bluuebunny/crossref_metadata_2025 huggingface dataset:
Modular Synthesis of Trifunctional Peptide-oligonucleotide Conjugates via Native Chemical Ligation
Authors: Dastpeyman Mohadeseh , Karas John A. , Amin Azin , Turner Bradley J. , Shabanpoor Fazel
Published: March 2021

Cell penetrating peptides (CPPs) are being increasingly used as efficient vectors for intracellular delivery of biologically active agents, such as therapeutic antisense oligonucleotides (ASOs). Unfortunately, ASOs have poor cell membrane permeability. The conjugation of ASOs to CPPs have been shown to significantly improve their cellular permeability and therapeutic efficacy. CPPs are often covalently conjugated to ASOs through a variety of chemical linkages. Most of the reported approaches for ligation of CPPs to ASOs relies on methodologies that forms non-native bond due to incompatibility with in-solution phase conjugation. These approaches have low efficiency and poor yields. Therefore, in this study, we have exploited native chemical ligation (NCL) as an efficient strategy for synthesizing CPP-ASO conjugates. A previously characterized CPP [ApoE(133–150)] was used to conjugate to a peptide nucleic acid (PNA) sequence targeting human survival motor neuron-2 (SMN2) mRNA which has been approved by the FDA for the treatment of spinal muscular atrophy. The synthesis of ApoE(133–150)-PNA conjugate using chemo-selective NCL was highly efficient and the conjugate was obtained in high yield. Toward synthesizing trifunctional CPP-ASO conjugates, we subsequently conjugated different functional moieties including a phosphorodiamidate morpholino oligonucleotide (PMO), an additional functional peptide or a fluorescent dye (Cy5) to the thiol that was generated after NCL. The in vitro analysis of the bifunctional CPP-PNA and trifunctional CPP-(PMO)-PNA, CPP-(peptide)-PNA and CPP-(Cy5)-PNA showed that all conjugates are cell-permeable and biologically active. Here we demonstrated chemo-selective NCL as a highly efficient and superior conjugation strategy to previously published methods for facile solution-phase synthesis of bi-/trifunctional CPP-ASO conjugates.
Proliferation of Isoëtalean Lycophytes During the Permo-Triassic Biotic Crises: A Proxy for the State of the Terrestrial Biosphere
Authors: Looy Cindy V. , van Konijnenburg-van Cittert Johanna H. A. , Duijnstee Ivo A. P.
Published: March 2021

Throughout their 420-Ma-long history, Lycopodiopsida have played a subordinate role at the landscape level with very few exceptions. One being the arborescent Lepidodendrales that dominated Pennsylvanian peat swamps in equatorial regions. Another is the enigmatic world-wide proliferation of sub-arborescent Isoëtales during, and in the aftermath of the Permo-Triassic terrestrial biosphere crisis that extended deep into the Triassic. Palynological as well as megafossil data shows that in a great proportion of locations around the globe that produced a fossil record, the provincial floras characteristic for the latest Permian were replaced by communities dominated by Isoëtales such as Pleuromeia and its allies. Our analysis of the isoëtalean biology, especially of the genus Pleuromeia, reveals an unusual suite of physiological and life-history traits, all indicating that it was an excellent stress-tolerator, but also a slow-growing weak competitor. This enabled Pleuromeia to thrive during environmental crises and occupy diverse habitats following the decline of other plants groups. Given their unusual biology, Isoëtales’ repeated ubiquity throughout the Early Triassic implies prolonged and repeated environmental stress in localities worldwide. Additionally, it demonstrates that the cosmopolitan isoëtalean-dominated systems produced a low-productivity, low-diversity terrestrial trophic base of the food web that no longer provided the same level of ecological and evolutionary goods and services (energy source, niche construction, ecosystem engineering, etc.) as the communities they replaced.
A Crab Is Not a Fish: Unique Aspects of the Crustacean Endocrine System and Considerations for Endocrine Toxicology
Authors: Knigge Thomas , LeBlanc Gerald A. , Ford Alex T.
Published: March 2021

Crustaceans—and arthropods in general—exhibit many unique aspects to their physiology. These include the requirement to moult (ecdysis) in order to grow and reproduce, the ability to change color, and multiple strategies for sexual differentiation. Accordingly, the endocrine regulation of these processes involves hormones, receptors, and enzymes that differ from those utilized by vertebrates and other non-arthropod invertebrates. As a result, environmental chemicals known to disrupt endocrine processes in vertebrates are often not endocrine disruptors in crustaceans; while, chemicals that disrupt endocrine processes in crustaceans are often not endocrine disruptors in vertebrates. In this review, we present an overview of the evolution of the endocrine system of crustaceans, highlight endocrine endpoints known to be a target of disruption by chemicals, and identify other components of endocrine signaling that may prove to be targets of disruption. This review highlights that crustaceans need to be evaluated for endocrine disruption with consideration of their unique endocrine system and not with consideration of the endocrine system of vertebrates.
Application of a Nomogram for Predicting the Risk of Subchorionic Hematoma in Early Pregnancy With In Vitro Fertilization-Embryo Transfer/Frozen Embryo Transfer
Authors: Yue Ma , Ma Linna , Cao Yurong , Zhai Jun
Published: March 2021

Background

Subchorionic hematoma (SCH) is common in early pregnancy achieved by in vitro fertilization-embryo transfer/frozen embryo transfer (IVF-ET/FET), and is associated with adverse obstetric outcomes. However, there are no methods known to accurately predict the occurrence of SCH.

Objective

To establish a nomogram prediction model for predicting the risk of SCH in early pregnancy with IVF-ET/FET and to analyze pregnancy outcomes of patients with SCH.

Methods

Patients who underwent IVF-ET/FET treatment and were diagnosed with clinical pregnancy were enrolled in our study. A total of 256 patients with SCH were enrolled in the SCH group, and 526 patients without SCH in the control group. Logistic regression was used to screen risk factors for SCH, and the nomogram was developed according to the regression coefficient of relevant variables. Discrimination, effect, calibration, and the predictive model’s clinical usefulness were assessed using the C-index, the area under the receiver operating characteristic standard curve, calibration plot, and decision curve analysis. Internal validation was assessed using bootstrapping validation. The effects of SCH on pregnancy outcomes were analyzed.

Results

A multivariate logistic regression analysis showed that fresh embryo transfer, polycystic ovary syndrome, hydrosalpinx, and thin endometrium were risk factors affecting the occurrence of SCH. Based on the above factors, a predictive model for the risk of SCH was created. The model displayed good discrimination, with a C-index of 0.783 (95% confidence interval: 0.750–0.816), area under the receiver operating characteristic standard curve of 0.783, and good calibration. A high C-index value of 0.765 could still be reached in the interval validation. Decision curve analysis showed that the nomogram was clinically useful when the intervention was decided at the SCH possibility threshold of 4%–87%. For patients with successful deliveries, the occurrence of SCH did not influence the gestational weeks of delivery, mode of delivery, preterm birth, height, and weight of the newborn.

Conclusion

We screened the risk factors for SCH in patients who underwent IVF-ET/FET treatment. Successful establishment of a nomogram can effectively predict the occurrence of SCH. Furthermore, the incidence of miscarriage is higher in patients with SCH.
Exposure to Inactivated Deformed Wing Virus Leads to Trans-Generational Costs but Not Immune Priming in Honeybees (Apis mellifera)
Authors: Leponiemi Matti , Amdam Gro V. , Freitak Dalial
Published: March 2021

Pathogens are identified as one of the major drivers behind the honeybee colony losses, as well as one of the reasons for the reported declines in terrestrial insect abundances in recent decades. To fight infections, animals rely on their immune system. The immune system of many invertebrates can be primed by exposure to a pathogen, so that upon further exposure the animal is better protected. The protective priming effect can even extend to the next generation, but the species capable of priming the immune system of their offspring are still being investigated. Here we studied whether honeybees could prime their offspring against a viral pathogen, by challenging honeybee queens orally with an inactivated deformed wing virus (DWV), one of the most devastating honeybee viruses. The offspring were then infected by viral injection. The effects of immune priming were assayed by measuring viral loads and two typical symptoms of the virus, pupal mortality, and abnormal wing phenotype. We saw a low amount of wing deformities and low pupal mortality. While no clear priming effect against the virus was seen, we found that the maternal immune challenge, when combined with the stress caused by an injection during development, manifested in costs in the offspring, leading to an increased number of deformed wings.
Strengthening International Legal Cooperation to Combat the Illegal Wildlife Trade Between Southeast Asia and China
Authors: Jiao Yunbo , Yeophantong Pichamon , Lee Tien Ming
Published: March 2021

China is among the world’s leading consumer markets for wildlife extracted both legally and illegally from across the globe. Due to its mega-richness in biodiversity and strong economic ties with China, Southeast Asia (SEA) has long been implicated as a source and transit hub in the transnational legal and illegal wildlife trade with China. Although several cross-border and domestic wildlife enforcement mechanisms have been established to tackle this illegal trade in the region, international legal cooperation and policy coordination between China and its SEA neighbors remain limited in both scope and effectiveness. Difficulties in investigating and prosecuting offenders in overseas jurisdictions, as well as organized criminal groups that sustain the illicit supply chain, continue to undermine efforts by the region’s governments to combat wildlife trafficking. In addition to reviewing the key trends in both the legal and illegal wildlife trade between SEA and China, this paper examines existing legal and policy frameworks in SEA countries and China, and provides a synthesis of evidence on the latest developments in regional efforts to curtail this multibillion-dollar trade. In particular, it discusses how proactive and effective China has been in cooperating with its SEA neighbors on this issue. The paper also draws on the United Nations Convention against Transnational Organized Crime (UNTOC) framework to suggest pathways to deepen legal cooperation between China and SEA countries in order to disrupt and dismantle transnational wildlife trafficking in the region.
Severe Altered Immune Status After Burn Injury Is Associated With Bacterial Infection and Septic Shock
Authors: Moins-Teisserenc Hélène , Cordeiro Debora Jorge , Audigier Vincent , Ressaire Quentin , Benyamina Mourad , Lambert Jérome , Maki Guitta , Homyrda Laurence , Toubert Antoine , Legrand Matthieu
Published: March 2021

Introduction: Burn injury is associated with a high risk of death. Whether a pattern of immune and inflammatory responses after burn is associated with outcome is unknown. The aim of this study was to explore the association between systemic immune and inflammatory responses and outcome in severely-ill burn patients.

Materials and Methods: Innate immunity, adaptive immunity, activation and stress and inflammation biomarkers were collected at admission and days 2, 7, 14, and 28 in severely-ill adult burn patients. Primary endpoint was mortality at day 90, secondary endpoint was secondary infections. Healthy donors (HD) served as controls. Multiple Factorial Analysis (MFA) was used to identify patterns of immune response.

Results: 50 patients were included. Age was 49.2 (44.2–54.2) years, total burn body surface area was 38.0% (32.7–43.3). Burn injury showed an upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. High interleukin-10 (IL-10) at admission was associated with risk of death. However, no cluster of immune/inflammatory biomarkers at early timepoints was associated with mortality. HLA-DR molecules on monocytes at admission were associated with bacterial infections and septic shock. Later altered immune/inflammatory responses in patients who died may had been driven by the development of septic shock.

Conclusion: Burn injury induced an early and profound upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. Immune and inflammatory responses were associated with bacterial infection and septic shock. Absence of immune recovery patterns was associated with poor prognosis.
Tick Immune System: What Is Known, the Interconnections, the Gaps, and the Challenges
Authors: Fogaça Andréa C. , Sousa Géssica , Pavanelo Daniel B. , Esteves Eliane , Martins Larissa A. , Urbanová Veronika , Kopáček Petr , Daffre Sirlei
Published: March 2021

Ticks are ectoparasitic arthropods that necessarily feed on the blood of their vertebrate hosts. The success of blood acquisition depends on the pharmacological properties of tick saliva, which is injected into the host during tick feeding. Saliva is also used as a vehicle by several types of pathogens to be transmitted to the host, making ticks versatile vectors of several diseases for humans and other animals. When a tick feeds on an infected host, the pathogen reaches the gut of the tick and must migrate to its salivary glands via hemolymph to be successfully transmitted to a subsequent host during the next stage of feeding. In addition, some pathogens can colonize the ovaries of the tick and be transovarially transmitted to progeny. The tick immune system, as well as the immune system of other invertebrates, is more rudimentary than the immune system of vertebrates, presenting only innate immune responses. Although simpler, the large number of tick species evidences the efficiency of their immune system. The factors of their immune system act in each tick organ that interacts with pathogens; therefore, these factors are potential targets for the development of new strategies for the control of ticks and tick-borne diseases. The objective of this review is to present the prevailing knowledge on the tick immune system and to discuss the challenges of studying tick immunity, especially regarding the gaps and interconnections. To this end, we use a comparative approach of the tick immune system with the immune system of other invertebrates, focusing on various components of humoral and cellular immunity, such as signaling pathways, antimicrobial peptides, redox metabolism, complement-like molecules and regulated cell death. In addition, the role of tick microbiota in vector competence is also discussed.
The Macroautophagy Machinery in MHC Restricted Antigen Presentation
Authors: Münz Christian
Published: March 2021

Autophagy-related (ATG) gene products regulate macroautophagy, LC3-associated phagocytosis (LAP) and LC3-dependent extracellular vesicle loading and secretion (LDELS). These processes also influence antigen processing for presentation on major histocompatibility complex (MHC) molecules to T cells. Here, I summarize how these different pathways use the macroautophagy machinery, contribute to MHC class I and II restricted antigen presentation and influence autoimmunity, tumor immunology and immune control of infectious diseases. Targeting these different pathways should allow the regulation of intracellular and extracellular antigen presentation to T cells to modulate protective and pathological immune responses.
Mutation of Framework Residue H71 Results in Different Antibody Paratope States in Solution
Authors: Fernández-Quintero Monica L. , Kroell Katharina B. , Hofer Florian , Riccabona Jakob R. , Liedl Klaus R.
Published: March 2021

Characterizing and understanding the antibody binding interface have become a pre-requisite for rational antibody design and engineering. The antigen-binding site is formed by six hypervariable loops, known as the complementarity determining regions (CDRs) and by the relative interdomain orientation (VH–VL). Antibody CDR loops with a certain sequence have been thought to be limited to a single static canonical conformation determining their binding properties. However, it has been shown that antibodies exist as ensembles of multiple paratope states, which are defined by a characteristic combination of CDR loop conformations and interdomain orientations. In this study, we thermodynamically and kinetically characterize the prominent role of residue 71H (Chothia nomenclature), which does not only codetermine the canonical conformation of the CDR-H2 loop but also results in changes in conformational diversity and population shifts of the CDR-H1 and CDR-H3 loop. As all CDR loop movements are correlated, conformational rearrangements of the heavy chain CDR loops also induce conformational changes in the CDR-L1, CDR-L2, and CDR-L3 loop. These overall conformational changes of the CDR loops also influence the interface angle distributions, consequentially leading to different paratope states in solution. Thus, the type of residue of 71H, either an alanine or an arginine, not only influences the CDR-H2 loop ensembles, but co-determines the paratope states in solution. Characterization of the functional consequences of mutations of residue 71H on the paratope states and interface orientations has broad implications in the field of antibody engineering.
Recombinant Human C1 Esterase Inhibitor for the Management of Adverse Events Related to Intravenous Immunoglobulin Infusion in Patients With Common Variable Immunodeficiency or Polyneuropathy: A Pilot Open-Label Study
Authors: Melamed Isaac R. , Miranda Holly , Heffron Melinda , Harper Joseph R.
Published: March 2021

It has been hypothesized that low levels of C1 esterase inhibitor (C1-INH), a key inhibitor of the complement pathway, may play a role in the occurrence of adverse events (AEs) associated with intravenous immunoglobulin (IVIG) therapy. This open-label pilot study evaluated C1-INH replacement, with recombinant human C1-INH (rhC1-INH), as a potential therapy for adults requiring IVIG and experiencing AEs. Patients received two rounds of IVIG infusion [pre-treatment phase (no rhC1-INH), 4–8 weeks] and then three rounds of one dose of intravenous rhC1-INH 50 U/kg (maximum, 4,200 U) with subsequent IVIG infusion (treatment phase, 6–12 weeks). Nineteen adults completed the study; all had an autoimmune condition linked to common variable immunodeficiency (CVID) or polyneuropathy, and 57.9% had low baseline C1-INH levels. Mean ± SD total scores improved significantly with the Headache Impact Test (from 62.8 ± 6.2 at pre-treatment to 57.7 ± 9.1 after treatment; mean Δ, −5.0; p = 0.02) and Modified Fatigue Impact Scale (from 59.3 ± 13.1 to 51.2 ± 15.4; mean Δ, −8.1; p = 0.006). Significant improvements in the Migraine Disability Assessment were observed for three of five items (p ≤ 0.002). Mean ± SD C1-INH level increased from 26.8 ± 5.9 mg/dl after the second round of IVIG (pre-treatment) to 32.1 ± 7.8 mg/dl after the third rhC1-INH treatment; functional C1-INH levels increased from 115.8 ± 34.7% to 158.3 ± 46.8%. Future research is warranted to explore the benefit of C1-INH therapy for reduction of IVIG-related AEs, as well as the role of C1-INH in patients with CVID and autoimmune disease.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT03576469.
Performance of a Point of Care Test for Detecting IgM and IgG Antibodies Against SARS-CoV-2 and Seroprevalence in Blood Donors and Health Care Workers in Panama
Authors: Villarreal Alcibiades , Rangel Giselle , Zhang Xu , Wong Digna , Britton Gabrielle , Fernandez Patricia L. , Pérez Ambar , Oviedo Diana , Restrepo Carlos , Carreirra María B. , Sambrano Dilcia , Eskildsen Gilberto A. , De La Guardia Carolina , Flores-Cuadra Julio , Carrera Jean-Paul , Zaldivar Yamitzel , Franco Danilo , López-Vergès Sandra , Zhang Dexi , Fan Fangjing , Wang Baojun , Sáez-Llorens Xavier , DeAntonio Rodrigo , Torres-Atencio Ivonne , Blanco Isabel , Subía Fernando Diaz , Mudarra Laiss , Benzadon Aron , Valverde Walter , López Lineth , Hurtado Nicolás , Rivas Neyla , Jurado Julio , Carvallo Aixa , Rodriguez Juan , Perez Yaseikiry , Morris Johanna , Luque Odemaris , Cortez David , Ortega-Barria Eduardo , Kosagisharaf Rao , Lleonart Ricardo , Li Chong , Goodridge Amador
Published: March 2021

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has reached 28 million cases worldwide in 1 year. The serological detection of antibodies against the virus will play a pivotal role in complementing molecular tests to improve diagnostic accuracy, contact tracing, vaccine efficacy testing, and seroprevalence surveillance. Here, we aimed first to evaluate a lateral flow assay's ability to identify specific IgM and IgG antibodies against SARS-CoV-2 and second, to report the seroprevalence estimates of these antibodies among health care workers and healthy volunteer blood donors in Panama. We recruited study participants between April 30th and July 7th, 2020. For the test validation and performance evaluation, we analyzed serum samples from participants with clinical symptoms and confirmed positive RT-PCR for SARS-CoV-2, and a set of pre-pandemic serum samples. We used two by two table analysis to determine the test positive and negative percentage agreement as well as the Kappa agreement value with a 95% confidence interval. Then, we used the lateral flow assay to determine seroprevalence among serum samples from COVID-19 patients, potentially exposed health care workers, and healthy volunteer donors. Our results show this assay reached a positive percent agreement of 97.2% (95% CI 84.2–100.0%) for detecting both IgM and IgG. The assay showed a Kappa of 0.898 (95%CI 0.811–0.985) and 0.918 (95% CI 0.839–0.997) for IgM and IgG, respectively. The evaluation of serum samples from hospitalized COVID-19 patients indicates a correlation between test sensitivity and the number of days since symptom onset; the highest positive percent agreement [87% (95% CI 67.0–96.3%)] was observed at ≥15 days post-symptom onset (PSO). We found an overall antibody seroprevalence of 11.6% (95% CI 8.5–15.8%) among both health care workers and healthy blood donors. Our findings suggest this lateral flow assay could contribute significantly to implementing seroprevalence testing in locations with active community transmission of SARS-CoV-2.
The Anatomical Distribution of Mechanoreceptors in Mouse Hind Paw Skin and the Influence of Integrin α1β1 on Meissner-Like Corpuscle Density in the Footpads
Authors: Wai Valerie , Roberts Lauren , Michaud Jana , Bent Leah R. , Clark Andrea L.
Published: March 2021

Afferent neurons and their mechanoreceptors provide critical sensory feedback for gait. The anatomical distribution and density of afferents and mechanoreceptors influence sensory feedback, as does mechanoreceptor function. Electrophysiological studies of hind paw skin reveal the different types of afferent responses and their receptive fields, however, the anatomical distribution of mechanoreceptor endings is unknown. Also, the role of integrin α1β1 in mechanoreceptor function is unclear, though it is expressed by keratinocytes in the stratum basale where it is likely involved in a variety of mechanotransduction pathways and ion channel functionalities. For example, it has been shown that integrin α1β1 is necessary for the function of TRPV4 that is highly expressed by afferent units. The purpose of this study, therefore, was to determine and compare the distribution of mechanoreceptors across the hind paw skin and the footfall patterns of itga1-null and wild type mice. The itga1-null mouse is lacking the integrin α1 subunit, which binds exclusively to the β1 subunit, thus rendering integrin α1β1 nonfunctional while leaving the numerous other pairings of the β1 subunit undisturbed. Intact hind paws were processed, serially sectioned, and stained to visualize mechanoreceptors. Footfall patterns were analyzed as a first step in correlating mechanoreceptor distribution and functionality. Merkel cells and Meissner-like corpuscles were present, however, Ruffini endings and Pacinian corpuscles were not observed. Meissner-like corpuscles were located exclusively in the glabrous skin of the footpads and digit tips, however, Merkel cells were found throughout hairy and glabrous skin. The increased density of Merkel cells and Meissner-like corpuscles in footpads 1 and 3 and Meissner-like corpuscles in footpad 4 suggests their role in anteroposterior balance, while Meissner-like corpuscle concentrations in digits 2 and 5 support their role in mediolateral balance. Finally, a larger density of Meissner-like corpuscles in footpads 3 and 4 in male itga1-null mice compared to wild type controls paves the way for future site-specific single fiber in vivo recordings to provide insight into the role of integrin α1β1 in tactile mechanotransduction.
Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease
Authors: Gcwensa Nolwazi Z. , Russell Drèson L. , Cowell Rita M. , Volpicelli-Daley Laura A.
Published: March 2021

Parkinson’s disease (PD) is a progressive neurodegenerative disease that impairs movement as well as causing multiple other symptoms such as autonomic dysfunction, rapid eye movement (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) and loss of dopamine terminals in the striatum contribute to characteristic motor features. Although therapies ease the symptoms of PD, there are no treatments to slow its progression. Accumulating evidence suggests that synaptic impairments and axonal degeneration precede neuronal cell body loss. Early synaptic changes may be a target to prevent disease onset and slow progression. Imaging of PD patients with radioligands, post-mortem pathologic studies in sporadic PD patients, and animal models of PD demonstrate abnormalities in presynaptic terminals as well as postsynaptic dendritic spines. Dopaminergic and excitatory synapses are substantially reduced in PD, and whether other neuronal subtypes show synaptic defects remains relatively unexplored. Genetic studies implicate several genes that play a role at the synapse, providing additional support for synaptic dysfunction in PD. In this review article we: (1) provide evidence for synaptic defects occurring in PD before neuron death; (2) describe the main genes implicated in PD that could contribute to synapse dysfunction; and (3) show correlations between the expression of Snca mRNA and mouse homologs of PD GWAS genes demonstrating selective enrichment of Snca and synaptic genes in dopaminergic, excitatory and cholinergic neurons. Altogether, these findings highlight the need for novel therapeutics targeting the synapse and suggest that future studies should explore the roles for PD-implicated genes across multiple neuron types and circuits.
Radiological and Clinical Value of 7T MRI for Evaluating 3T-Visible Lesions in Pharmacoresistant Focal Epilepsies
Authors: Wang Z. Irene , Oh Se-Hong , Lowe Mark , Larvie Mykol , Ruggieri Paul , Hill Virginia , Statsevych Volodymyr , Moon Doksu , Lee Jonathan , Emch Todd , Bena James , Blümcke Ingmar , Bingaman William , Gonzalez-Martinez Jorge A. , Najm Imad , Jones Stephen E.
Published: March 2021

Objective: The recent FDA approval of the first 7T MRI scanner for clinical diagnostic use in October 2017 will likely increase the utilization of 7T for epilepsy presurgical evaluation. This study aims at accessing the radiological and clinical value of 7T in patients with pharmacoresistant focal epilepsy and 3T-visible lesions.

Methods: Patients with pharmacoresistant focal epilepsy were included if they had a lesion on pre-operative standard-of-care 3T MRI and also a 7T research MRI. An epilepsy protocol was used for the acquisition of the 7T MRI. Prospective visual analysis of 7T MRI was performed by an experienced board-certified neuroradiologist and communicated to the patient management team. The clinical significance of the additional 7T findings was assessed by intracranial EEG (ICEEG) ictal onset, surgical resection, post-operative seizure outcome and histopathology. A subset of lesions were demarked with arrows for subsequent, retrospective comparison between 3T and 7T by 7 neuroradiologists using a set of quantitative scales: lesion presence, conspicuity, boundary, gray-white tissue contrast, artifacts, and the most helpful sequence for diagnosis. Conger's kappa for multiple raters was performed for chance-adjusted agreement statistics.

Results: A total of 47 patients were included, with the main pathology types of focal cortical dysplasia (FCD), hippocampal sclerosis, periventricular nodular heterotopia (PVNH), tumor and polymicrogyria (PMG). 7T detected additional smaller lesions in 19% (9/47) of patients, who had extensive abnormalities such as PMG and PVNH; however, these additional findings were not necessarily epileptogenic. 3T−7T comparison by the neuroradiologist team showed that lesion conspicuity and lesion boundary were significantly better at 7T (p < 0.001), particularly for FCD, PVNH and PMG. Chance-adjusted agreement was within the fair range for lesion presence, conspicuity and boundary. Gray-white contrast was significantly improved at 7T (p < 0.001). Significantly more artifacts were encountered at 7T (p < 0.001).

Significance: For patients with 3T-visible lesions, 7T MRI may better elucidate the extent of multifocal abnormalities such as PVNH and PMG, providing potential targets to improve ICEEG implantation. Patients with FCD, PVNH and PMG would likely benefit the most from 7T due to improved lesion conspicuity and boundary. Pathologies in the antero–inferior temporal regions likely benefit less due to artifacts.
The Inert Brain: Explaining Neural Inertia as Post-anaesthetic Sleep Inertia
Authors: Luppi Andrea I. , Spindler Lennart R. B. , Menon David K. , Stamatakis Emmanuel A.
Published: March 2021

“Neural inertia” is the brain’s tendency to resist changes in its arousal state: it is manifested as emergence from anaesthesia occurring at lower drug doses than those required for anaesthetic induction, a phenomenon observed across very different species, from invertebrates to mammals. However, the brain is also subject to another form of inertia, familiar to most people: sleep inertia, the feeling of grogginess, confusion and impaired performance that typically follows awakening. Here, we propose a novel account of neural inertia, as the result of sleep inertia taking place after the artificial sleep induced by anaesthetics. We argue that the orexinergic and noradrenergic systems may be key mechanisms for the control of these transition states, with the orexinergic system exerting a stabilising effect through the noradrenergic system. This effect may be reflected at the macroscale in terms of altered functional anticorrelations between default mode and executive control networks of the human brain. The hypothesised link between neural inertia and sleep inertia could explain why different anaesthetic drugs induce different levels of neural inertia, and why elderly individuals and narcoleptic patients are more susceptible to neural inertia. This novel hypothesis also enables us to generate several empirically testable predictions at both the behavioural and neural levels, with potential implications for clinical practice.
Analysis of Chronic Mild Stress-Induced Hypothalamic Proteome: Identification of Protein Dysregulations Associated With Vulnerability and Resiliency to Depression or Anxiety
Authors: Gong Weibo , Liao Wei , Fang Chui , Liu Yanchen , Xie Hong , Yi Faping , Huang Rongzhong , Wang Lixiang , Zhou Jian
Published: March 2021

Chronic stress as a known risk factor leads to hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis in both depression and anxiety. However, the stress-induced dysfunction of the HPA axis in these disorders especially the common and unique molecular dysregulations have not been well-explored. Previously, we utilized a chronic mild stress (CMS) paradigm to segregate and gain depression-susceptible, anxiety-susceptible, and insusceptible groups. In this study, we continue to examine the possible protein expression alterations of the hypothalamus as the center of the HPA axis in these three groups by using a proteomic approach. Though isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative analysis, a total of 593 dysregulated proteins were identified. These were potentially associated with vulnerability and adaptability of CMS-caused depression or anxiety and therefore might become novel investigative protein targets. Further independent analysis using parallel reaction monitoring (PRM) indicated that 5, 7, and 21 dysregulated proteins were specifically associated with depression-susceptible, anxiety-susceptible, and insusceptible groups, respectively, suggesting that the same CMS differently affected the regulation system of the rat hypothalamic proteome. In summary, the current proteomic research on the hypothalamus provided insights into the specific and common molecular basis for the HPA dysfunction mechanisms that underlie resiliency and vulnerability to stress-induced depression or anxiety.
The NEAT1_2/miR-491 Axis Modulates Papillary Thyroid Cancer Invasion and Metastasis Through TGM2/NFκb/FN1 Signaling
Authors: Sun Wei , Qin Yuan , Wang Zhihong , Dong Wenwu , He Liang , Zhang Ting , Zhang Hao
Published: March 2021

NEAT1 (nuclear paraspeckle assembly transcript 1) is an oncogenic long non-coding RNA (lncRNA) that facilitates tumorigenesis in multiple cancers. In papillary thyroid cancer (PTC), the molecular mechanism by which NEAT1 affects invasion and metastasis remains elusive. RNA sequencing was used to discover differentially expressed NEAT1_2 downstream genes. Protein and RNA expression analyses and immunohistochemistry detected the expression of NEAT1_2, Transglutaminase 2 (TGM2), and microRNA-491 (miR-491) among PTC and non-cancerous tissues. Transwell and wound healing assays, and a mouse model of lung metastasis were used for further functional analyses. Bioinformatics was performed to predict miRNAs binding to both NEAT1_2 and TGM2. Rescue experiments and dual-luciferase reporter assays were performed. In PTC tissues, NEAT1_2 expression was markedly increased and regulated TGM2 expression. TGM2 was overexpressed in PTC, correlating positively with exthyroidal extension and lymph node metastasis. TGM2 knockdown significantly inhibited invasion and metastasis. NEAT1_2 sponged miR-491, acting as a competing endogenous RNA to regulate TGM2 expression. Fibronectin 1 (FN1) was predicted as a TGM2 target. TGM2 could transcriptionally activate FN1 by promoting nuclear factor kappa B (NFκb) p65 nuclear translocation, ultimately promoting PTC invasion/metastasis. These findings identify that NEAT1_2 sponges miR-491 to regulate TGM2 expression. TGM2 activates FN1 via NFκb to promote PTC invasion and metastasis.
The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma
Authors: Liu Zaoqu , Wang Libo , Liu Long , Lu Taoyuan , Jiao Dechao , Sun Yuling , Han Xinwei
Published: March 2021

Background

Ferroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive.

Methods

Based on 74 ferroptosis related genes (FRGs) and 3,933 HCC samples from 32 datasets, we comprehensively explored the heterogenous ferroptosis subtypes. The clinical significance, functional status, immune infiltration, immune escape mechanisms, and genomic alterations of different subtypes were further investigated.

Results

We identified and validated two heterogeneous ferroptosis subtypes: C1 was metabolismlowimmunityhigh subtype and C2 was metabolismhighimmunitylow subtype. Compared to C2, C1 owned worse prognosis, and C1 tended to occur in the patients with clinical characteristics such as younger, female, advanced stage, higher grade, vascular invasion. C1 and C2 were more sensitive to immunotherapy and sorafenib, respectively. The immune escape mechanisms of C1 might be accumulating more immunosuppressive cells, inhibitory cytokines, and immune checkpoints, while C2 was mainly associated with inferior immunogenicity, defecting in antigen presentation, and lacking leukocytes. In addition, C1 was characterized by BAP1 mutation, MYC amplification, and SCD1 methylation, while C2 was characterized by the significant alterations in cell cycle and chromatin remodeling processes. We also constructed and validated a robust and promising signature termed ferroptosis related risk score (FRRS) for assessing prognosis and immunotherapy.

Conclusion

We identified and validated two heterogeneous ferroptosis subtypes and a reliable risk signature which used to assess prognosis and immunotherapy. Our results facilitated the understood of ferroptosis as well as clinical management and precise therapy of HCC.
Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling
Authors: Yin Lan , Yang Yuhan , Zhu Wanglong , Xian Yu , Han Zhengyu , Huang Houyi , Peng Liaotian , Zhang Kun , Zhao Ye
Published: March 2021

Ovarian cancer is the most lethal gynaecologic tumor, with which multi-drug resistance as the major therapeutic hindrance. Heat shock protein 90 (Hsp90) has been involved in cancer malignant behaviors. However, its role and mechanism in multi-drug resistance of ovarian cancer remains poorly understood. Our results demonstrated that Hsp90 was overexpressed in multi-drug resistant ovarian cancer cells. Hsp90 downregulation by shHsp90 or inhibitor BIIB021 increased the sensitivity of multi-drug resistant ovarian cancer cells to paclitaxel and cisplatin, and augmented the drugs-induced apoptosis. Hsp90 positively regulated the expressions of multi-drug resistance protein 1 (P-gp/MDR1), breast cancer resistance protein (BCRP), Survivin and Bcl-2 expressions closely associated with multi-drug resistance. Moreover, overexpression of Hsp90 promoted β-catenin accumulation, while Hsp90 downregulation decreased the accumulation, nuclear translocation and transcriptional activity of β-catenin. We also identified that β-catenin was responsible for Hsp90-mediated expressions of P-gp, BCRP, Survivin, and Bcl-2. Furthermore, Hsp90 enhanced the AKT/GSK3β signaling, and AKT signaling played a critical role in Hsp90-induced accumulation and transcriptional activity of β-catenin, as well as multi-drug resistance to paclitaxel and cisplatin. In conclusion, Hsp90 enhanced the AKT/GSK3β/β-catenin signaling to induce multi-drug resistance of ovarian cancer. Suppressing Hsp90 chemosensitized multi-drug resistant ovarian cancer cells via impairing the AKT/GSK3β/β-catenin signaling, providing a promising therapeutic strategy for a successful treatment of ovarian cancer.
Hemostatic Challenges in Neonates
Authors: Davenport Patricia , Sola-Visner Martha
Published: March 2021

The neonatal hemostatic system is strikingly different from that of adults. Among other differences, neonates exhibit hyporeactive platelets and decreased levels of coagulation factors, the latter translating into prolonged clotting times (PT and PTT). Since pre-term neonates have a high incidence of bleeding, particularly intraventricular hemorrhages, neonatologists frequently administer blood products (i.e., platelets and FFP) to non-bleeding neonates with low platelet counts or prolonged clotting times in an attempt to overcome these “deficiencies” and reduce bleeding risk. However, it has become increasingly clear that both the platelet hyporeactivity as well as the decreased coagulation factor levels are effectively counteracted by other factors in neonatal blood that promote hemostasis (i.e., high levels of vWF, high hematocrit and MCV, reduced levels of natural anticoagulants), resulting in a well-balanced neonatal hemostatic system, perhaps slightly tilted toward a prothrombotic phenotype. While life-saving in the presence of active major bleeding, the administration of platelets and/or FFP to non-bleeding neonates based on laboratory tests has not only failed to decrease bleeding, but has been associated with increased neonatal morbidity and mortality in the case of platelets. In this review, we will present a clinical overview of bleeding in neonates (incidence, sites, risk factors), followed by a description of the key developmental differences between neonates and adults in primary and secondary hemostasis. Next, we will review the clinical tests available for the evaluation of bleeding neonates and their limitations in the context of the developmentally unique neonatal hemostatic system, and will discuss current and emerging approaches to more accurately predict, evaluate and treat bleeding in neonates.
A Bidimensional Gay-Berne Calamitic Fluid: Structure and Phase Behavior in Bulk and Strongly Confined Systems
Authors: Calderón-Alcaraz A. , Munguía-Valadez J. , Hernández S. I. , Ramírez-Hernández A. , Sambriski E. J. , Moreno-Razo J. A.
Published: March 2021

A bidimensional (2D) thermotropic liquid crystal (LC) is investigated with Molecular Dynamics (MD) simulations. The Gay-Berne mesogen with parameterization GB(3, 5, 2, 1) is used to model a calamitic system. Spatial orientation of the LC samples is probed with the nematic order parameter: a sharp isotropic-smectic (I-Sm) transition is observed at lower pressures. At higher pressures, the I-Sm transition involves an intermediate nematic phase. Topology of the orthobaric phase diagram for the 2D case differs from the 3D case in two important respects: 1) the nematic region appears at lower temperatures and slightly lower densities, and 2) the critical point occurs at lower temperature and slightly higher density. The 2D calamitic model is used to probe the structural behavior of LC samples under strong confinement when either planar or homeotropic anchoring prevails. Samples subjected to circular, square, and triangular boundaries are gradually cooled to study how orientational order emerges. Depending on anchoring mode and confining geometry, characteristic topological defects emerge. Textures in these systems are similar to those observed in experiments and simulations of lyotropic LCs.
Impacts of Changes in Atmospheric O2 on Human Physiology. Is There a Basis for Concern?
Authors: Keeling Ralph F. , Powell Frank L. , Shaffer Gary , Robbins Peter A. , Simonson Tatum S.
Published: March 2021

Concern is often voiced over the ongoing loss of atmospheric O2. This loss, which is caused by fossil-fuel burning but also influenced by other processes, is likely to continue at least for the next few centuries. We argue that this loss is quite well understood, and the eventual decrease is bounded by the fossil-fuel resource base. Because the atmospheric O2 reservoir is so large, the predicted relative drop in O2 is very small even for extreme scenarios of future fossil-fuel usage which produce increases in atmospheric CO2 sufficient to cause catastrophic climate changes. At sea level, the ultimate drop in oxygen partial pressure will be less than 2.5 mm Hg out of a baseline of 159 mmHg. The drop by year 2300 is likely to be between 0.5 and 1.3 mmHg. The implications for normal human health is negligible because respiratory O2 consumption in healthy individuals is only weakly dependent on ambient partial pressure, especially at sea level. The impacts on top athlete performance, on disease, on reproduction, and on cognition, will also be very small. For people living at higher elevations, the implications of this loss will be even smaller, because of a counteracting increase in barometric pressure at higher elevations due to global warming.
Secondary siRNAs in Plants: Biosynthesis, Various Functions, and Applications in Virology
Authors: Sanan-Mishra Neeti , Abdul Kader Jailani A. , Mandal Bikash , Mukherjee Sunil K.
Published: March 2021

The major components of RNA silencing include both transitive and systemic small RNAs, which are technically called secondary sRNAs. Double-stranded RNAs trigger systemic silencing pathways to negatively regulate gene expression. The secondary siRNAs generated as a result of transitive silencing also play a substantial role in gene silencing especially in antiviral defense. In this review, we first describe the discovery and pathways of transitivity with emphasis on RNA-dependent RNA polymerases followed by description on the short range and systemic spread of silencing. We also provide an in-depth view on the various size classes of secondary siRNAs and their different roles in RNA silencing including their categorization based on their biogenesis. The other regulatory roles of secondary siRNAs in transgene silencing, virus-induced gene silencing, transitivity, andtrans-species transfer have also been detailed. The possible implications and applications of systemic silencing and the different gene silencing tools developed are also described. The details on mobility and roles of secondary siRNAs derived from viral genome in plant defense against the respective viruses are presented. This entails the description of other compatible plant–virus interactions and the corresponding small RNAs that determine recovery from disease symptoms, exclusion of viruses from shoot meristems, and natural resistance. The last section presents an overview on the usefulness of RNA silencing for management of viral infections in crop plants.
The Association Between Smartphone Addiction and Sleep: A UK Cross-Sectional Study of Young Adults
Authors: Sohn Sei Yon , Krasnoff Lauren , Rees Philippa , Kalk Nicola J. , Carter Ben
Published: March 2021

Background:In a large UK study we investigated the relationship between smartphone addiction and sleep quality in a young adult population.

Methods:We undertook a large UK cross-sectional observational study of 1,043 participants aged 18 to 30 between January 21st and February 30th 2019. Participants completed the Smartphone Addiction Scale Short Version, an adapted Pittsburgh Sleep Quality Score Index and reported smartphone use reduction strategies using both in-person (n= 968) and online (n= 75) questionnaires. A crude and adjusted logistic regression was fitted to assess risk factors for smartphone addiction, and the association between smartphone addiction and poor sleep.

Results:One thousand seventy one questionnaires were returned, of which 1,043 participants were included, with median age 21.1 [interquartile range (IQR) 19–22]. Seven hundred and sixty three (73.2%) were female, and 406 reported smartphone addiction (38.9%). A large proportion of participants disclosed poor sleep (61.6%), and in those with smartphone addiction, 68.7% had poor sleep quality, compared to 57.1% of those without. Smartphone addiction was associated with poor sleep (aOR = 1.41, 95%CI: 1.06–1.87,p= 0.018).

Conclusions:Using a validated instrument, 39% young adults reported smartphone addiction. Smartphone addiction was associated with poor sleep, independent of duration of usage, indicating that length of time should not be used as a proxy for harmful usage.