bluuebunny/crossref_metadata_2025 huggingface dataset:
Donor-Derived CD4+ T Cells and Human Herpesvirus 6B Detection After Allogeneic Hematopoietic Cell Transplantation
Authors: Hanson Derek J , Xie Hu , Zerr Danielle M , Leisenring Wendy M , Jerome Keith R , Huang Meei-Li , Stevens-Ayers Terry , Boeckh Michael , Koelle David M , Hill Joshua A
Published: July 2020

We sought to determine whether donor-derived human herpesvirus (HHV) 6B–specific CD4+ T-cell abundance is correlated with HHV-6B detection after allogeneic hematopoietic cell transplantation. We identified 33 patients who received HLA-matched, non–T-cell–depleted, myeloablative allogeneic hematopoietic cell transplantation and underwent weekly plasma polymerase chain reaction testing for HHV-6B for 100 days thereafter. We tested donor peripheral blood mononuclear cells for HHV-6B–specific CD4+ T cells. Patients with HHV-6B detection above the median peak viral load (200 copies/mL) received approximately 10-fold fewer donor-derived total or HHV-6B–specific CD4+ T cells than those with peak HHV-6B detection at ≤200 copies/mL or with no HHV-6B detection. These data suggest the importance of donor-derived immunity for controlling HHV-6B reactivation.
Influences on antibiotic prescribing by non-medical prescribers for respiratory tract infections: a systematic review using the theoretical domains framework
Authors: Chater Angel , Family Hannah , Lim Rosemary , Courtenay Molly
Published: July 2020

Background

The need to conserve antibiotic efficacy, through the management of respiratory tract infections (RTIs) without recourse to antibiotics, is a global priority. A key target for interventions is the antibiotic prescribing behaviour of healthcare professionals including non-medical prescribers (NMPs: nurses, pharmacists, paramedics, physiotherapists) who manage these infections.

Objectives

To identify what evidence exists regarding the influences on NMPs’ antimicrobial prescribing behaviour and analyse the operationalization of the identified drivers of behaviour using the Theoretical Domains Framework (TDF).

Methods

The search strategy was applied across six electronic bibliographic databases (eligibility criteria included: original studies; written in English and published before July 2019; non-medical prescribers as participants; and looked at influences on prescribing patterns of antibiotics for RTIs). Study characteristics, influences on appropriate antibiotic prescribing and intervention content to enhance appropriate antibiotic prescribing were independently extracted and mapped to the TDF.

Results

The search retrieved 490 original articles. Eight papers met the review criteria. Key issues centred around strategies for managing challenges experienced during consultations, managing patient concerns, peer support and wider public awareness of antimicrobial resistance. The two most common TDF domains highlighted as influences on prescribing behaviour, represented in all studies, were social influences and beliefs about consequences.

Conclusions

The core domains highlighted as influential to appropriate antibiotic prescribing should be considered when developing future interventions. Focus should be given to overcoming social influences (patients, other clinicians) and reassurance in relation to beliefs about negative consequences (missing something that could lead to a negative outcome).
MEDICINE AND COLONIAL PATENT LAW IN INDIA: A Study of Patent Medicines and the Indian Patents and Designs Act, 1911 in Early- Twentieth-Century India
Authors: Chowdhury Subhadeep
Published: July 2020

This paper investigates the history of drugs sold as “patent medicines” in India in the early twentieth century. The paper investigates their legitimacy as patenting of medicines was forbidden by the Indian Patents and Designs Act, 1911 (IPDA). The paper argues that the instrument of letters patents functioning as the prerogative of the Crown that gave monopolistic rights to grantees to sell any compound without having to disclose its constituents was the reason behind this seemingly conflicting historical relationship between the law and the market. Colonial law-making left sufficient space within the ambit of the IPDA for letters patents to have their ill effects. The colonial state made attempts to address this as a public health issue by incorporating concerns related to this class of medicines within regulations addressed to the drugs market in the 1930s. The currency of patent medicines in the market was further added to by Indian indigenous entrepreneurs fueled by cultural nationalism of Swadeshi ideology in Bengal in the early twentieth century. However, even such indigenous responses or attempts at hybridization of manufacturing and selling practices related to patent medicines were mostly informed by upper-caste/ upper-class interests and not so much by those of consumers of these medicines.
Immunotherapy for squamous cell carcinoma of the head and neck
Authors: Yokota Tomoya , Homma Akihiro , Kiyota Naomi , Tahara Makoto , Hanai Nobuhiro , Asakage Takahiro , Matsuura Kazuto , Ogawa Takenori , Saito Yuki , Sano Daisuke , Kodaira Takeshi , Motegi Atsushi , Yasuda Koichi , Takahashi Shunji , Tanaka Kaoru , Onoe Takuma , Okano Susumu , Imamura Yoshinori , Ariizumi Yosuke , Hayashi Ryuichi ,   Japan Clinical Oncology Group (JCOG) Head and Neck Cancer Study Group
Published: July 2020

Squamous cell carcinoma of the head and neck is characterized by an immunosuppressive environment and evades immune responses through multiple resistance mechanisms. A breakthrough in cancer immunotherapy employing immune checkpoint inhibitors has evolved into a number of clinical trials with antibodies against programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for patients with squamous cell carcinoma of the head and neck. CheckMate141 and KEYNOTE-048 were practice-changing randomized phase 3 trials for patients with platinum-refractory and platinum-sensitive recurrent or metastatic squamous cell carcinoma of the head and neck, respectively. Furthermore, many combination therapies using anti-CTLA-4 inhibitors, tyrosine kinase inhibitors and immune accelerators are currently under investigation. Thus, the treatment strategy of recurrent or metastatic squamous cell carcinoma of the head and neck is becoming more heterogeneous and complicated in the new era of individualized medicine. Ongoing trials are investigating immunotherapeutic approaches in the curative setting for locoregionally advanced disease. This review article summarizes knowledge of the role of the immune system in the development and progression of squamous cell carcinoma of the head and neck, and provides a comprehensive overview on the development of immunotherapeutic approaches in both recurrent/metastatic and locoregionally advanced diseases.
Internet-Delivered Acceptance and Commitment Therapy for Adolescents with Chronic Pain and Their Parents: A Nonrandomized Pilot Trial
Authors: Zetterqvist Vendela , Gentili Charlotte , Rickardsson Jenny , Sörensen Isabel , Wicksell Rikard K
Published: July 2020

Background

Acceptance and Commitment Therapy (ACT) is an empirically supported treatment for chronic pain in adults. There is also a small but growing evidence base of ACT for pediatric chronic pain. However, because of limited access to psychological treatment for pain, and geographical distances from pain facilities, many patients will not receive such treatment.

Objective

The aim of the study was to evaluate the feasibility and preliminary effects of an internet-delivered ACT for adolescents with chronic pain, and their parents.

Methods

In this nonrandomized pilot study 28 self-recruited adolescents, aged 13–17 years, received 8 weeks of internet-delivered ACT, while outcomes were assessed at pre-, posttreatment, and at follow-up (17–25 weeks). Parents of the adolescents received an 8-week internet-delivered parental program, and their outcomes were assessed at the same timepoints. Both treatments were guided by a therapist experienced in ACT and chronic pain.

Results

Some threats to feasibility were identified such as slow recruitment rate, low compliance and a delay in completion of follow-up assessments. Preliminary outcome evaluation showed that adolescents showed a large significant improvement on their main outcome (pain interference, d = 1.09), and parents a medium improvement on their main outcome, pain reactivity (d = 0.70). Improvements were also seen in adolescents’ depressive symptoms and insomnia severity.

Conclusion

The preliminary results of internet-delivered ACT are promising with regards to improvements in adolescent and parent outcome. Measures to improve feasibility are needed prior to conducting a larger randomized trial.
Deletion of maize RDM4 suggests a role in endosperm maturation as well as vegetative and stress-responsive growth
Authors: Jia Shangang , Yobi Abou , Naldrett Michael J , Alvarez Sophie , Angelovici Ruthie , Zhang Chi , Holding David R
Published: July 2020

Opaque kernels in maize may result from mutations in many genes, such as OPAQUE-2. In this study, a maize null mutant of RNA-DIRECTED DNA METHYLATION 4 (RDM4) showed an opaque kernel phenotype, as well as plant developmental delay, male sterility, and altered response to cold stress. We found that in opaque kernels, all zein proteins were reduced and amino acid content was changed, including increased lysine. Transcriptomic and proteomic analysis confirmed the zein reduction and proteomic rebalancing of non-zein proteins, which was quantitatively and qualitatively different from opaque-2. Global transcriptional changes were found in endosperm and leaf, including many transcription factors and tissue-specific expressed genes. Furthermore, of the more than 8000 significantly differentially expressed genes in wild type in response to cold, a significant proportion (25.9% in moderate cold stress and 40.8% in near freezing stress) were not differentially expressed in response to cold in rdm4, suggesting RDM4 may participate in regulation of abiotic stress tolerance. This initial characterization of maize RDM4 provides a basis for further investigating its function in endosperm and leaf, and as a regulator of normal and stress-responsive development.
SBAR as a Standardized Communication Tool for Medical Laboratory Science Students
Authors: Oliveira Ana L , Brown Michelle
Published: July 2020

Objective

Laboratory professionals must communicate effectively on an interprofessional team. It is the responsibility of Medical Laboratory Science (MLS) programs to teach communication. The structured communication tool Situation, Background, Assessment, and Recommendation (SBAR) is one way to promote effective communication.

Methods

Students participated in a case-based simulation activity on the importance of teamwork/communication and the use of SBAR and completed a pre/post survey on communicating interprofessionally.

Results

Students reported increased confidence and competence with interprofessional communication after the activity with 4 of 5 questions demonstrating a statistically significant increase in scores post SBAR instruction.

Conclusions

Our study demonstrates that SBAR is a suitable communication tool that can be used to increase our MLS students’ confidence and competency in interprofessional communication. Educators should use this communication tool to empower MLS students to be effective members of the healthcare team.
Phase-locked polarization by photospheric reflection in the semidetached eclipsing binary μ1 Sco
Authors: Cotton Daniel V , Bailey Jeremy , Kedziora-Chudczer Lucyna , De Horta Ain
Published: July 2020

We report the detection of phase-locked polarization in the bright (mV = 2.98−3.24) semidetached eclipsing binary μ1 Sco (HD 151890). The phenomenon was observed in multiple photometric bands using two different HIPPI-class (HIgh Precision Polarimetric Instrument) polarimeters with telescopes ranging in size from 35 cm to 3.9 m. The peak-to-trough amplitude of the polarization is wavelength dependent and large, ∼700 ppm in green light, and is easily seen with even the smallest telescope. We fit the polarization phase curve with a synspec/vlidort polarized radiative transfer model and a Wilson–Devinney geometric formalism, which we describe in detail. Light from each star reflected by the photosphere of the other, together with a much smaller contribution from tidal distortion and eclipse effects, wholly accounts for the polarization amplitude. In the past, polarization in semidetached binaries has been attributed mostly to scattering from extra-stellar gas. Our new interpretation facilitates determining masses of such stars in non-eclipsing systems.
CO-to-H2 conversion and spectral column density in molecular clouds: the variability of the XCO factor
Authors: Sofue Yoshiaki , Kohno Mikito
Published: July 2020

Analysing the Galactic plane CO survey with the Nobeyama 45-m telescope, we compared the spectral column density (SCD) of $N_{\rm H_2}$ calculated for the 12CO (J = 1–0) line using the current conversion factor $X_{\rm ^{12}CO}$ to that for the 13CO (J = 1–0) line under the LTE (local thermal equilibrium) assumption in the M16 and W43 regions. Here, SCD is defined by $\mathrm{d}N_{\rm H_2}/\mathrm{d}v$ with $N_{\rm H_2}$ and v being the column density and radial velocity, respectively. It is found that the $X_{\rm ^{12}CO}$ method significantly underestimates the H2 density in a cloud or region, where SCD exceeds a critical value (∼3 × 1021 [H2 cm−2 (km s−1)−1]), but overestimates in lower SCD regions. We point out that the actual CO-to-H2 conversion factor varies with the H2 column density or with the CO line intensity: it increases in the inner and opaque parts of molecular clouds, whereas it decreases in the low-density envelopes. However, in so far as the current $X_{^{12}{\rm CO}}$ is used combined with the integrated 12CO intensity averaged over an entire cloud, it yields a consistent value with that calculated using the 13CO intensity by LTE. Based on the analysis, we propose a new CO-to-H2 conversion relation, $N_{\rm H_2}^* = \int X^*_{\rm CO} (T_{\rm B}) T_{\rm B}\ \mathrm{d}v$, where $X^*_{\rm CO} (T_{\rm B})=(T_{\rm B}/T_{\rm B}^*)^\beta X_{\rm ^{12}CO}$ is the modified spectral conversion factor as a function of the brightness temperature, TB, of the 12CO (J = 1–0) line, and β ∼ 1–2 and $T_{\rm B}^*=12\!-\!16$ K are empirical constants obtained by fitting to the observed data. The formula corrects for the over/underestimation of the column density at low/high CO line intensities, and is applicable to molecular clouds with TB ≥ 1 K (12CO (J = 1–0) line rms noise in the data) from envelope to cores at sub-parsec scales (spatial resolution).
Systematic investigation of the effect of 56Ni mixing in the early photospheric velocity evolution of stripped-envelope supernovae
Authors: Moriya Takashi J , Suzuki Akihiro , Takiwaki Tomoya , Pan Yen-Chen , Blinnikov Sergei I
Published: July 2020

Mixing of 56Ni, whose nuclear decay energy is a major luminosity source in stripped-envelope supernovae, is known to affect the observational properties of stripped-envelope supernovae such as light-curve and colour evolution. Here we systematically investigate the effect of 56Ni mixing on the photospheric velocity evolution in stripped-envelope supernovae. We show that 56Ni mixing significantly affects the early photospheric velocity evolution. The photospheric velocity, which is often used to constrain the ejecta mass and explosion energy, significantly varies by just changing the degree of 56Ni mixing. In addition, the models with a small degree of 56Ni mixing show a flattening in the early photospheric velocity evolution, while the fully mixed models show a monotonic decrease. The velocity flattening appears in both helium and carbon+oxygen progenitor explosions with a variety of ejecta mass, explosion energy, and 56Ni mass. Some stripped-envelope supernovae with early photospheric velocity information do show such a flattening. We find that Type Ib SN 2007Y, which has early photospheric velocity information, has a signature of a moderate degree of 56Ni mixing in the photospheric velocity evolution and about half of the ejecta is mixed in it. The immediate spectroscopic follow-up observations of stripped-envelope supernovae shortly after the explosion providing the early photospheric evolution give an important clue to constrain 56Ni mixing in the ejecta.
Towards understanding physical origin of 2175 Å extinction bump in interstellar medium
Authors: Ma Xing-Yu , Zhu Yan-Yan , Yan Qing-Bo , You Jing-Yang , Su Gang
Published: July 2020

The 2175 Å ultraviolet (UV) extinction bump in interstellar medium (ISM) of the Milky Way was discovered in 1965. After intensive exploration of more than a half century, however, its exact origin still remains a big conundrum that is being debated. Here, we propose a mixture model by which the extinction bump in ISM is argued possibly relevant to the clusters of hydrogenated T-carbon (HTC) molecules (C40H16) that have intrinsically a sharp absorption peak at the wavelength 2175 Å. By linearly combining the calculated absorption spectra of HTC mixtures, graphite, MgSiO3, and Fe2SiO4, we show that the UV extinction curves of optional six stars can be nicely fitted. This work poses an alternative explanation towards understanding the physical origin of the 2175 Å extinction bump in ISM of the Milky Way.
DropSynth 2.0: high-fidelity multiplexed gene synthesis in emulsions
Authors: Sidore Angus M , Plesa Calin , Samson Joyce A , Lubock Nathan B , Kosuri Sriram
Published: July 2020

Multiplexed assays allow functional testing of large synthetic libraries of genetic elements, but are limited by the designability, length, fidelity and scale of the input DNA. Here, we improve DropSynth, a low-cost, multiplexed method that builds gene libraries by compartmentalizing and assembling microarray-derived oligonucleotides in vortexed emulsions. By optimizing enzyme choice, adding enzymatic error correction and increasing scale, we show that DropSynth can build thousands of gene-length fragments at >20% fidelity.
H/ACA snoRNA levels are regulated during stem cell differentiation
Authors: McCann Kathleen L , Kavari Sanam L , Burkholder Adam B , Phillips Bart T , Hall Traci M Tanaka
Published: July 2020

H/ACA small nucleolar RNAs (snoRNAs) guide pseudouridylation as part of a small nucleolar ribonucleoprotein complex (snoRNP). Disruption of H/ACA snoRNA levels in stem cells impairs pluripotency, yet it remains unclear how H/ACA snoRNAs contribute to differentiation. To determine if H/ACA snoRNA levels are dynamic during differentiation, we comprehensively profiled H/ACA snoRNA abundance in multiple murine cell types and during differentiation in three cellular models, including mouse embryonic stem cells and mouse myoblasts. We determined that the profiles of H/ACA snoRNA abundance are cell-type specific, and we identified a subset of snoRNAs that are specifically regulated during differentiation. Additionally, we demonstrated that a decrease in Snora27 abundance upon differentiation corresponds to a decrease in pseudouridylation of its target site within the E-site transfer RNA (tRNA) binding region of the 28S ribosomal RNA (rRNA) in the large ribosomal subunit. Together, these data point toward a potential model in which H/ACA snoRNAs are specifically regulated during differentiation to alter pseudouridylation and fine tune ribosome function.
The science of consciousness does not need another theory, it needs a minimal unifying model
Authors: Wiese Wanja
Published: July 2020

This article discusses a hypothesis recently put forward by Kanai et al., according to which information generation constitutes a functional basis of, and a sufficient condition for, consciousness. Information generation involves the ability to compress and subsequently decompress information, potentially after a temporal delay and adapted to current purposes. I will argue that information generation should not be regarded as a sufficient condition for consciousness, but could serve as what I will call a “minimal unifying model of consciousness.” A minimal unifying model (MUM) specifies at least one necessary feature of consciousness, characterizes it in a determinable way, and shows that it is entailed by (many) existing theories of consciousness. Information generation fulfills these requirements. A MUM of consciousness is useful, because it unifies existing theories of consciousness by highlighting their common assumptions, while enabling further developments from which empirical predictions can be derived. Unlike existing theories (which probably contain at least some false assumptions), a MUM is thus likely to be an adequate model of consciousness, albeit at a relatively general level. Assumptions embodied in such a model are less informative than assumptions made by more specific theories and hence function more in the way of guiding principles. Still, they enable further refinements, in line with new empirical results and broader theoretical and evolutionary considerations. This also allows developing the model in ways that facilitate more specific claims and predictions.
Long-Term Disease Burden and Survivorship Issues After Surgery and Radiotherapy of Intracranial Meningioma Patients
Authors: Zamanipoor Najafabadi Amir H , van der Meer Pim B , Boele Florien W , Taphoorn Martin J B , Klein Martin , Peerdeman Saskia M , van Furth Wouter R , Dirven Linda ,   Dutch Meningioma Consortium Moojen Wouter A MD, PhD University Neurosurgical Centre Holland, Leiden University Medical Centre, Haaglanden Medical Centre and Haga Teaching Hospital, Leiden and The Hague, the Netherlands Reijneveld Jaap C MD, PhD Brain Tumor Center Amsterdam at Amsterdam University Medical Centers, location VUmc, Amsterdam, the Netherlands Department of Neurology, Amsterdam University Medical Centers, location VUmc, Amsterdam, the Netherlands, Moojen Wouter A , Reijneveld Jaap C
Published: July 2020

BACKGROUND

Many intracranial meningioma patients have an impaired health-related quality of life (HRQoL) and neurocognitive functioning up to 4 yr after intervention.

OBJECTIVE

To assess the long-term (≥5 yr) disease burden of meningioma patients.

METHODS

In this multicenter cross-sectional study, patients ≥5 yr after intervention (including active magnetic resonance imaging (MRI) surveillance) were included and assessed for HRQoL (Short-Form Health Survey 36), neurocognitive functioning (neuropsychological assessment), anxiety and depression (Hospital Anxiety and Depression Scale), and work productivity (Short Form-Health and Labour Questionnaire). Multivariable and propensity score regression analyses were used to compare patients and controls, and different treatment strategies corrected for possible confounders. Clinically relevant differences were reported.

RESULTS

At a median of 9 yr follow-up after intervention, meningioma patients (n = 190) reported more limitations due to physical (difference 12.5 points, P = .008) and emotional (13.3 points, P = .002) health problems compared with controls. Patients also had an increased risk to suffer from anxiety (odds ratio [OR]: 2.6, 95% CI: 1.2-5.7) and depression (OR: 3.7, 95% CI: 1.3-10.5). Neurocognitive deficits were found in 43% of patients. Although postoperative complications, radiotherapy, and reresection were associated with worse verbal memory, attention, and executive functioning when compared to patients resected once, the only clinically relevant association was between reresection and worse attention (–2.11, 95% CI: –3.52 to –0.07). Patients of working age less often had a paid job (48%) compared with the working-age Dutch population (72%) and reported more obstacles at work compared with controls.

CONCLUSION

In the long term, a large proportion of meningioma patients have impaired HRQoL, neurocognitive deficits, and high levels of anxiety or depression. Patients treated with 1 resection have the best neurocognitive functioning.
Systematic literature review of non-topical treatments for early, untreated (systemic therapy naïve) psoriatic disease: a GRAPPA initiative
Authors: De Marco Gabriele , Berekméri Anna , Coates Laura C , Dubash Sayam , Emmel Jenny , Gladman Dafna D , Lubrano Ennio , McGonagle Dennis G , Mahmood Farrouq , Marchesoni Antonio , Mason Laura , Ogdie Alexis , Wittmann Miriam , Helliwell Philip S , Marzo-Ortega Helena
Published: July 2020

Background

Psoriatic disease (PsD) is a complex systemic disorder with cutaneous and musculoskeletal manifestations. Current evidence on pharmacological interventions, effective across the spectrum of clinical manifestations of early, systemic treatment-naïve PsD, is limited. This review aims to appraise such evidence.

Methods

This systematic review examined seven patient–intervention–comparator–outcome research questions to address the efficacy of the interventions on the following: across the spectrum of clinical manifestations PsD activity; peripheral arthritis; dactylitis; spondylitis; enthesitis; skin; and nails. Early PsD was defined as a disease duration of ≤2 years, except for studies investigating outcomes restricted to the skin. Eligible references were clinical trials or well-designed prospective studies/series reporting on adult humans, untreated, with cutaneous and/or musculoskeletal features of PsD.

Results

Nine references (out of 160 319, publication range 1946–2019) fulfilled the eligibility criteria. No study adopted comprehensive (that is, simultaneous assessment of different PsD manifestations) composite indices as primary outcome measures. Individual studies reported that apremilast and biologics successfully improved outcomes (disease activity index for PsA, minimal disease activity, PsA DAS, psoriasis area and severity index, PsA response criteria) when efficacy analyses were restricted to single manifestations of untreated PsD. Only qualitative synthesis of evidence was possible, owing to the following factors: data heterogeneity (disease classification criteria, outcome measures); unavailable data subsets (focused on early, untreated PsD) at the single study level; and insufficient data on the exposure of participants to previous treatment.

Conclusion

Effective interventions, albeit limited in scope, were found for early, treatment-naïve PsD. No study provided evidence about the management of co-occurring cutaneous and musculoskeletal manifestations in early, treatment-naïve PsD. This review highlights an unmet need in research on early PsD.
DNMT1-mediated Foxp3 gene promoter hypermethylation involved in immune dysfunction caused by arsenic in human lymphocytes
Authors: Ma Yemei , Ye Ying , Liu Yining , Chen Jing , Cen Yanli , Chen Wenyan , Yu Chun , Zeng Qibing , Zhang Aihua , Yang Guanghong
Published: July 2020

Growing evidence indicates that arsenic can cause long-lasting and irreversible damage to the function of the human immune system. It is known that forkhead box protein 3(Foxp3), which is specifically expressed in regulatory T cells (Tregs), plays a decisive role in immunoregulation and is regulated by DNA methylation. While evidence suggests that epigenetic regulated Foxp3 is involved in the immune disorders caused by arsenic exposure, the specific mechanism remains unclear. In this study, after primary human lymphocytes were treated with different doses of NaAsO2, our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35), and increasing the ratio of CD4+/CD8+ T cells in lymphocytes. Treatment with DNA methyltransferase inhibitor 5-Aza-CdR can notably inhibit the expression of DNMT1, effectively restoring the hypermethylation of the Foxp3 promoter region in primary human lymphocytes and upregulating the expression levels of Foxp3, balancing the ratio of CD4+/CD8+ T cells in lymphocytes. It also activates the secretion of anti-inflammatory cytokines and restores the immune regulatory functions of Tregs. In conclusion, our study provides limited evidence that DNMT1-mediated Foxp3 gene promoter hypermethylation is involved in immune dysfunction caused by arsenic in primary human lymphocytes. The study can provide a scientific basis for further understanding the arsenic-induced immune dysfunction in primary human lymphocytes.
Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors
Authors: Palmer Adam C. , Izar Benjamin , Hwangbo Haeun , Sorger Peter K.
Published: July 2020

Hundreds of clinical trials are testing combinations of Immune Checkpoint Inhibitors (ICIs) with other cancer therapies in the hope that they will have additive or synergistic efficacy involving mechanisms such as immune priming. However we find that the clinically observed benefits of recently reported and approved combination therapies with ICIs are fully and accurately accounted for by increasing the chance of a single-agent response in individual patients (drug independence), with no requirement for additive or synergistic efficacy (correlation between observed and expected Progression Free Survival: Pearson r = 0.98, P = 5×10−9, n = 4173 patients in 14 trials). Thus, the likely anti-tumor efficacy of new ICI combinations can be predicted if monotherapy data are available; predicting adverse effects remain challenging. Realizing the promise of drug additivity or synergy is likely to require better response biomarkers that identify patients in whom multiple constituents of a combination therapy are active.
Muting, not fragmentation, of functional brain networks under general anesthesia
Authors: Areshenkoff Corson N. , Nashed Joseph Y. , Hutchison R. Matthew , Hutchison Melina , Levy Ron , Cook Douglas J. , Menon Ravi S. , Everling Stefan , Gallivan Jason P.
Published: July 2020

Changes in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and disruption in the brains ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities considered hallmarks of fragmentation are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness.
Convergent Evolution of Pain-Inducing Defensive Venom Components in Spitting Cobras
Authors: Kazandjian T.D. , Petras D. , Robinson S.D. , van Thiel J. , Greene H.W. , Arbuckle K. , Barlow A. , Carter D.A. , Wouters R.M. , Whiteley G. , Wagstaff S.C. , Arias A.S. , Albulescu L-O. , von Plettenberg Laing A. , Hall C. , Heap A. , Penrhyn-Lowe S. , McCabe C.V. , Ainsworth S. , da Silva R.R. , Dorrestein P.C. , Richardson M.K. , Gutiérrez J.M. , Calvete J.J. , Harrison R.A. , Vetter I. , Undheim E.A.B. , Wüster W. , Casewell N.R.
Published: July 2020

Convergent evolution provides unparalleled insights into the selective drivers underlying evolutionary change. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of spitting cobras have independently evolved the ability to use venom as a defensive projectile. Using gene, protein and functional analyses, we show that the three spitting lineages possess venom characterized by an upregulation of PLA2toxins, which potentiate the action of venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by exaptations. Notably, the timing of their origins suggests that defensive venom spitting may have evolved in response to the emergence of bipedal hominids in Africa and Asia.

One Sentence Summary

Venom spitting by snakes coincides with the emergence of hominins and is underpinned by convergent increases in pain-enhancing toxins
PTM-Shepherd: analysis and summarization of post-translational and chemical modifications from open search results
Authors: Geiszler Daniel J. , Kong Andy T. , Avtonomov Dmitry M. , Yu Fengchao , Leprevost Felipe V. , Nesvizhski Alexey I.
Published: July 2020

Open searching has proven to be an effective strategy for identifying both known and unknown modifications in shotgun proteomics experiments. Rather than being limited to a small set of user-specified modifications, open searches identify peptides with any mass shift that may correspond to a single modification or a combination of several modifications. Here we present PTM-Shepherd, a bioinformatics tool that automates characterization of PTM profiles detected in open searches based on attributes such as amino acid localization, fragmentation spectra similarity, retention time shifts, and relative modification rates. PTM-Shepherd can also perform multi-experiment comparisons for studying changes in modification profiles, e.g. in data generated in different laboratories or under different conditions. We demonstrate how PTM-Shepherd improves the analysis of data from formalin-fixed paraffin-embedded samples, detects extreme underalkylation of cysteine in some datasets, discovers an artefactual modification introduced during peptide synthesis, and uncovers site-specific biases in sample preparation artifacts in a multi-center proteomics profiling study.
CircTulp4 functions in Alzheimer’s disease pathogenesis by regulating its parental gene, Tulp4
Authors: Ma Nana , Pan Jie , Wu Qi , Yu Bo , Wan Jun , Zhang Wei
Published: July 2020

Alzheimer’s disease (AD)—one of the most common neurodegenerative diseases worldwide—impairs cognition, memory, and language ability and causes dementia. However, AD pathogenesis remains poorly elucidated. Recently, a potential link between AD and circular RNAs (circRNAs) has been uncovered, but only a few circRNAs that might be involved in AD have been identified. Here, we systematically investigated circRNAs in the APP/PS1 model mouse brain through deep RNA-sequencing. We report that circRNAs are markedly enriched in the brain and that several circRNAs exhibit differential expression between wild-type and APP/PS1 mice. We characterized one abundant circRNA, circTulp4, derived from Intron1 of the geneTulp4. Our results indicate that circTulp4 predominantly localizes in the nucleus and interacts with U1 snRNP and RNA polymerase II to modulate the transcription of its parental gene,Tulp4, and thereby regulate the function of the nervous system and might participate in the development of AD.
Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition
Authors: Dearden Richard P. , Giles Sam
Published: July 2020

The teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching ‘acanthodian’-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckel’s cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth ofAcanthodopsisare borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly.
Reference data based insights expand understanding of human metabolomes
Authors: Gauglitz Julia M. , Bittremieux Wout , Williams Candace L. , Weldon Kelly C. , Panitchpakdi Morgan , Di Ottavio Francesca , Aceves Christine M. , Brown Elizabeth , Sikora Nicole C. , Jarmusch Alan K. , Martino Cameron , Tripathi Anupriya , Sayyari Erfan , Shaffer Justin P. , Coras Roxana , Vargas Fernando , Goldasich Lindsay DeRight , Schwartz Tara , Bryant MacKenzie , Humphrey Gregory , Johnson Abigail J. , Spengler Katharina , Belda-Ferre Pedro , Diaz Edgar , McDonald Daniel , Zhu Qiyun , Nguyen Dominic S. , Elijah Emmanuel O. , Wang Mingxun , Marotz Clarisse , Sprecher Kate E. , Robles Daniela Vargas , Withrow Dana , Ackermann Gail , Herrera Lourdes , Bradford Barry J. , Mauriz Marques Lucas Maciel , Amaral Juliano Geraldo , Silva Rodrigo Moreira , Veras Flávio Protaso , Cunha Thiago Mattar , Ribeiro Oliveira Rene Donizeti , Louzada-Junior Paulo , Mills Robert H. , Galasko Douglas , Dulai Parambir S. , Wittenberg Curt , Gonzalez David J. , Terkeltaub Robert , Doty Megan M. , Kim Jae H. , Rhee Kyung E. , Beauchamp-Walters Julia , Wright Kenneth P. , Dominguez-Bello Maria Gloria , Manary Mark , Oliveira Michelli F. , Boland Brigid S. , Lopes Norberto Peporine , Guma Monica , Swafford Austin D. , Dutton Rachel J. , Knight Rob , Dorrestein Pieter C.
Published: July 2020

The human metabolome has remained largely unknown, with most studies annotating ∼10% of features. In nucleic acid sequencing, annotating transcripts by source has proven essential for understanding gene function. Here we generalize this concept to stool, plasma, urine and other human metabolomes, discovering that food-based annotations increase the interpreted fraction of molecular features 7-fold, providing a general framework for expanding the interpretability of human metabolomic “dark matter.”
The Cuban Human Brain Mapping Project population based normative EEG, MRI, and Cognition dataset
Authors: Valdes-Sosa Pedro A. , Galan Lidice , Bosch-Bayard Jorge , Bringas Vega Maria L. , Vazquez Eduardo Aubert , Das Samir , Alba Trinidad Virues , Madjar Cecile , Mohades Zia , MacIntyre Leigh C. , Rogers Christine , Brown Shawn , Urrutia Lourdes Valdes , Gil Iris Rodriguez , Evans Alan C. , Valdes Sosa Mitchell J.
Published: July 2020

The Cuban Human Brain Mapping Project (CHBMP) repository is an open multimodal neuroimaging and cognitive dataset from 282 healthy participants (31.9 ± 9.3 years, age range 18–68 years). This dataset was acquired from 2004 to 2008 as a subset of a larger stratified random sample of 2,019 participants from La Lisa municipality in La Habana, Cuba. The exclusion included presence of disease or brain dysfunctions. The information made available for all participants comprises: high-density (64-120 channels) resting state electroencephalograms (EEG), magnetic resonance images (MRI), psychological tests (MMSE, Wechsler Adult Intelligence Scale -WAIS III, computerized reaction time tests using a go no-go paradigm), as well as general information (age, gender, education, ethnicity, handedness and weight). The EEG data contains recordings with at least 30 minutes duration including the following conditions: eyes closed, eyes open, hyperventilation and subsequent recovery. The MRI consisted in anatomical T1 and T2 as well as diffusion weighted (DWI) images acquired on a 1.5 Tesla system. The data is available for registered users on the LORIS database which is part of the MNI neuroinformatics ecosystem.
Temperature impacts the transmission of malaria parasites byAnopheles gambiaeandAnopheles stephensimosquitoes
Authors: Villena Oswaldo C. , Ryan Sadie J. , Murdock Courtney C. , Johnson Leah R.
Published: July 2020

Extrinsic environmental factors influence the spatio-temporal dynamics of many organisms, including insects that transmit the pathogens responsible for vector-borne diseases (VBDs). Temperature is an especially important constraint on the fitness of a wide variety of insects, as they are primarily ectotherms. Temperature constrains the distribution of ectotherms and therefore of the infections that they spread in both space and time. More concretely, a mechanistic understanding of how temperature impacts traits of ectotherms to predict the distribution of ectotherms and vector-borne infections is key to predicting the consequences of climate change on transmission of VBDs like malaria. However, the response of transmission to temperature and other drivers is complex, as thermal traits of ectotherms are typically non-linear, and they interact to determine transmission constraints. In this study, we assess and compare the effect of temperature on the transmission of two malaria parasites,Plasmodium falciparumandPlasmodium vivax, by two malaria vector species,Anopheles gambiaeandAnopheles stephensi. We model the non-linear responses of temperature dependent mosquito and parasite traits (mosquito development rate, bite rate, fecundity, egg to adult survival, vector competence, mortality rate, and parasite development rate) and incorporate these traits into a suitability metric based on a model for the basic reproductive number across temperatures. Our model predicts that the optimum temperature for transmission suitability is similar for the four mosquito-parasite combinations assessed in this study. The main differences are found at the thermal limits. More specifically, we found significant differences in the upper thermal limit between parasites spread by the same mosquito (An. stephensi) and between mosquitoes carryingP. falciparum. In contrast, at the lower thermal limit the significant differences were primarily between the mosquito species that both carried the same pathogen (e.g.,An. stephensiandAn. gambiaeboth withP. falciparum). Using prevalence data from Africa and Asia, we show that the transmission suitability metricS(T) calculated from our mechanistic model is an important predictor of malaria prevalence. We mapped risk to illustrate the areas in Africa and Asia that are suitable for malaria transmission year-round based temperature.
Inactivation analysis of SARS-CoV-2 by specimen transport media, nucleic acid extraction reagents, detergents and fixatives
Authors: Welch Stephen R. , Davies Katherine A. , Buczkowski Hubert , Hettiarachchi Nipunadi , Green Nicole , Arnold Ulrike , Jones Matthew , Hannah Matthew J. , Evans Reah , Burton Christopher , Burton Jane E. , Guiver Malcolm , Cane Patricia A. , Woodford Neil , Bruce Christine B. , Roberts Allen D. G. , Killip Marian J.
Published: July 2020

The COVID-19 pandemic has necessitated a rapid multi-faceted response by the scientific community, bringing researchers, health officials and industry together to address the ongoing public health emergency. To meet this challenge, participants need an informed approach for working safely with the etiological agent, the novel human coronavirus SARS-CoV-2. Work with infectious SARS-CoV-2 is currently restricted to high-containment laboratories, but material can be handled at a lower containment level after inactivation. Given the wide array of inactivation reagents that are being used in laboratories during this pandemic, it is vital that their effectiveness is thoroughly investigated. Here, we evaluated a total of 23 commercial reagents designed for clinical sample transportation, nucleic acid extraction and virus inactivation for their ability to inactivate SARS-CoV-2, as well as seven other common chemicals including detergents and fixatives. As part of this study, we have also tested five filtration matrices for their effectiveness at removing the cytotoxic elements of each reagent, permitting accurate determination of levels of infectious virus remaining following treatment. In addition to providing critical data informing inactivation methods and risk assessments for diagnostic and research laboratories working with SARS-CoV-2, these data provide a framework for other laboratories to validate their inactivation processes and to guide similar studies for other pathogens.
The Rice Plastidial Phosphorylase Participates Directly In Both Sink And Source Processes
Authors: Koper Kaan , Hwang Seon-Kap , Wood Magnus , Singh Salvinder , Cousins Asaph , Kirchhoff Helmut , Okita Thomas W.
Published: July 2020

A distinctive structural feature of the higher plant plastidial starch phosphorylase (Pho1) is a 50 to 82 amino acid long peptide (L50 - L82), which is absent in phosphorylases from non-plant organisms. To study the function of the rice Pho1 L80 peptide, we complemented apho1−rice mutant (BMF136) with the wildtype Pho1 gene or with a Pho1 gene lacking the L80 region (Pho1ΔL80). While expression of Pho1 in BMF136 restored normal wildtype phenotype, the introduction of Pho1ΔL80 enhanced growth rate and plant productivity above wildtype levels. Mass spectrometry analysis of proteins captured by anti-Pho1 showed the surprising presence of PsaC, the terminal electron acceptor/donor subunit of photosystem I (PSI). This unexpected interaction was substantiated by reciprocal immobilized protein pulldown assays of seedling extracts and supported by the presence of Pho1 on isolated PSI complexes resolved by blue native gels. Spectrophotometric studies showed that Pho1ΔL80 plants exhibited modified PSI and enhanced CO2assimilation properties. Collectively, these findings indicate that the higher plant Pho1 has dual roles as a potential modulator of source and sink processes.
Intraspecific genetic variation for anesthesia success in a New Zealand freshwater snail
Authors: Song Qiudong , Magnuson Richard , Jalinsky Joseph , Roseman Marissa , Neiman Maurine
Published: July 2020

Intraspecific genetic variation can drive phenotypic variation even across very closely related individuals. Here, we demonstrate that genetic differences between snails are a major contributor to wide variation in menthol anesthesia success in an important freshwater snail model system,Potamopyrgus antipodarum. Anesthesia is used to immobilize organisms for experiments and surgical procedures and to humanely mitigate pain. This is the first example of which we are aware of a role for genetic variation in anesthesia success in a mollusk. These findings highlight the fact that using only one strain or lineage for many experiments will not provide a full picture of phenotypic variation, demonstrate the importance of optimizing biomedically relevant techniques and protocols across a variety of genetic backgrounds, illuminate a potential mechanism underlying previously documented challenges in molluscan anesthesia, and set the stage for powerful and humane manipulative experiments inP. antipodarum.