bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and Tolerability of Once Daily Coformulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide for Postexposure Prophylaxis After Sexual Exposure
Authors: Mayer Kenneth H. , Gelman Marcy , Holmes Johnathon , Kraft Jessica , Melbourne Kathleen , Mimiaga Matthew J.
Published: January 2022

Background:

Antiretroviral post-exposure prophylaxis (PEP) is recommended to prevent HIV infection after a high-risk exposure, but current regimens have presented challenges in tolerability, regimen completion, and potential drug–drug interactions. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide [BIC/FTC/tenofovir alafenamide (TAF)] is effective for HIV treatment, it was evaluated for use for PEP.

Setting:

Boston community health center.

Methods:

Individuals accessing PEP were enrolled in an open-label study of coformulated BIC/FTC/TAF, taken as one pill daily for 28 days. Pearson's χ2 and Fisher's exact tests were used to assess whether BIC/FTC/TAF differed with respect to side effects and regimen completion rates compared with historical PEP regimens.

Results:

Between August, 2018 and March, 2020, 52 individuals enrolled in the study. Most identified as cisgender gay (67.3%) or bisexual (11.5%) men, but 7.7% identified as cisgender heterosexual men and 3.8% cisgender heterosexual women. The most common regimen side effects were nausea or vomiting (15.4%), fatigue (9.6%), and diarrhea/loose stools (7.7%), which were less common than historical controls using other PEP regimens, including those containing other integrase strand transfer inhibitors. Only 1 participant discontinued the regimen because of fatigue, and all other side effects were self-limited. Almost all participants (90.4%) completed the indicated regimen, which was a higher completion rate compared with earlier PEP regimens, and none became HIV-positive.

Conclusions:

BIC/FTC/TAF coformulated as a single daily pill was found to be safe, well-tolerated, and highly acceptable when used for PEP, and compared more favorably than historical PEP regimens used at an urban health center.
A Useful Tool for Various Problems in Nasal Tip: The Cephalic Transdomal Suture
Authors: Bilkay Ufuk , Biçer Ahmet , Erçin Burak Sercan , Durukan Kutay , Özek Zeyyat Cüneyt , Gürler Tahir
Published: January 2022

Surgical manipulation of the nasal tip is a critical point in functional and aesthetic rhinoplasty procedure. Cephalic strip excision from the lower lateral cartilages, elongation or shortening the caudal septum, structural grafting for supporting the medial and lateral crura are major structural moves in building a durable cartilaginous framework. However, it is suture techniques that make up the final touch in fine tuning of the shape, projection, definition, and angulation (rotation) of the nasal tip over this framework.

Problems with fine-tuning of the nasal tip include inadequate or excessive definition, or projection resulting with bulbous or boxy appearance can be overcome reversibly with correctly placed sutures. One of the most decisive sutures in this context is transdomal sutures. Incorrect placement of which can result with too narrow or too wide nostril apices, as well as a cephalic malposition deformity of the lower lateral cartilages, botching an otherwise perfectly executed rhinoplasty procedure.

In this article, cephalad placement of the transdomal sutures, and its relevance is disclosed in 223 consecutive cases of primary rhinoplasty.
A nonrandomized phase 2 trial of EG-Mirotin, a novel, first-in-class, subcutaneously delivered peptide drug for non-proliferative diabetic retinopathy
Authors: Yoo Seunghoon , You Dae Hyuk , Lee Jeongyoon , Hong H. Christian , Lee Sung Jin
Published: January 2022

Aim

EG-Mirotin (active ingredient EGT022) targets non-proliferative diabetic retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin reverses capillary damage before NPDR progresses to an irreversible stage. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate-to-severe NPDR.

Methods

In this open-label, single-arm, single-center, exploratory phase II study, 10 patients (20 eyes) received EG-Mirotin once a day (3 mg/1.5 ml sterile saline) for 5 days and were evaluated for ischemic index changes and safety. End-of-study was approximately 8±1 weeks (57±7 days) after the first drug administration.

Results

EG-Mirotin injections were well tolerated with no dose-limiting adverse events, serious adverse events, or deaths. Four treatment-emergent adverse events (TEAEs) unrelated to the investigational drug were observed in 2 out of 10 participants (20.00%) who had received the investigational drug. The overall average percent change in ischemic index at each evaluation point compared to baseline was statistically significant (Greenhouse-Geisser F=9.456, p=0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse-Geisser F=10.946, p=0.002 for time × group interaction).

Conclusions

EG-Mirotin was well tolerated and reversed diabetes-induced ischemia and leakage of capillaries in the retina.
Immune responses to inactivated and vector-based vaccines in individuals previously infected with SARS-CoV-2
Authors: Suntronwong Nungruthai , Yorsaeng Ritthideach , Auphimai Chompoonut , Thongmee Thanunrat , Vichaiwattana Preeyaporn , Kanokudom Sitthichai , Assawakosri Suvichada , Nilyanimit Pornjarim , Srimuan Donchida , Thatsanatorn Thaksaporn , Sudhinaraset Natthinee , Wanlapakorn Nasamon , Poovorawan Yong
Published: January 2022

Immunity wanes in individuals previously infected with SARS-CoV-2, and vaccinating those individuals may help reduce reinfection. Herein, reactogenicity and immunogenicity following vaccination with inactivated (CoronaVac) and vector-based (ChAdOx1-S, AZD1222) vaccines were examined in previously infected individuals. Immune response was also compared between short and long intervals between first date of detection and vaccination. Adverse events were mild but were higher with AZD1222 than with CoronaVac. Baseline IgG-specific antibodies and neutralizing activity were significantly higher with shorter than longer intervals. With a single-dose vaccine, IgG and IgA-specific binding antibodies, neutralizing activity, and total interferon-gamma response peaked at 14 days. Immune response was significantly higher in recovered individuals than in infection-naïve individuals. Antibody response was greater with longer than shorter intervals. AZD1222 induced higher antibody and T cell responses than those of CoronaVac. Thus, to achieve immunity, individuals with prior SARS-CoV-2 exposure may require only a single dose of AZD1222 or two doses of CoronaVac to achieve the immune response. These findings supported vaccine strategies in previously infected individuals.
Linked-Read Sequencing of Eight Falcons Reveals a Unique Genomic Architecture in Flux
Authors: Wilcox Justin J.S. , Arca-Ruibal Barbara , Samour Jaime , Mateuta Victor , Idaghdour Youssef , Boissinot Stéphane
Published: January 2022

Falcons are diverse birds of cultural and economic importance. They have undergone major lineage-specific chromosomal rearrangements, resulting in greatly-reduced chromosome counts relative to other birds. Here, we use 10X Genomics linked reads to provide new high-contiguity genomes for two gyrfalcons, a saker falcon, a lanner falcon, three subspecies of peregrine falcons, and the common kestrel. Assisted by a transcriptome sequenced from 22 gyrfalcon tissues, we annotate these genomes for a variety of genomic features, estimate historical demography, and then investigate genomic equilibrium in the context of falcon-specific chromosomal rearrangements. We find that falcon genomes are not in AT-GC equilibrium with a bias in mutations towards higher AT content; this bias is predominantly driven by—but not dependent on—hypermutability of CpG sites. Small indels and large structural variants were also biased towards insertions rather than deletions. Patterns of disequilibrium were linked to chromosomal rearrangements: falcons have lost GC content in regions that have fused to larger chromosomes from microchromosomes and gained GC content in regions of macrochromosomes that have translocated to microchromosomes. Inserted bases have accumulated on regions ancestrally belonging to microchromosomes, consistent with insertion-biased gene conversion. We also find an excess of interspersed repeats on regions of microchromosomes that have fused to macrochromosomes. Our results reveal that falcon genomes are in a state of flux. They further suggest that many of the key differences between microchromosomes and macrochromosomes are driven by differences in chromosome size, and indicate a clear role for recombination and biased-gene-conversion in determining genomic equilibrium.

Significance

Falcons are a particularly diverse and widespread genus of birds of particular cultural and economic importance. Falcons have also undergone recent large-scale chromosomal rearrangements to arrive at atypically low chromosome counts relative to other birds. We produced eight new high-quality falcon genomes to support general research on falcons, and we analyze these genomes to assess how chromosome loss has influenced specific aspects of genomic architecture.
Statistical analysis reveals the onset of synchrony in sparse swarms of Photinus knulli fireflies
Authors: Sarfati Raphaël , Gaudette Laura , Cicero Joseph M. , Peleg Orit
Published: January 2022

Flash synchrony within firefly swarms is an elegant but elusive manifestation of collective animal behaviour. It has been observed, and sometimes demonstrated, in a few populations across the world, but exactly which species are capable of large-scale synchronization remains unclear, especially in low-density swarms. The underlying question which we address here is: how does one qualify a collective flashing display as synchronous, given that the only information available is the time and location of flashes? We propose different statistical approaches and apply them to high-resolution stereoscopic video recordings of the collective flashing of Photinus knulli fireflies, hence establishing the occurrence of synchrony in this species. These results substantiate detailed visual observations published in the early 1980s and made at the same experimental site: Peña Blanca Canyon, Coronado National Forest, Arizona, USA. We also remark that P. knulli’s collective flashing patterns mirror that observed in Photinus carolinus fireflies in the Eastern United States, consisting of synchronous flashes in periodic bursts with rapid accretion and quick decay.
Conflicting effects of recombination on the evolvability and robustness in neutrally evolving populations
Authors: Klug Alexander , Krug Joachim
Published: January 2022

Understanding the benefits and costs of recombination under different scenarios of evolutionary adaptation remains an open problem for theoretical and experimental research. In this study, we focus on finite populations evolving on neutral networks comprising viable and unfit genotypes. We provide a comprehensive overview of the effects of recombination by jointly considering different measures of evolvability and mutational robustness over a broad parameter range, such that many evolutionary regimes are covered. We find that several of these measures vary non-monotonically with the rates of mutation and recombination. Moreover, the presence of unfit genotypes that introduce inhomogeneities in the network of viable states qualitatively alters the effects of recombination. We conclude that conflicting trends induced by recombination can be explained by an emerging trade-off between evolvability on the one hand, and mutational robustness on the other. Finally, we discuss how different implementations of the recombination scheme in theoretical models can affect the observed dependence on recombination rate through a coupling between recombination and genetic drift.

Author summary

Many genetic mechanisms have been invoked to explain the advantage of sex, but a coherent picture is still to emerge. Here we present a systematic theoretical and computational investigation of the effects of recombination in populations evolving on neutral fitness landscapes with unfit genotypes. We focus on populations that are large enough to be polymorphic, but nevertheless strongly affected by drift, which causes them to diffuse across the neutral network of viable genotypes. We identify a novel trade-off between evolvability, robustness and fitness that can lead to a dramatic reduction of the genetic diversity at large recombination rates. This disproves the common notion (often referred to as Weismann’s hypothesis) that recombination generally increases diversity and evolvability, and instead highlights the interplay of recombination and mutational robustness.
TheWeight: A simple and flexible algorithm for simulating non-ideal, age-structured populations
Authors: Waples Robin S.
Published: January 2022

The Wright-Fisher model, which directs how matings occur and how genes are transmitted across generations, has long been a lynchpin of evolutionary biology. This model is elegantly simple, analytically tractable, and easy to implement, but it has one serious limitation: essentially no real species satisfies its many assumptions. With growing awareness of the importance of jointly considering both ecology and evolution in eco-evolutionary models, this limitation has become more apparent, causing many researchers to search for more realistic simulation models.

A recently described variation retains most of the Wright-Fisher simplicity but provides greater flexibility to accommodate departures from model assumptions. This generalized Wright-Fisher model relaxes the assumption that all individuals have identical expected reproductive success by introducing a vector of parental weights w that specifies relative probabilities different individuals have of producing offspring. With parental weights specified this way, expectations of key demographic parameters are simple functions of w. This allows researchers to quantitatively predict the consequences of non-Wright-Fisher features incorporated into their models.

An important limitation of the Wright-Fisher model is that it assumes discrete generations, whereas most real species are age-structured. Here I show how an algorithm (TheWeight) that implements the generalized Wright-Fisher model can be used to model evolution in age-structured populations with overlapping generations. Worked examples illustrate simulation of seasonal and lifetime reproductive success and show how the user can pick vectors of weights expected to produce a desired level of reproductive skew or a desired Ne/N ratio. Alternatively, weights can be associated with heritable traits to provide a simple, quantitative way to model natural selection. Using TheWeight, it is easy to generate positive or negative correlations of individual reproductive success over time, thus allowing explicit modeling of common biological processes like skip breeding and persistent individual differences.

Code is provided to implement basic features of TheWeight and applications described here. However, required coding changes to the Wright-Fisher model are modest, so the real value of the new algorithm is to encourage users to adopt its features into their own or others’ models.
Where we perceive before we look: The distribution of presaccadic attention assessed with dynamic 1/f noise
Authors: Hanning Nina M. , Deubel Heiner
Published: January 2022

Already before the onset of a saccadic eye movement, we preferentially process visual information at the upcoming eye fixation. This ‘presaccadic shift of attention’ is typically assessed via localized test items, which potentially bias the attention measurement. Here we show how presaccadic attention shapes perception from saccade origin to target when no scene-structuring items are presented. Participants made saccades into a 1/f (“pink”) noise field, in which we embedded a brief orientation signal at various locations shortly before saccade onset. Local orientation discrimination performance served as a proxy for the allocation of attention. Results demonstrate that (1) saccades are preceded by shifts of attention to their goal location even if they are directed into an unstructured visual field, but the spread of attention, compared to target-directed saccades, is broad; (2) the presaccadic attention shift is accompanied by considerable attentional costs at the presaccadic eye fixation; (3) objects markedly shape the distribution of presaccadic attention – demonstrating the relevance of an item-free approach for measuring attentional dynamics across the visual field.
A novel method for multi-scale recording of intracranial EEG through dynamic alteration of electrode surface area
Authors: Sindhu Kavyakantha Remakanthakurup , Ngo Duy , Ombao Hernando , Olaya Joffre E. , Shrey Daniel W. , Lopour Beth A.
Published: January 2022

Intracranial EEG (iEEG) plays a critical role in the treatment of neurological diseases, such as epilepsy and Parkinson’s disease, as well as the development of neural prostheses and brain computer interfaces. While electrode geometries vary widely across these applications, the impact of electrode size on iEEG features and morphology is not well understood. Some insight has been gained from computer simulation studies and experiments in which signals are recorded using electrodes of different sizes concurrently in different brain regions. Here, we introduce a novel method to record from electrodes of different sizes in the exact same location by changing the size of iEEG electrodes after implantation in the brain. We first present a theoretical model and an in vitro validation of the method. We then report the results of an in vivo implementation in three human subjects with refractory epilepsy. We recorded iEEG data from three different electrode sizes and compared the amplitudes, power spectra, inter-channel correlations, and signal-to-noise ratio (SNR) of interictal epileptiform discharges, i.e., epileptic spikes. We found that iEEG amplitude and power decreased as electrode size increased, while inter-channel correlation increased with electrode size. The SNR of epileptic spikes was generally highest in the smallest electrodes, but 39% of spikes had maximal SNR in medium or large electrodes. This likely depends on the precise location and spatial spread of each spike. Overall, this new method enables multi-scale measurements of electrical activity in the human brain that facilitate our understanding of neurophysiology, treatment of neurological disease, and development of novel technologies.
IKKalpha-Mediated Non-canonical NF-kappaB Signaling is Required to Support Murine Gammaherpesvirus 68 LatencyIn Vivo
Authors: Cieniewicz Brandon , Kirillov Varvara , Daher Isabel , Li Xiaofan , Oldenburg Darby G. , Dong Qiwen , Bettke Julie A. , Marcu Kenneth B. , Krug Laurie T.
Published: January 2022

Non-canonical NF-kappaB signaling is activated in B cells via TNF receptor superfamily members CD40, Lymphotoxin beta-R, and BAFF-R. The non-canonical pathway is required at multiple stages of B-cell maturation and differentiation, including the germinal center reaction. However, the role of this pathway in gammaherpesvirus latency is not well understood. Murine gammaherpesvirus 68 (MHV68) is a genetically tractable system used to define pathogenic determinants. Mice lacking the BAFF-R exhibit defects in splenic follicle formation and are greatly reduced for MHV68 latency. We report a novel approach to disrupt non-canonical NF-kappaB signaling exclusively in cells infected with MHV68. We engineered a recombinant virus that expresses a dominant negative form of IKKalpha, named IKKα-SA, with S176A and S180A mutations that prevent phosphorylation by NIK. We controlled for the transgene insertion by introducing two all-frame stop codons into the IKKα-SA gene. The IKKα-SA mutant but not the IKKα-SA.STOP control virus impaired LTbetaR-mediated activation of NF-kappaB p52 upon fibroblast infection. IKKα-SA expression did not impact replication in primary fibroblasts or in the lungs of mice following intranasal inoculation. However, the IKKα-SA mutant was severely defective in colonization of the spleen and in the establishment of latency compared to the IKKα-SA.STOP control and WT MHV68 at 16 dpi. Reactivation was undetectable in splenocytes infected with the IKKα-SA mutant, but reactivation in peritoneal cells was not impacted by IKKα-SA. Taken together, the non-canonical NF-kappaB signaling pathway is essential for the establishment of latency in the secondary lymphoid organs of mice infected with the murine gammaherpesvirus pathogen MHV68.

IMPORTANCE

The latency programs of the human gammaherpesviruses EBV and KSHV are associated with B cell lymphomas. It is critical to understand the signaling pathways that are used by gammaherpesviruses to establish and maintain latency in primary B cells. We used a novel approach to block non-canonical NF-kappaB signaling only in the infected cells of mice. We generated a recombinant virus that expresses a dominant negative mutant of IKKalpha that is non-responsive to upstream activation. Latency was reduced in a route- and cell type-dependent manner in mice infected with this recombinant virus. These findings identify a significant role for the non-canonical NF-kappaB signaling pathway that might provide a novel target to prevent latent infection of B cells with oncogenic gammaherpesviruses.
Dysfunctional Senescent Herpes Simplex Virus Specific CD57+CD8+ T cells are Associated with Recurrent Symptomatic Herpes in Humans
Authors: Khan Arif A. , Srivastava Ruchi , Vahed Hawa , BenMohamed Lbachir
Published: January 2022

Herpes simplex virus (HSV)-specific CD8+ T cells protect mice from herpes infection and disease. However, the phenotype and function of HSV-specific CD8+ T cells that play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. We previously reported that symptomatic (SYMP) patients (who have frequent bouts of recurrent herpes disease) had more less-differentiated and dysfunctional HSV-specific CD8+ T cells. In contrast, healthy ASYMP individuals maintained a significantly higher proportion of differentiated polyfunctional CD8+ T cells. Here we report that, HSV-specific CD8+ T cells from SYMP patients, but not from ASYMP individuals, have phenotypic and functional characteristics of cellular senescence, including: (i) high frequency of senescent (CD57+) and exhausted (PD-1+) CD8+ T cells; (ii) late terminally differentiated (KLRG1+), non-proliferating CD8+ T cells; (iii) HSV-specific CD8+ T cells were declined overtime and were not maintained homeostatistically (CD127+CD8+ T cells); (iv) loss of co-stimulatory molecule (CD28) on HSV-specific CD8+ T cells; (v) decreased production of effector molecules (granzyme B and perforin) by HSV-specific CD8+ T cells. Our findings provide insights into the role of senescence in HSV-specific CD8+ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.

IMPORTANCE

Reactivation of herpes simplex virus 1 (HSV-1) from latency leads to recurrent herpetic disease in symptomatic (SYMP) individuals. A role of T cells in herpes immunity against recurrent herpetic disease is established. However, the phenotype and function of HSV-specific CD8+ T cells that play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In the present study, we report that, HSV-specific CD8+ T cells from SYMP patients, but not from ASYMP individuals, have phenotypic and functional characteristics of cellular senescence. Our findings provide insights into the role of senescence in HSV-specific CD8+ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.
A 2-Gene Host Signature for Improved Accuracy of COVID-19 Diagnosis Agnostic to Viral Variants
Authors: Albright Jack , Mick Eran , Sanchez-Guerrero Estella , Kamm Jack , Mitchell Anthea , Detweiler Angela M. , Neff Norma , Tsitsiklis Alexandra , Serpa Paula Hayakawa , Ratnasiri Kalani , Havlir Diane , Kistler Amy , DeRisi Joseph L. , Pisco Angela Oliveira , Langelier Charles R.
Published: January 2022

The continued emergence of SARS-CoV-2 variants is one of several factors that may cause false negative viral PCR test results. Such tests are also susceptible to false positive results due to trace contamination from high viral titer samples. Host immune response markers provide an orthogonal indication of infection that can mitigate these concerns when combined with direct viral detection. Here, we leverage nasopharyngeal swab RNA-seq data from patients with COVID-19, other viral acute respiratory illnesses and non-viral conditions (n=318) to develop support vector machine classifiers that rely on a parsimonious 2-gene host signature to predict COVID-19. Optimal classifiers achieve an area under the receiver operating characteristic curve (AUC) greater than 0.9 when evaluated on an independent RNA-seq cohort (n=553). We show that a classifier relying on a single interferon-stimulated gene, such as IFI6 or IFI44, measured in RT-qPCR assays (n=144) achieves AUC values as high as 0.88. Addition of a second gene, such as GBP5, significantly improves the specificity compared to other respiratory viruses. The performance of a clinically practical 2-gene RT-qPCR classifier is robust across common SARS-CoV-2 variants, including Omicron, and is unaffected by cross-contamination, demonstrating its utility for improving accuracy of COVID-19 diagnostics.
Evaluating Real-World COVID-19 Vaccine Effectiveness Using a Test-Negative Case-Control Design
Authors: Reynolds Matthew W , Secora Alex , Joules Alice , Albert Lisa , Brinkley Emma , Kwon Tom , Mack Christina , Toovey Stephen , Dreyer Nancy A.
Published: January 2022

It is important to assess the extent to which the real-world effectiveness of marketed vaccines is consistent with that observed in the clinical trials, and to characterize how well vaccines prevent COVID-19 symptoms. We conducted a modified test-negative design (TND) to evaluate the RW effectiveness of three COVID-19 vaccines by leveraging data from an on-going, US community-based registry. Vaccine effectiveness was examined in two ways: considering cases who (1) tested positive for COVID-19 (695 cases, 1,786 controls) and who (2) tested positive with at least one moderate/severe COVID-19 symptom (165 cases, 2,316 controls). Any vaccination (full or partial) was associated with a 95% reduction in the odds of having a positive COVID-19 test [adjusted odds ratio (aOR) = 0.05 (95% confidence interval (CI): 0.04, 0.06)]. Full vaccination was associated with an aOR of 0.03 (95% CI: 0.03, 0.05) while partial vaccination had an aOR of 0.08 (95% CI: 0.06, 0.12). Any vaccination was associated with a 71% reduction in the odds of testing positive and having at least one moderate/severe symptom (aOR=0.29 (95% CI: 0.20, 0.40)). High effectiveness was observed across all three vaccine manufacturers both for prevention of positive COVID-19 test results and prevention of moderate/severe COVID-19 symptoms.

Clinicaltrials.govNCT04368065
Older adults mount less durable humoral responses to two doses of COVID-19 mRNA vaccine, but strong initial responses to a third dose
Authors: Mwimanzi Francis , Lapointe Hope R. , Cheung Peter K. , Sang Yurou , Yaseen Fatima , Umviligihozo Gisele , Kalikawe Rebecca , Datwani Sneha , Omondi F. Harrison , Burns Laura , Young Landon , Leung Victor , Agafitei Olga , Ennis Siobhan , Dong Winnie , Basra Simran , Lim Li Yi , Ng Kurtis , Pantophlet Ralph , Brumme Chanson J. , Montaner Julio S.G. , Prystajecky Natalie , Lowe Christopher F. , DeMarco Mari L. , Holmes Daniel T. , Simons Janet , Niikura Masahiro , Romney Marc G. , Brumme Zabrina L. , Brockman Mark A.
Published: January 2022

Background

Third COVID-19 vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults.

Methods

We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and Omicron (BA.1) strains from pre-vaccine up to one month following the third dose, in 151 adults aged 24-98 years who received COVID-19 mRNA vaccines.

Results

Following two vaccine doses, humoral immunity was weaker, less functional and less durable in older adults, where a higher number of chronic health conditions was a key correlate of weaker responses and poorer durability. Third doses boosted antibody binding and function to higher levels than second-doses, and induced responses in older adults that were comparable in magnitude to those in younger adults. Humoral responses against Omicron were universally weaker than against the ancestral strain after both second and third doses; nevertheless, after three doses, anti-Omicron responses in older adults reached equivalence to those in younger adults. After three vaccine doses, the number of chronic health conditions, but not age per se, was the strongest consistent correlate of weaker humoral responses.

Conclusion

Results underscore the immune benefits of third COVID-19 vaccine doses, particularly in older adults.
Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis
Authors: Kar Siddhartha P. , Quiros Pedro M. , Gu Muxin , Jiang Tao , Langdon Ryan , Iyer Vivek , Barcena Clea , Vijayabaskar M.S. , Fabre Margarete A. , Carter Paul , Burgess Stephen , Vassiliou George S.
Published: January 2022

Clonal hematopoiesis (CH) is one of the most extensively studied somatic mutational phenomena, yet its causes and consequences remain poorly understood. We identify 10,924 individuals with CH amongst 200,453 whole-exome sequenced UK Biobank participants and use their linked genome-wide DNA genotypes to map the landscape of inherited predisposition to CH. We increase the number of European-ancestry genome-wide significant (P<5×10−8) germline associations with CH from four to 14 and identify one new transcriptome-wide significant (P<3.2×10−6) association. Genes at new loci implicate DNA damage repair (PARP1, ATM, andCHEK2), hematopoietic stem cell migration/homing (CD164), and myeloid oncogenesis (SETBP1) in CH development. Several associations were CH-subtype specific and, strikingly, variants atTCL1AandCD164had opposite associations withDNMT3A-versusTET2-mutant CH, mirroring recently reported differences in lifelong behavior of these two most common CH subtypes and proposing important roles for these loci in CH pathogenesis. Using Mendelian randomization, we show, amongst other findings, that smoking and longer leukocyte telomere length are causal risk factors for CH and demonstrate that genetic predisposition to CH increases risks of myeloproliferative neoplasia, several non-hematological malignancies, atrial fibrillation, and blood epigenetic age acceleration.
Updated projections for COVID-19 omicron wave in Florida
Authors: Hladish Thomas J. , Pillai Alexander N. , Longini Ira M.
Published: January 2022

In this report, we use a detailed simulation model to assess and project the COVID-19 epidemic in Florida. The model is a data-driven, stochastic, discrete-time, agent based model with an explicit representation of people and places. Using the model, we find that the omicron variant wave in Florida is likely to cause many more infections than occurred during the delta variant wave. Due to testing limitations and often mild symptoms, however, we anticipate that omicron infections will be underreported compared to delta. We project that reported cases of COVID-19 will continue to grow significantly and peak in early January 2022, and that the number of reported COVID-19 deaths due to omicron may be 1/3 of the total caused by the delta wave.
A novel time-based surface EMG measure for quantifying hypertonia in paretic arm muscles during daily activities after hemiparetic stroke
Authors: Sohn M. Hongchul , Deol Jasjit , Dewald Julius P.A.
Published: January 2022

After stroke, paretic arm muscles are constantly exposed to abnormal neural drive from the injured brain. As such, hypertonia, broadly defined as an increase in muscle tone, is prevalent especially in distal muscles, which impairs daily function or in long-term leads to a flexed resting posture in the wrist and fingers. However, there currently is no quantitative measure that can reliably track how hypertonia is expressed on daily basis. In this study, we propose a novel time-based surface electromyography (sEMG) measure that can overcome the limitations of the coarse clinical scales often measured in functionally irrelevant context and the magnitude-based sEMG measures that suffer from signal non-stationarity. We postulated that the key to robust quantification of hypertonia is to capture the “true” baseline in sEMG for each measurement session, by which we can define the relative duration of activity over a short time segment continuously tracked in a sliding window fashion. We validate that the proposed measure of sEMG active duration is robust across parameter choices (e.g., sampling rate, window length, threshold criteria), robust against typical noise sources present in paretic muscles (e.g., low signal-to-noise ratio, sporadic motor unit action potentials), and reliable across measurements (e.g., sensors, trials, and days), while providing a continuum of scale over the full magnitude range for each session. Furthermore, sEMG active duration could well characterize the clinically observed differences in hypertonia expressed across different muscles and impairment levels. The proposed measure can be used for continuous and quantitative monitoring of hypertonia during activities of daily living while at home, which will allow for the study of the practical effect of pharmacological and/or physical interventions that try to combat its presence.
Modeling the USA Winter 2021 CoVID-19 Resurgence
Authors: Eng Genghmun
Published: January 2022

The current USA 2021 CoVID-19 Winter Resurgence is modeled here with the same function used for analyzing prior USA CoVID-19 waves:

Here, N(t) gives the total number of CoVID-19 cases above the previous baseline, and tR sets the initial tdbl = tR (ln 2) pandemic tdbl doubling time. Larger αS values indicate that uninfected people are improving their pandemic mitigation efforts, such as Social Distancing and vaccinations ; while δ0> 0 accelerates the post-peak tail-off, and is empirically associated with mask-wearing. The pandemic wave end is when N(t) no longer increases.

The USA Summer 2021 resurgence results from our prior medrxiv.org preprints* were used as a baseline. By 11/15/2021, an additional cases above baseline were found, signaling the USA Winter 2021 resurgence. This CoVID-19 wave is still in its initial stages. Presently, our analysis indicates that this CoVID-19 wave can infect virtually all susceptible persons; just like the initial stage of the USA Summer 2021 resurgence. Data up through 12/30/2021 gives these paremeter values:

These values are identical to the prior 2020 USA Winter Resurgence results. Also, the and the values are similar. However, while the Winter 2020 Resurgence showed a significant mask-wearing effect , this initial USA Winter 2021 Resurgence shows practically no mask-wearing effects . If mask-wearing were to quickly rise to the Winter 2020 levels, it would give these projected totals:

More robust mask-wearing and enhanced Social Distancing measures could further reduce these values (with 3 Figures).
STREAMING-tag system reveals spatiotemporal relationships between transcriptional regulatory factors and transcriptional activity
Authors: Ohishi Hiroaki , Shimada Seiru , Uchino Satoshi , Li Jieru , Sato Yuko , Shintani Manabu , Owada Hitoshi , Ohkawa Yasuyuki , Pertsinidis Alexandros , Yamamoto Takashi , Kimura Hiroshi , Ochiai Hiroshi
Published: January 2022

Transcription is a dynamic process that stochastically switches between the ON and OFF states. To detect the dynamic relationship among protein clusters of RNA polymerase II (RNAPII) and coactivators, gene loci, and transcriptional activity, we inserted an MS2 repeat, a TetO repeat, and inteins with a selection marker just downstream of the transcription start site (TSS). By optimizing the individual elements, we have developed the Spliced TetO REpeAt, MS2 repeat, and INtein sandwiched reporter Gene tag (STREAMING-tag) system. Clusters of RNAPII and BRD4 were observed proximally to the TSS ofNanogwhen the gene was transcribed in mouse embryonic stem cells. In contrast, clusters of MED19 and MED22 Mediator subunits were constitutively located near the TSS. Thus, the STREAMING-tag system revealed the spatiotemporal relationships between transcriptional activity and protein clusters near the gene. This powerful tool is useful for quantitatively understanding dynamic transcriptional regulation in living cells.
MethylScore, a pipeline for accurate and context-aware identification of differentially methylated regions from population-scale plant WGBS data
Authors: Hüther Patrick , Hagmann Jörg , Nunn Adam , Kakoulidou Ioanna , Pisupati Rahul , Langenberger David , Weigel Detlef , Johannes Frank , Schultheiss Sebastian J. , Becker Claude
Published: January 2022

Whole-genome bisulfite sequencing (WGBS) is the standard method for profiling DNA methylation at single-nucleotide resolution. Many WGBS-based studies aim to identify biologically relevant loci that display differential methylation between genotypes, treatment groups, tissues, or developmental stages. Over the years, different tools have been developed to extract differentially methylated regions (DMRs) from whole-genome data. Often, such tools are built upon assumptions from mammalian data and do not consider the substantially more complex and variable nature of plant DNA methylation. Here, we present MethylScore, a pipeline to analyze WGBS data and to account for plant-specific DNA methylation properties. MethylScore processes data from genomic alignments to DMR output and is designed to be usable by novice and expert users alike. It uses an unsupervised machine learning approach to segment the genome by classification into states of high and low methylation, substantially reducing the number of necessary statistical tests while increasing the signal-to-noise ratio and the statistical power. We show how MethylScore can identify DMRs from hundreds of samples and how its data-driven approach can stratify associated samples without prior information. We identify DMRs in the A. thaliana 1001 Genomes dataset to unveil known and unknown genotype-epigenotype associations. MethylScore is an accessible pipeline for plant WGBS data, with unprecedented features for DMR calling in small- and large-scale datasets; it is built as a Nextflow pipeline and its source code is available at https://github.com/Computomics/MethylScore.
neuromaps: structural and functional interpretation of brain maps
Authors: Markello Ross D. , Hansen Justine Y. , Liu Zhen-Qi , Bazinet Vincent , Shafiei Golia , Suárez Laura E. , Blostein Nadia , Seidlitz Jakob , Baillet Sylvain , Satterthwaite Theodore D. , Chakravarty M. Mallar , Raznahan Armin , Misic Bratislav
Published: January 2022

Imaging technologies are increasingly used to generate high-resolution reference maps of brain structure and function. Modern scientific discovery relies on making comparisons between new maps (e.g. task activations, group structural differences) and these reference maps. Although recent data sharing initiatives have increased the accessibility of such brain maps, data are often shared in disparate coordinate systems (or “spaces”), precluding systematic and accurate comparisons among them. Here we introduce the neuromaps toolbox, an open-access software package for accessing, transforming, and analyzing structural and functional brain annotations. We implement two registration frameworks to generate high-quality transformations between four standard coordinate systems commonly used in neuroimaging research. The initial release of the toolbox features >40 curated reference maps and biological ontologies of the human brain, including maps of gene expression, neurotransmitter receptors, metabolism, neurophysiological oscillations, developmental and evolutionary expansion, functional hierarchy, individual functional variability, and cognitive specialization. Robust quantitative assessment of map-to-map similarity is enabled via a suite of spatial autocorrelation-preserving null models. By combining open-access data with transparent functionality for standardizing and comparing brain maps, the neuromaps software package provides a systematic workflow for comprehensive structural and functional annotation enrichment analysis of the human brain.
Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a pan-Ebolavirus Immunotherapeutic
Authors: Kuang Erin , Cross Robert W. , McCavitt-Malvido Maria , Abelson Dafna M. , Borisevich Viktoriya , Agans Krystle N. , Mlakar Neil , Marimuthu Arumugapradeep , Deer Daniel J. , Shestowsky William S. , Kim Do , Geisbert Joan B. , Zeitlin Larry , Moyer Crystal L. , Roy Chad J. , Geisbert Thomas , Bornholdt Zachary A.
Published: January 2022

Intravenous administration (IV) of antiviral monoclonal antibodies (mAbs) is challenging due to limited resources for performing infusions during an ongoing epidemic. An ebolavirus therapeutic administered via intramuscular (IM) injection would reduce these burdens and allow rapid treatment of exposed individuals during an outbreak. Here, we demonstrate how MBP134, a two mAb pan-ebolavirus cocktail, reverses the course of Sudan ebolavirus (SUDV/Gulu) disease with a single IV or IM dose in non-human primates (NHPs) as far as five days post-exposure. Furthermore, we investigated the utility of adding half-life extension mutations to the MBP134 mAbs, ultimately creating a half-life extended cocktail designated MBP431. MBP431 demonstrated an extended serum half-life in vivo and offered complete or significant protection with a single IM dose delivered as a post-exposure prophylactic (PEP) or therapeutic in NHPs challenged with EBOV. These results support the use of MBP431 as a rapidly deployable IM medical countermeasure against every known ebolavirus.
Random Compressed Coding with Neurons
Authors: Malerba Simone Blanco , Pieropan Mirko , Burak Yoram , Azeredo da Silveira Rava
Published: January 2022

Classical models of efficient coding in neurons assume simple mean responses—‘tuning curves’—such as bellshaped or monotonic functions of a stimulus feature. Real neurons, however, can be more complex: grid cells, for example, exhibit periodic responses which impart the neural population code with high accuracy. But do highly accurate codes require fine tuning of the response properties? We address this question with the use of a benchmark model: a neural network with random synaptic weights which result in output cells with irregular tuning curves. Irregularity enhances the local resolution of the code but gives rise to catastrophic, global errors. For optimal smoothness of the tuning curves, when local and global errors balance out, the neural network compresses information from a high-dimensional representation to a low-dimensional one, and the resulting distributed code achieves exponential accuracy. An analysis of recordings from monkey motor cortex points to such ‘compressed efficient coding’. Efficient codes do not require a finely tuned design—they emerge robustly from irregularity or randomness.
Fibrin, Bone Marrow Cells and macrophages interactively modulate cardiomyoblast fate
Authors: Borrego Inês , Frobert Aurélien , Ajalbert Guillaume , Valentin Jérémy , Kaltenrieder Cyrielle , Fellay Benoît , Stumpe Michael , Cook Stéphane , Dengjel Joern , Giraud Marie-Noelle
Published: January 2022

Interactions between macrophages, cardiac cells and the extracellular matrix are crucial for cardiac repair following myocardial infarction (MI). The paracrine effects of cell-based treatments of MI might modulate these interactions and impact cardiac repair. The immunomodulatory capacity of the therapeutic cells is therefore of interest and could be modulated by the use of biomaterials. We first showed that bone marrow cells (BMC) associated with fibrin could treat MI. Then, we interrogated the influence of fibrin, as a biologically active scaffold, on the secretome of BMC and the impact of their association on macrophage fate and cardiomyoblast proliferation.

Methods

In vivo, two weeks post-MI, rats were treated with epicardial implantation of BMC and fibrin or sham-operated. High-resolution echocardiography was performed to evaluate the heart function and structure changes after 4 weeeks. Histology and immunostaining were performed on harvested hearts.In vitro, BMC were first primed with fibrin. Second, non-polarized macrophages were differentiated toward either pro-inflammatory or anti-inflammatory phenotypes and stimulated with the conditioned medium of fibrin-primed BMC (F-BMC). Proteomic, cytokine levels quantification, and RT-PCR were performed. EdU incorporation and real-time cell analysis assessed cell proliferation.

Results

The epicardial implantation of fibrin and BMC reduced the loss of cardiac function induced by MI, increased wall thickness and prevented the fibrotic scar expansion. After 4 and 12 weeks, the infarct content of CD68+and CD206+was similar in control and treated animals. In vitro, we showed that fibrin profoundly influenced the gene expression and the secretome of BMC, simultaneously upregulating both pro- and anti-inflammatory mediators. Furthermore, the conditioned medium from F-BMC significantly increased the proliferation of macrophages in a subsets dependent manner and modulated their gene expression and cytokines secretion. For instance, F-BMC significantly downregulated the expression ofNos2,Il6andCcl2/Mcp1whileArg1,TgfbandIL10were upregulated. Interestingly, macrophages educated by F-BMC increased cardiomyoblast proliferation.

In conclusion, our study provides evidence that BMC/fibrin-based treatment lowered the infarct extent and improved cardiac function. The macrophage content was unmodified when measured at a chronic stage. Nevertheless, acutely andin vitro, the F-BMC secretome promotes an anti-inflammatory response that stimulates cardiac cell growth. Finally, our study emphases the acute impact of F-BMC educated macrophages on cardiac cell fate.