externally caused. When used non-causatively, the verb is intransitive and interpreted as spontaneous. The alternation typically exhibits an affected argument (i.e., a Theme) in both intransitive and transitive uses, whereas the transitive use also involves a Causer that brings about the event. Although they are often volitional agents (e.g., John broke the window with a stone), external causers may also be non-volitional causers (e.g., The earthquake broke the windows) and instruments (e.g., The hammer broke the window).

Morphologically, languages exhibit different patterns reflecting the alternation, even intralinguistically. In languages like English, alternations are not morphologically coded, but they are in most languages. Languages like Hindi commonly mark causative (or transitive) alternations by means of different mechanisms, such as internal vowel changes or causative morphology. In many European languages, a subset of alternating verbs may exhibit an uncoded alternation, but most alternating verbs mark anticausativization with a reflexive-like clitic. In Yaqui (Uto-Aztecan), different patterns are associated with different verbal roots. The alternation may be uncoded, equipollent (i.e., both alternating forms are coded), and anticausative.

Theoretically, different approaches have explored the alternation. Both lexical and syntactic causativization and anticausativization accounts have been proposed to explain the alternation. A third approach postulates that both forms are derived from a common source.
Real-Time Intraoperative Consultation Reporting in the Electronic Health Record
Authors: Klein Molly E , Rudolf Joseph W , Tarbunova Maryna , Jorden Tanya , Clark Susanna R , Khalifa Mahmoud A
Published: March 2020

Objectives

We sought to make pathologists’ intraoperative consultation (IOC) results immediately available to the surgical team, other clinicians, and laboratory medicine colleagues to improve communication and decrease postanalytic errors.

Methods

We created an IOC report in our stand-alone laboratory information system that could be signed out prior to, and independent of, the final report, and transfer immediately to the electronic health record (EHR) as a preliminary diagnosis. We evaluated two metrics: preliminary (IOC) result review in the EHR by clinicians and postanalytic errors.

Results

We assessed 2,886 IOC orders from the first 22 months after implementation. Clinicians reviewed 1,956 (68%) of the IOC results while in preliminary status, including 1,399 (48%) within the first 24 hours. We evaluated 150 cases preimplementation and 300 cases postimplementation for discrepancies between the pathologist’s IOC result and the IOC result recorded by the surgeon in the operative note. Discrepancies dropped from 12 of 150 preimplementation to 6 of 150 and 7 of 150 in postimplementation years 1 and 2. One of the 25 discrepancies had a major clinical impact.

Conclusions

Real-time reporting of IOC results to the EHR reliably transmits results immediately to clinical teams. This strategy reduces but does not eliminate postanalytic interpretive errors by clinical teams.
Nemo-like kinase reduces mutant huntingtin levels and mitigates Huntington’s disease
Authors: Jiang Mali , Zhang Xiaoyan , Liu Hongshuai , LeBron Jared , Alexandris Athanasios , Peng Qi , Gu Hao , Yang Fanghan , Li Yuchen , Wang Ruiling , Hou Zhipeng , Arbez Nicolas , Ren Qianwei , Dong Jen-Li , Whela Emma , Wang Ronald , Ratovitski Tamara , Troncoso Juan C , Mori Susumu , Ross Christopher A , Lim Janghoo , Duan Wenzhen
Published: March 2020

Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, is highly expressed in the brain, but its function in the adult brain remains not well understood. In this study, we identify NLK as an interactor of huntingtin protein (HTT). We report that NLK levels are significantly decreased in HD human brain and HD models. Importantly, overexpression of NLK in the striatum attenuates brain atrophy, preserves striatal DARPP32 levels and reduces mutant HTT (mHTT) aggregation in HD mice. In contrast, genetic reduction of NLK exacerbates brain atrophy and loss of DARPP32 in HD mice. Moreover, we demonstrate that NLK lowers mHTT levels in a kinase activity-dependent manner, while having no significant effect on normal HTT protein levels in mouse striatal cells, human cells and HD mouse models. The NLK-mediated lowering of mHTT is associated with enhanced phosphorylation of mHTT. Phosphorylation defective mutation of serine at amino acid 120 (S120) abolishes the mHTT-lowering effect of NLK, suggesting that S120 phosphorylation is an important step in the NLK-mediated lowering of mHTT. A further mechanistic study suggests that NLK promotes mHTT ubiquitination and degradation via the proteasome pathway. Taken together, our results indicate a protective role of NLK in HD and reveal a new molecular target to reduce mHTT levels.
Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice
Authors: Xu Huijuan , Qu Chao , Gan Li , Sun Kuanxiang , Tan Junkai , Liu Xuyang , Jiang Zhilin , Tian Wanli , Liu Wenjing , Zhang Shanshan , Yang Yeming , Jiang Li , Zhu Xianjun , Zhang Lin
Published: March 2020

Variants in interphotoreceptor matrix proteoglycans (IMPG2) have been reported in retinitis pigmentosa (RP) and vitelliform macular dystrophy (VMD) patients. However, the underlying molecular mechanisms remain elusive due to a lack of suitable disease models. We developed two independent Impg2 knockout (KO) mouse models using the CRISPR/Cas9 technique to assess the in vivo functions of Impg2 in the retina. Impg2 ablation in mice recapitulated the RP phenotypes of patients, including an attenuated electroretinogram (ERG) response and the progressive degeneration of photoreceptors. The histopathological examination of Impg2-KO mice revealed irregularly arranged rod cells and mislocalized rhodopsin protein in the inner segment at 6 months of age. In addition to the pathological changes in rod cells, cone cells were also affected in KO retinas. KO retinas exhibited progressive cone cell death and impaired cone cell elongation. Further immunoblotting analysis revealed increased levels of endoplasmic reticulum (ER) stress-related proteins, including C/EBP homologous protein (CHOP), immunoglobulin heavy-chain-binding protein (BIP) and protein disulfide isomerase (PDI), in Impg2-KO mouse retinas. Increased gliosis and apoptotic cell death were also observed in the KO retinas. As autophagy is closely associated with ER stress, we then checked whether autophagy was disturbed in Impg2-KO mouse retinas. The results showed that autophagy was impaired in KO retinas, as revealed by the increased accumulation of SQSTM1 and other proteins involved in autophagy. Our results demonstrate the essential roles of Impg2 in the retina, and this study provides novel models for mechanistic investigations and development of therapies for RP caused by IMPG2 mutations.
The braking index of PSR B0540−69 and the associated pulsar wind nebula emission after spin-down rate transition
Authors: Wang L J , Ge M Y , Wang J S , Weng S S , Tong H , Yan L L , Zhang S N , Dai Z G , Song L M
Published: March 2020

In 2011 December, PSR B054−69 experienced a spin-down rate transition (SRT), after which the spin-down power of the pulsar increased by $\sim 36{{\ \rm per\ cent}}$. About 1000 d after the SRT, the X-ray luminosity of the associated pulsar wind nebula (PWN) was found to brighten by $32\pm 8{{\ \rm per\ cent}}$. After the SRT, the braking index n of PSR B0540−69 changes from n = 2.12 to 0.03 and then keeps this value for about five years before rising to n = 0.9 in the following years. We find that most of the current models have difficulties in explaining the measured braking index. One exceptive model of the braking index evolution is the increasing dipole magnetic field of PSR B0540−69. We suggest that the field increase may result from some instabilities within the pulsar core that enhance the poloidal component at the price of toroidal component of the magnetic field. The increasing dipole magnetic field will result in the X-ray brightening of the PWN. We fit the PWN X-ray light curve by two models: one assumes a constant magnetic field within the PWN during the brightening and the other assumes an enhanced magnetic field proportional to the energy density of the PWN. It appears that the two models fit the data well, though the later model seems to fit the data a bit better. This provides marginal observational evidence that magnetic field in the PWN is generated by the termination shock. Future high-quality and high-cadence data are required to draw a solid conclusion.
Location and stability of distant retrograde orbits around the Moon
Authors: Pires P , Winter O C
Published: March 2020

Recently has grown the interest of placing natural or artificial objects in the neighbourhood of the Moon. We numerically investigate a region of retrograde orbits around the Moon associated with the C Family of periodic orbits and the quasi-periodic orbits that oscillate around them (Broucke 1968; Winter 2000). We have given continuity to Winter (2000) investigations by introducing a more realistic dynamical scenario, one based on the four-body Sun–Earth–Moon–particle problem. Our results showed that the region of stability diminished to approximately 4 ${{\ \rm per\ cent}}$, the original size encountered for the circular-restricted three-body problem (CRTBP), mainly due to the Sun’s gravitational perturbations. None the less, the size of the region continues to be significant and we were able to found distant retrograde orbits (DROs) around the Moon with eccentricity following e = 2.259 63 × 10−6a + 0.238 45 (standard error of 1 ${{\ \rm per\ cent}}$) and semimajor axis values of the initial osculating orbits, varying between 110 000 and 185 000 km, remaining stable for a time span of 104 lunar periods. This set of distant orbits from the Moon are characterized by a narrow range of acceptable initial positions (0.8–0.83) and velocities of ∼0.5, in the rotating Earth–Moon frame. The out of plane amplitude oscillations of $\pm 15\, 000$ km presented by these DROs are a natural outcome of the significant Moon’s inclination of 5.15°. Some results presented on this work can be useful for lunar missions, such as the ones that would require prolonged stays around the satellite and use stable distant orbits as ‘parking’ orbits, such as the advanced concepts of NASA’s Asteroid Redirect Mission, proposed a few years ago.
How runaway stars boost galactic outflows
Authors: Andersson Eric P , Agertz Oscar , Renaud Florent
Published: March 2020

Roughly 10 per cent of OB stars are kicked out of their natal clusters before ending their life as supernovae. These so-called runaway stars can travel hundreds of parsecs into the low-density interstellar medium, where momentum and energy from stellar feedback is efficiently deposited. In this work, we explore how this mechanism affects large-scale properties of the galaxy, such as outflows. To do so we use a new model that treats OB stars and their associated feedback processes on a star-by-star basis. With this model, we compare two hydrodynamical simulations of Milky Way-like galaxies, one where we include runaways, and one where we ignore them. Including runaway stars leads to twice as many supernovae explosions in regions with gas densities ranging from $10^{-5}\, \mathrm{\,cm^{-3}}$ to $10^{-3}\, \mathrm{\,cm^{-3}}$. This results in more efficient heating of the inter-arm regions, and drives strong galactic winds with mass loading factors boosted by up to one order of magnitude. These outflows produce a more massive and extended multiphase circumgalactic medium, as well as a population of dense clouds in the halo. Conversely, since less energy and momentum is released in the dense star-forming regions, the cold phase of the interstellar medium is less disturbed by feedback effects.
Electric heating and angular momentum transport in laminar models of protoplanetary discs
Authors: Béthune William , Latter Henrik
Published: March 2020

The vertical temperature structure of a protoplanetary disc bears on several processes relevant to planet formation, such as gas and dust grain chemistry, ice lines, and convection. The temperature profile is controlled by irradiation from the central star and by any internal source of heat such as might arise from gas accretion. We investigate the heat and angular momentum transport generated by the resistive dissipation of magnetic fields in laminar discs. We use local 1D simulations to obtain vertical temperature profiles for typical conditions in the inner disc (0.5–4 au). Using simple assumptions for the gas ionization and opacity, the heating and cooling rates are computed self-consistently in the framework of radiative non-ideal magnetohydrodynamics. We characterize steady solutions that are symmetric about the mid-plane and which may be associated with saturated Hall-shear unstable modes. We also examine the dissipation of electric currents driven by global accretion-ejection structures. In both cases we obtain significant heating for a sufficiently high opacity. Strong magnetic fields can induce an order-unity temperature increase in the disc mid-plane, a convectively unstable entropy profile, and a surface emissivity equivalent to a viscous heating of α ∼ 10−2. These results show how magnetic fields may drive efficient accretion and heating in weakly ionized discs where turbulence might be inefficient, at least for a range of radii and ages of the disc.
A kinematically hot population of young stars in the solar neighbourhood
Authors: Binks A S , Jeffries R D , Wright N J
Published: March 2020

In the last three decades several hundred nearby members of young stellar moving groups (MGs) have been identified, but there has been less systematic effort to quantify or characterize young stars that do not belong to previously identified MGs. Using a kinematically unbiased sample of 225 lithium-rich stars within 100 pc, we find that only 50 ± 10 per cent of young (≲125 Myr), low-mass (0.5 < M/M⊙ < 1.0) stars, are kinematically associated with known MGs. Whilst we find some evidence that five of the non-MG stars may be connected with the Lower Centaurus–Crux association, the rest form a kinematically ‘hotter’ population, much more broadly dispersed in velocity, and with no obvious concentrations in space. The mass distributions of the MG members and non-MG stars are similar, but the non-MG stars may be older on average. We briefly discuss several explanations for the origin of the non-MG population.
Systematic versus statistical uncertainties in masses and magnifications of the Hubble Frontier Fields
Authors: Raney Catie A , Keeton Charles R , Brennan Sean , Fan Hsin
Published: March 2020

The Hubble Frontier Fields data, along with multiple data sets obtained by other telescopes, have provided some of the most extensive constraints on cluster lenses to date. Multiple lens modelling teams analyzed the fields and made public a number of deliverables. By comparing these results, we can then undertake a unique and vital test of the state of cluster lens modelling. Specifically, we see how well the different teams can reproduce similar magnifications and mass profiles. We find that the circularly averaged mass profiles of the fields are remarkably constrained (scatter $\lt 5{{\ \rm per\ cent}}$) at distances of 1 arcmin from the cluster core, yet magnifications can vary significantly. Averaged across the six fields, we find a bias of −6 per  cent (−17 per cent) and a scatter of ∼40 per cent (∼65 per cent) at a modest magnification of 3 (10). Statistical errors reported by individual teams are often significantly smaller than the differences among all the teams, indicating the importance of continued systematics studies in cluster lensing.
Exploring EEG Spectral Patterns in Episodic and Chronic Migraine During the Interictal State: Determining Frequencies of Interest in the Resting State
Authors: Gomez-Pilar Javier , García-Azorín David , Gomez-Lopez-de-San-Roman Claudia , Guerrero Ángel L , Hornero Roberto
Published: March 2020

Objective

The analysis of particular (electroencephalographic) EEG frequency bands has revealed new insights relative to the neural dynamics that, when studying the EEG spectrum as a whole, would have remained hidden. This study is aimed at characterizing spectral resting state EEG patterns for assessing possible differences of episodic and chronic migraine during the interictal period. For that purpose, a novel methodology for analyzing specific frequencies of interest was performed.

Methods

Eighty-seven patients with migraine (45 with episodic and 42 with chronic migraine) and 39 age- and sex-matched controls performed a resting-state EEG recording. Spectral measures were computed using conventional frequency bands. Additionally, particular frequency bands were determined to distinguish between controls and migraine patients, as well as between migraine subgroups.

Results

Frequencies ranging from 11.6 Hz to 12.8 Hz characterized migraine as a whole, with differences evident in the central and left parietal regions (controlling for false discovery rate). An additional band between 24.1 Hz and 29.8 Hz was used to discriminate between migraine subgroups. Interestingly, the power in this band was positively correlated with time from onset in episodic migraine, but no correlation was found for chronic migraine.

Conclusions

Specific frequency bands were proposed to identify the spectral characteristics of the electrical brain activity in migraine during the interictal stage. Our findings support the importance of discriminating between migraine subgroups to avoid hiding relevant features in migraine.
Tuberculosis in Children
Authors: Frederick Katherine
Published: March 2020

Background

The rate of tuberculosis and other crowding diseases is increasing in vulnerable populations worldwide. Limited resources, shared environments, and densely populated areas are factors in the spreading of disease.

Method

Via case study analysis, the author explores how the presence of tuberculosis-positive patients is handled in the emergency room and their journey to the operating room.

Results

A solutions-oriented approach is suggested along with a discussion of the value and importance of adequate personal protective equipment and the consideration of using an augmented technology to aid in the prevention of environmental contamination.
Serum neurofilament light chain predicts long-term prognosis in Guillain-Barré syndrome patients
Authors: Martín-Aguilar Lorena , Camps-Renom Pol , Lleixà Cinta , Pascual-Goñi Elba , Diaz-Manera Jordi , Rojas-García Ricard , de Luna Noemí , Gallardo Eduard , Cortés-Vicente Elena , Muñoz Laia , Alcolea Daniel , Lleó Alberto , Casasnovas Carlos , Homedes Christian , Gutiérrez-Gutiérrez Gerardo , Jimeno-Montero María Concepción , Berciano José , Sedano Tous Maria José , Garcia-Sobrino Tania , Pardo-Fernandez Julio , Márquez-Infante Celedonio , Rojas-Marcos Iñigo , Pascual Ivonne Jericó , Martínez-Hernández Eugenia , de la Tassa Germán Morís , Domínguez-González Cristina , Illa Isabel , Querol Luis
Published: March 2020

Objective

To study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barré syndrome (GBS).

Methods

We measured NfL using SiMoA in serum (98 samples) and CSF (24 samples) of GBS patients prospectively included in the International GBS Outcome Study (IGOS) in Spain and compared them with controls (HC). We performed multivariable regression to analyze the association between sNfL levels and functional outcome at one year.

Results

GBS patients had higher NfL levels than HC in serum (55.49pg/mL vs 9.13pg/mL, p<0,0001) and CSF (1308.5pg/mL vs 440.24pg/mL, p=0.034). Patients with preceding diarrhea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90pg/mL vs 47.86pg/mL vs 38.02pg/mL, p=0.016). sNfL levels correlated with GDS and R-ODS scales. Patients with pure motor variant and Miller- Fisher syndrome showed higher sNfL levels than patients with sensory-motor GBS (162.18pg/mL vs 95.50pg/mL vs 38.02pg/mL; p=0.025). AMAN patients had higher sNfL levels than other variants (190.55pg/mL vs 46.79pg/mL, p=0.013). sNfL returned to normal levels at one year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14-2.40, p=0.009) and lower R-ODS (β −2.60, 95% β −4.66-(−0.54), p=0.014) at one year. Cut-off points predicting clinically relevant outcomes at one year with high specificity were calculated: inability to walk independently (>319pg/mL), inability to run (>248pg/mL) and ability to run (<34pg/mL).

Conclusion

Baseline sNfL levels are increased in patients with GBS, they are associated with disease severity and axonal variants and they have an independent prognostic value in GBS patients.
Structure of the ForT/PRPP complex uncovers the mechanism of C-C bond formation in C-nucleotide antibiotic biosynthesis
Authors: Gao Sisi , Radadiya Ashish , Li Wenbo , Liu Huanting , Zhu Wen , de Crécy-Lagard Valérie , Richards Nigel G. J. , Naismith James H.
Published: March 2020

C-C bond formation is at the heart of anabolism and organic chemistry, but relatively few enzymatic strategies for catalyzing this reaction are known. The enzyme ForT catalyzes C-C bond formation between 5’-phosphoribosyl-1’-pyrophosphate (PRPP) and 4-amino-1H-pyrazole-3,5-dicarboxylate to make a key intermediate in the biosynthesis of the C-nucleotide formycin A 5’-phosphate; we now report the 2.5 Å resolution structure of the ForT/PRPP complex and thus locate the active site. Site-directed mutagenesis has identified those residues critical for PRPP recognition and catalysis. Structural conservation with GHMP kinases suggests that stabilization of the negatively charged pyrophosphate leaving group is crucial for catalysis in ForT. A mechanism for this new class of C-C bond forming enzymes is proposed.

Entry for the Table of Contents

A new class of enzymes catalyse C-C bond formation by irreversible CO2and pyrophosphate production.
SARS-CoV-2 detection from nasopharyngeal swab samples without RNA extraction
Authors: Beltrán-Pavez Carolina , Márquez Chantal L. , Muñoz Gabriela , Valiente-Echeverría Fernando , Gaggero Aldo , Soto-Rifo Ricardo , Barriga Gonzalo P.
Published: March 2020

The ongoing COVID-19 pandemic has reached more than 200 countries and territories worldwide. Given the large requirement of SARS-CoV-2 diagnosis and considering that RNA extraction kits are in short supply, we investigated whether two commercial RT-qPCR kits were compatible with direct SARS-CoV-2 detection from nasopharyngeal swab samples. We show that one of the tested kits is fully compatible with direct SARS-CoV-2 detection suggesting that omission of an RNA extraction step should be considered in SARS-CoV-2 diagnosis.
The NAD Metabolome is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-related Liver Disease
Authors: Parker Richard , Schmidt Mark S. , Cain Owen , Gunson Bridget , Brenner Charles
Published: March 2020

Nicotinamide adenine dinucleotide (NAD+) and related coenzymes play critical roles in liver function. Though hepatic alcohol metabolism depresses NAD+, current understanding of the NAD+metabolome in alcohol-related liver disease (ArLD) is based on animal models. We used human liver samples to quantify the NAD+metabolome in ArLD with samples obtained at the time of liver transplantation or resection at University Hospitals Birmingham NHS Foundation Trust (UHB). The severity of steatohepatitis in liver from patients with ArLD was assessed with standard liver function tests (LFT) and histology. NAD-targeted quantitative metabolomic analysis of liver tissue was performed by liquid chromatography-tandem mass spectrometry (LC-MS). Seventy-two human liver specimens were analyzed including 43 with ArLD. The NAD+metabolome differed significantly between different types of liver disease (two-way ANOVA p = 0.001). ArLD liver tissue showed markedly depressed concentrations of NAD+(432 μM vs. 616 μM in NL) and precursor molecules nicotinic acid and nicotinamide riboside. There was a significant overall difference in the NAD+metabolome between ArLD samples with and without steatohepatitis (two-way ANOVA p = 0.018). After correcting for multiple comparisons, a significant difference for individual components of the metabolome was observed for the concentration of NAD+(mean 451 μM vs. 381 μM, p = 0.045). NAD+concentration was inversely related to serum bilirubin concentration (r2−0.127, p = 0.04) and positively correlated with myeloperoxidase activity (r20.31, p = 0.003). The concentration of NAD+and its precursor molecules are significantly reduced in ArLD and are associated with disease activity. Conclusion: Liver samples from people with ArLD show depressed NAD+and precursor levels as well as depressed myeloperoxidase activity.
Computational Design of Peptides to Block Binding of the SARS-CoV-2 Spike Protein to Human ACE2
Authors: Huang Xiaoqiang , Pearce Robin , Zhang Yang
Published: March 2020

The outbreak of COVID-19 has now become a global pandemic and it continues to spread rapidly worldwide, severely threatening lives and economic stability. Making the problem worse, there is no specific antiviral drug that can be used to treat COVID-19 to date. SARS-CoV-2 initiates its entry into human cells by binding to angiotensin-converting enzyme 2 (hACE2) via the receptor binding domain (RBD) of its spike protein. Therefore, molecules that can block SARS-CoV-2 from binding to hACE2 may potentially prevent the virus from entering human cells and serve as an effective antiviral drug. Based on this idea, we designed a series of peptides that can strongly bind to SARS-CoV-2 RBD in computational experiments. Specifically, we first constructed a 31-mer peptidic scaffold by linking two fragments grafted from hACE2 (a.a. 22-44 and 351-357) with a linker glycine, and then redesigned the peptide sequence to enhance its binding affinity to SARS-CoV-2 RBD. Compared with several computational studies that failed to identify that SARS-CoV-2 shows higher binding affinity for hACE2 than SARS-CoV, our protein design scoring function, EvoEF2, makes a correct identification, which is consistent with the recently reported experimental data, implying its high accuracy. The top designed peptide binders exhibited much stronger binding potency to hACE2 than the wild-type (−53.35 vs. −46.46 EvoEF2 energy unit for design and wild-type, respectively). The extensive and detailed computational analyses support the high reasonability of the designed binders, which not only recapitulated the critical native binding interactions but also introduced new favorable interactions to enhance binding. Due to the urgent situation created by COVID-19, we share these computational data to the community, which should be helpful to develop potential antiviral peptide drugs to combat this pandemic.
No Evidence for Temperature-Dependence of the COVID-19 Epidemic
Authors: Jamil Tahira , Alam Intikhab , Gojobori Takashi , Duarte Carlos M.
Published: March 2020

1.

The pandemic of the COVID-19 disease extended from China across the north-temperate zone, and more recently to the tropics and southern hemisphere. We find no evidence that spread rates decline with temperatures above 20 °C, suggesting that the COVID-19 disease is unlikely to behave as a seasonal respiratory virus.
CD8+T-cell transcription and DNA methylation show age specific differences and lack correlation with clinical outcome in pediatric Inflammatory Bowel Disease
Authors: Gasparetto M , Payne F , Nayak K , Kraiczy J , Glemas C , Philip-McKenzie Y , Ross A , Edgar RD , Zerbino D , Salvestrini C , Torrente F , Sarkies P , Heuschkel R , Zilbauer M
Published: March 2020

Background & Aims

CD8+T-cell gene expression has been implicated in the pathogenesis of Inflammatory Bowel Diseases (IBD) and has been shown to correlate with disease outcome in adult patients. Moreover, CD8+T-cell exhaustion was identified as a contributing mechanism that impacts on disease behaviour. We aimed to explore CD8+T-cell gene expression and DNA methylation in children newly diagnosed with IBD and test their correlation with disease outcome.

Methods

We prospectively recruited 112 children with IBD at the point of diagnosis and 19 non-IBD controls. Follow-up samples were obtained from a subset of patients at 3-month intervals (n=62). CD8+T-cells were purified from peripheral blood samples using magnetic bead sorting and genome-wide transcriptional (n=192) and DNA methylation (n=66) profiles were generated using Affymetrix and Illumina arrays respectively. Publicly available adult CD8+T-cell transcriptomes and DNA methylomes were included in data analyses to investigate age dependant differences.

Results

Variation amongst CD8+T-cell transcriptomes obtained from children showed association with disease, systemic inflammation, age and gender but lacked correlation with disease outcome in pediatric IBD. In contrast to CD8+T-cell transcriptomes in adult Crohn’s Disease (CD), samples from pediatric patients did not show variation within genes forming part of the previously reported prognostic expression or T-cell exhaustion signatures. Pediatric CD patient derived DNA methylation profiles also lacked correlation with disease outcome but in comparison to adult CD8+methylomes showed a higher predicted proportion of CD8+naïve T-cells.

Conclusions

Our findings indicate age-related differences in IBD pathogenesis and highlight the importance of validating adult clinical biomarkers in pediatric cohorts.
Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats
Authors: Zhang Yuehui , Hu Min , Jia Wenyan , Liu Guoqi , Zhang Jiao , Wang Bing , Li Juan , Cui Peng , Li Xin , Lager Susanne , Sferruzzi-Perri Amanda Nancy , Han Yanhua , Liu Songjiang , Wu Xiaoke , Brannstrom Mats , Shao Linus R , Billig Hakan
Published: March 2020

Ferroptosis, a form of regulated necrotic cell death, plays roles in diverse physiological processes and diseases. Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance (HAIR) and an increased risk of miscarriage and placental dysfunction during pregnancy. However, whether maternal HAIR alters mechanisms leading to ferroptosis in the gravid uterus and placenta remains unknown. Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces HAIR and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., region-dependent Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction. In contrast, in placentas co-exposed to DHT and INS we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA (a mitochondria-encoded iron-export factor). Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.
Implicit modeling of the impact of adsorption on solid surfaces for protein mechanics and activity with a coarse-grain representation
Authors: Bourassin Nicolas , Baaden Marc , Lojou Elisabeth , Sacquin-Mora Sophie
Published: March 2020

Surface immobilized enzymes play a key role in numerous biotechnological applications such as biosensors, biofuel cells or biocatalytic synthesis. As a consequence, the impact of adsorption on the enzyme structure, dynamics and function needs to be understood on the molecular level as it is critical for the improvement of these technologies. With this perspective in mind, we used a theoretical approach for investigating protein local flexibility on the residue scale that couples a simplified protein representation with an elastic network and Brownian Dynamics simulations. The protein adsorption on a solid surface is implicitly modeled via additional external constraints between the residues in contact with the surface. We first performed calculations on a redox enzyme, bilirubin oxidase (BOD) fromM. verrucaria, to study the impact of adsorption on its mechanical properties. The resulting rigidity profiles show that, in agreement with the available experimental data, the mechanical variations observed in the adsorbed BOD will depend on its orientation and its anchor residues (i.e. residues that are in contact with the functionalized surface). Additional calculations on ribonuclease A and nitroreductase shed light on how seemingly stable adsorbed enzymes can nonetheless display an important decrease in their catalytic activity resulting from a perturbation of their mechanics and internal dynamics.
Uptake of exogenous serine is important to maintain sphingolipid homeostasis inSaccharomyces cerevisiae
Authors: Esch Bianca M. , Limar Sergej , Bogdanowski André , Gournas Christos , More Tushar , Sundag Celine , Walter Stefan , Heinisch Jürgen J. , Ejsing Christer S. , André Bruno , Fröhlich Florian
Published: March 2020

Sphingolipids are abundant and essential molecules in eukaryotes that have crucial functions as signaling molecules and as membrane components. Sphingolipid biosynthesis starts in the endoplasmic reticulum with the condensation of serine and palmitoyl-CoA. Sphingolipid biosynthesis is highly regulated to maintain sphingolipid homeostasis. Even though, serine is an essential component of the sphingolipid biosynthesis pathway, its role in maintaining sphingolipid homeostasis has not been precisely studied. Here we show that serine uptake is an important factor for the regulation of sphingolipid biosynthesis inSaccharomyces cerevisiae. Using genetic experiments, we find the broad-specificity amino acid permease Gnp1 to be important for serine uptake. We confirm these results with serine uptake assays ingnp1Δcells. We further show that uptake of exogenous serine by Gnp1 is important to maintain cellular serine levels and observe a specific connection between serine uptake and the first step of sphingolipid biosynthesis. Using mass spectrometry-based flux analysis, we further observed imported serine as the main source forde novosphingolipid biosynthesis. Our results demonstrate that yeast cells preferentially use the uptake of exogenous serine to regulate sphingolipid biosynthesis. Our study can also be a starting point to analyze the role of serine uptake in mammalian sphingolipid metabolism.

Author Summary

Sphingolipids (SPs) are membrane lipids globally required for eukaryotic life. In contrast to other lipid classes, SPs cannot be stored in the cell and therefore their levels have to be tightly regulated. Failure to maintain sphingolipid homeostasis can result in pathologies including neurodegeneration, childhood asthma and cancer. However, we are only starting to understand how SP biosynthesis is adjusted according to need. In this study, we use genetic and biochemical methods to show that the uptake of exogenous serine is necessary to maintain SP homeostasis inSaccharomyces cerevisiae. Serine is one of the precursors of long chain bases in cells, the first intermediate of SP metabolism. Our results suggest that the uptake of serine is directly coupled to SP biosynthesis at ER-plasma membrane contact sites. Overall, our study identifies serine uptake as a novel regulatory factor of SP homeostasis. While we use yeast as a discovery tool, these results also provide valuable insights into mammalian SP biology especially under pathological conditions.
The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation
Authors: Mohanty Suchitra , Han Teng , Choi Young Bong , Lavorgna Alfonso , Zhang Jiawen , Harhaj Edward W.
Published: March 2020

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), and the neurological disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein persistently activates the NF-κB pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-κB; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify novel Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax. Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by co-immunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-κB activation, whereas knockdown of UBE4B impaired Tax-induced NF-κB activation and the induction of NF-κB target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR/Cas9-mediated knockout of UBE4B attenuated both K48- and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-κB activation.

Author Summary

Infection with the retrovirus HTLV-1 leads to the development of either CD4+CD25+ leukemia/lymphoma (ATLL) or a demyelinating neuroinflammatory disease (HAM/TSP) in a subset of infected individuals. The HTLV-1 Tax protein is a regulatory protein which regulates viral gene expression and persistently activates cellular signaling pathways such as NF-κB to drive the clonal expansion and longevity of HTLV-1 infected CD4+ T cells. Polyubiquitination of Tax is a key mechanism of NF-κB activation by assembling and activating IκB kinase (IKK) signaling complexes; however, the host factors regulating Tax ubiquitination have remained elusive. Here, we have identified the E3/E4 ubiquitin conjugation factor UBE4B as a novel Tax binding protein that promotes both K48- and K63-linked polyubiquitination of Tax. Knockdown or knockout of UBE4B impairs Tax-induced NF-κB activation and triggers apoptosis of HTLV-1 transformed cells. Therefore, UBE4B is an integral host factor that supports HTLV-1 Tax polyubiquitination, NF-κB activation and cell survival.
High-quality chromosome-level genomes of two tilapia species reveal their evolution of repeat sequences and sex chromosomes
Authors: Tao Wenjing , Xu Luohao , Zhao Lin , Zhu Zexian , Wu Xin , Min Qianwen , Wang Deshou , Zhou Qi
Published: March 2020

Background

Tilapias are one of the most farmed fishes that are coined as ‘aquatic chicken’ by the food industry. Like many other teleosts, Nile tilapia and blue tilapia exhibit very recent transition of sex chromosome systems since their divergence about 5 million years ago, making them a great model for elucidating the molecular and evolutionary mechanisms of sex chromosome turnovers. Studies into their sex-determining pathways are also critical for developing genetic sex control in aquaculture.

Results

We report here the newly produced genomes of Nile tilapia and blue tilapia that integrate long-read sequencing and chromatin conformation data. The two nearly complete genomes have anchored over 97% of the sequences into linkage groups (LGs), and assembled majorities of complex repetitive regions including telomeres, centromeres and rDNA clusters. In particular, we inferred two episodes of repeat expansion at LG3 respectively in the ancestor of cichlids and that of tilapias. The consequential large heterochromatic region concentrated at one end of LG3 comprises tandem arrays of mRNA and small RNA genes, among which we have identified a candidate female determining genePaicsin blue tilapia.Paicsshow female-specific patterns of single-nucleotide variants, copy numbers and expression patterns in gonads during early gonadogenesis.

Conclusions

Our work provide a very important genomic resource for functional studies of cichlids, and suggested that unequal distribution of repeat content that impacts the local recombination rate might make some chromosomes more likely to become sex chromosomes.
Optoregulated force application to cellular receptors using molecular motors
Authors: Zheng Yijun , Han Mitchell K.L. , Zhao Renping , Blass Johanna , Zhang Jingnan , Zhou Dennis W. , Colard-Itté Jean-Rémy , Dattler Damien , Hoth Markus , García Andrés J. , Qu Bin , Bennewitz Roland , Giuseppone Nicolas , del Campo Aránzazu
Published: March 2020

Mechanotransduction events in physiological environments are difficult to investigate, in part due to the lack of experimental tools to apply forces to mechanosensitive receptors remotely. Inspired by cellular mechanisms for force application (i.e. motor proteins pulling on cytoskeletal fibers), here we present a unique molecular machine that can apply forces at cell-matrix and cell-cell junctions using light as an energy source. The key actuator is a light-driven rotatory molecular motor linked to polymer chains, which is intercalated between a membrane receptor and an engineered biointerface. The light-driven actuation of the molecular motor is converted in mechanical twisting of the polymer chains, which will in turn effectively “pulls” on engaged cell membrane receptors (integrins, cadherins…) within the illuminated area. Applied forces have the adequate magnitude and occur at time scales within the relevant ranges for mechanotransduction at cell-friendly exposure conditions, as demonstrated in forcedependent focal adhesion maturation and T cell activation experiments. Our results reveal the potential of nanomotors for the manipulation of living cells at the molecular scale and demonstrate, for the first time, a functionality which at the moment cannot be achieved by any other means.