bluuebunny/crossref_metadata_2025 huggingface dataset:
A Mesoamerican Urban Road Network: An Analysis of Pedestrian Pathways of Angamuco, Michoacán
Authors: Solinis-Casparius Rodrigo
Published: February 2022

This article examines the urban layout and development of the ancient city of Angamuco (AD 250–1530)—a populated urban center located within the core area of the Purépecha Empire in Michoacán, Mexico—through the lens of its complex road network. Image and network analysis of lidar datasets revealed more than 3,000 roads distributed throughout the site, identified the main patterns of road arrangement, and documented variable accessibility within the city. After presenting a summary of these results, I propose that road networks are fundamental components of urban centers that can help reveal social configurations, local interactions, and models of governance. The study of the road network at the site of Angamuco suggests that this city developed organically without the strong influence of political hierarchy a few centuries prior to the formation of the Purépecha Empire. Angamuco inhabitants organized and negotiated space and settlement within their immediate community and had access to virtually all areas of the city.
Multimessenger astronomy with a kHz-band gravitational-wave observatory
Authors: Sarin Nikhil , Lasky Paul D.
Published: February 2022

Proposed next-generation networks of gravitational-wave observatories include dedicated kilohertz instruments that target neutron star science, such as the proposed Neutron Star Extreme Matter Observatory, NEMO. The original proposal for NEMO highlighted the need for it to exist in a network of gravitational-wave observatories to ensure detection confidence and sky localisation of sources. We show that NEMO-like observatories have significant utility on their own as coincident electromagnetic observations can provide the detection significance and sky localisation. We show that, with a single NEMO-like detector and expected electromagnetic observatories in the late 2020 s and early 2030 s such as the Vera C. Rubin observatory and SVOM, approximately 40% of all binary neutron star mergers detected with gravitational waves could be confidently identified as coincident multimessenger detections. We show that we expect

$2^{+10}_{-1}{yr^{-1}}{}$

coincident observations of gravitational-wave mergers with gamma-ray burst prompt emission,

$13^{+23}_{-10}{yr^{-1}}{}$

detections with kilonova observations, and

$4^{+18}_{-3}{yr^{-1}}{}$

with broadband afterglows and kilonovae, where the uncertainties are 90% confidence intervals arising from uncertainty in current merger-rate estimates. Combined, this implies a coincident detection rate of

$14^{+25}_{-11}{yr^{-1}}{}$

out to

$300\,\mathrm{Mpc}$

. These numbers indicate significant science potential for a single kilohertz gravitational-wave detector operating without a global network of other gravitational-wave observatories.
APPLICATIONS OF CIRCULANT MATRICES TO DETERMINANTS INVOLVING TH POWER RESIDUES
Authors: WU HAI-LIANG , WANG LI-YUAN
Published: February 2022

We use circulant matrices and hyperelliptic curves over finite fields to study some arithmetic properties of certain determinants involving Legendre symbols andkth power residues.
A novel approach to managing circumferential entrapment of a child's tongue within a plastic lid
Authors: Selwyn A , Praveen C V , De Silva R , Rehman F
Published: February 2022

Background

The increased popularity of reusable drinking bottles may have safety implications when used by children. This paper discusses the lessons learnt from managing two cases of children presenting to our ENT department who required surgical intervention for complications arising from their use.

Case report

This paper presents a case series of two five-year-old children who attended the emergency department with circumferential entrapment of their tongue within plastic drinking bottle lids of similar design. The unique anaesthetic and surgical challenges surrounding these cases are discussed.

Conclusion

These represent the only reported cases of circumferential entrapment of the tongue by a foreign body requiring general anaesthesia where orotracheal intubation was contraindicated. A creative general anaesthetic approach was taken using ketamine and Optiflow high-flow nasal oxygen therapy. A reproducible surgical technique using powered cutting instruments is also discussed.
The Forum-Basilica at Caerwent (Venta Silurum): A History of the Roman Silures
Authors: Guest Peter
Published: February 2022

Lying at the heart of the city of Venta Silurum, the forum-basilica at Caerwent tells the public, municipal, story of the Civitas Silurum in south Wales. The re-excavation of this complex between 1987 and 1995 revealed a wealth of new information that has a great deal to tell us about the history of the city and the fortunes of its inhabitants. Constructed in the early second century and rebuilt in the middle of the fourth century, the forum-basilica was where the administrative, judicial, commercial and religious functions of the city were located. The modifications to the basilica at the very end of the Roman period indicate continued use of this civic space in the later fourth and fifth centuries.
Look to the field
Authors: Iliev Rumen , Medin Douglas , Bang Megan
Published: February 2022

Yarkoni's paper makes an important contribution to psychological research by its insightful analysis of generalizability. We suggest, however, that broadening research practices to include field research and the correlated use of both converging and complementary observations gives reason for optimism.
Intent-Aware Optimal Collision Avoidance and Trajectory Planning for a Pursuit Vehicle
Authors: Biswas Karnika , Kar Indrani , Feron Eric
Published: February 2022

This paper presents an integrated optimal control framework for velocity and steering control of an autonomous pursuit vehicle, where the control objectives satisfy the requirements of collision avoidance and moving target tracking. A distinctive feature of the proposed velocity and steering control is the application of logarithmic penalty functions to both. The control barrier imposed by logarithmic function provides a unique tool in computing a balanced trajectory with optimal tracking error, control effort and safety margin. Trajectories compliant with the safety regulations for autonomous driving have been planned based on estimated intention of the target and the obstacles. Effects of the controller weights have been extensively simulated to assess the performance of the proposed strategy in a variety of dynamic situations. The controller has been validated on a real-life robot by using a shrinking horizon control policy for iterative optimisation.
The Quebec Observatory on End-of-Life Care for People with Dementia: Implementation and Preliminary Findings
Authors: Bravo Gina , Arcand Marcel , Wilchesky Machelle , Verreault René , Bilodeau Charles , Trottier Lise
Published: February 2022

Most Canadians with dementia die in long-term care (LTC) facilities. No data are routinely collected in Canada on the quality of end-of-life care provided to this vulnerable population, leading to significant knowledge gaps. The Quebec Observatory on End-of-Life Care for People with Dementia was created to address these gaps. The Observatory is a research infrastructure designed to support the collection of data needed to better understand, and subsequently enhance, care quality for residents dying with dementia. This article reports on the main steps involved in setting up the Observatory, as well as a pilot study that involved 172 residents with dementia who died between 2016 and 2018 in one of 13 participating facilities. It describes the data gathered, methodological changes that were made along the way, feedback from participating facilities, and future developments of the Observatory.
What shape grammars do that CAD should: the 14 cases of shape embedding
Authors: Hong Tzu-Chieh Kurt , Economou Athanassios
Published: February 2022

Shape queries based on shape embedding under a given Euclidean, affine, or linear transformation are absent from current CAD systems. The only systems that have attempted to implement shape embedding are the shape grammar interpreters albeit with promising but inconclusive results. The work here identifies all possible 14 cases of shape embedding with respect to the number of available registration points, four for determinate cases and ten for indeterminate ones, and an approach is sketched to take on the complexities underlying the indeterminate cases. All visual calculations are done with shapes consisting of straight lines in the Euclidean plane within the algebra U
ij
for i = 1 the dimension of lines and j = 2 the dimension of space in which the lines are defined, transformed and combined. Aspects of interface design and integration to current work design workflows are deliberately left aside.
Margin-based approach for outlier detection of industrial design data using a modified general regression neural network
Authors: Sivaramakrishnan Jayaram , Lee Gareth , Parlevliet David , Wong Kok Wai
Published: February 2022

The choice of components in industrial design involves setting design parameters that typically must reside inside permissible ranges called “design margins”. This paper proposes a novel automated method called the Margin-Based General Regression Neural Network (MB-GRNN) that classifies design errors for design parameters that are outside of permissible ranges as outliers, directly from industrial design data, using an unsupervised machine learning approach. The method is based on a modified GRNN that estimates extremal margin boundaries of design parameters by self-learning the features from datasets. These extremal permissible margin boundaries are determined by “stretching out” the upper and lower GRNN surfaces using an iterative application of stretch factors (a second kernel weighting factor). The method creates a variable insensitive band surrounding the data cloud, interlinked with the normal regression function, providing upper and lower margin boundaries. These boundaries can then be used to determine outliers and to predict a range of permissible values of design parameters during design. Pushing out extremal margin boundaries reduce the false identification of outliers. This classification technique could be used by industrial engineers to detect likely outliers and to predict a range of permissible output limits for chosen design parameters. The efficacy of this method has been validated against the widespread Parzen window method by comparing experimental results from three multivariate datasets. It was found that the two methods have different but complementary capabilities. The MB-GRNN also uses a modified algorithm for estimating the smoothing parameter using a combination of clustering, k-nearest neighbor, and localized covariance matrix.
Complications associated with peripherally inserted central catheters in paediatric cardiac patients
Authors: Patel Jay R. , Vellore Govardhan Shilpa , Anton-Martin Pilar
Published: February 2022

Objectives:

To characterise the use of peripherally inserted central catheters in paediatric cardiac patients and to identify risk factors associated with their complications.

Materials and Methods:

Observational retrospective cohort study in paediatric cardiac patients who underwent peripherally inserted central catheter placement in a tertiary children’s hospital from January 2000 to June 2018.

Results:

1822 cardiac patients underwent 2952 peripherally inserted central catheter placements in the study period. Median age was 29 days, with survival to hospital discharge of 96.4%. Successful placement achieved 94.5% of attempts, with a median line duration of 12 days. Factors associated with successful placement were the use of general anaesthesia (odds ratio 7.52, p < 0.001) and year of placement (odds ratio 1.08, p < 0.001). The incidence of complications was 28.6%, with thrombosis/occlusion being the most frequent (33%). Thrombosis/occlusion were associated with two and three lumens (odds ratio 1.96, p < 0.001 and 4.63, p = 0.037, respectively). Lines placed by interventional radiology had decreased infiltration (odds ratio 0.20, p = 0.002) and lower migration/malposition (odds ratio 0.36, p < 0.001). The use of maintenance intravenous fluids (odds ratio 3.98, p = 0.008) and peripheral tip position (odds ratio 3.82, p = 0.001) were associated with increased infiltration. The probability of infection decreased over time (odds ratio 0.79, p < 0.001).

Conclusion:

Peripherally inserted central catheters in paediatric cardiac patients have complication rates similar to other paediatric populations. A prospective assessment of the factors associated with their complications in this patient population may be beneficial in improving outcomes.
Parental work hours and household income as determinants of unhealthy food and beverage intake in young Australian children
Authors: Mauch Chelsea E , Wycherley Thomas P , Bell Lucinda K , Laws Rachel A , Byrne Rebecca , Golley Rebecca K
Published: February 2022

Objective:

This study examined parental work hours and household income as determinants of discretionary (energy-dense, nutrient-poor) food and beverage intake in young children, including differences by eating occasion.

Design:

Secondary analysis of cross-sectional data. Three hierarchical regression models were conducted with percentage of energy from discretionary food and beverages across the day, at main meals and at snack times being the outcomes. Dietary intake was assessed by 1 × 24-h recall and 1–2 × 24-h food record(s). Both maternal and paternal work hours were included, along with total household income. Covariates included household, parent and child factors.

Setting:

Data from the NOURISH/South Australian Infants Dietary Intake studies were collected between 2008 and 2013.

Participants:

Participants included 526 mother–child dyads (median (interquartile range) child age 1·99 (1·96, 2·03) years). Forty-one percentage of mothers did not work while 57 % of fathers worked 35–40 h/week. Most (85 %) households had an income of ≥$50 k AUD/year.

Results:

Household income was consistently inversely associated with discretionary energy intake (β = –0·12 to –0·15). Maternal part-time employment (21–35 h/week) predicted child consumption of discretionary energy at main meals (β = 0·10, P = 0·04). Paternal unemployment predicted a lower proportion of discretionary energy at snacks (β = -0·09, P = 0·047).

Conclusions:

This work suggests that household income should be addressed as a key opportunity-related barrier to healthy food provision in families of young children. Strategies to reduce the time burden of healthy main meal provision may be required in families where mothers juggle longer part-time working hours with caregiving and domestic duties. The need to consider the role of fathers and other parents/caregivers in shaping children’s intake was also highlighted.
Conflict-Driven Inductive Logic Programming
Authors: LAW MARK
Published: February 2022

The goal of inductive logic programming (ILP) is to learn a program that explains a set of examples. Until recently, most research on ILP targeted learning Prolog programs. The ILASP system instead learns answer set programs (ASP). Learning such expressive programs widens the applicability of ILP considerably; for example, enabling preference learning, learning common-sense knowledge, including defaults and exceptions, and learning non-deterministic theories. Early versions of ILASP can be considered meta-level ILP approaches, which encode a learning task as a logic program and delegate the search to an ASP solver. More recently, ILASP has shifted towards a new method, inspired by conflict-driven SAT and ASP solvers. The fundamental idea of the approach, called Conflict-driven ILP (CDILP), is to iteratively interleave the search for a hypothesis with the generation of constraints which explain why the current hypothesis does not cover a particular example. These coverage constraints allow ILASP to rule out not just the current hypothesis, but an entire class of hypotheses that do not satisfy the coverage constraint. This article formalises the CDILP approach and presents the ILASP3 and ILASP4 systems for CDILP, which are demonstrated to be more scalable than previous ILASP systems, particularly in the presence of noise.
Moral Injury and Suicide Ideation Among Combat Veterans
Authors: Levi-Belz Yossi , Shemesh Sharon , Zerach Gadi
Published: February 2022

Abstract. Background: Modern warfare in a civilian setting may expose combatants to severe moral challenges. Whereas most of these challenges are handled effectively, some potentially morally injurious events (PMIEs) may have deleterious psychological effects on the combatants, such as suicide ideation (SI). Self-disclosure, which includes sharing distressing thoughts and emotions, has been recognized as a protective factor against SI in the aftermath of stressful events. The current study is the first to examine the moderating role of self-disclosure in the relationship between PMIE exposure and SI among combat veterans. Method: A sample of 190 recently discharged Israeli combat veterans completed validated self-report questionnaires measuring combat exposure, PMIEs, depressive symptoms, SI, and self-disclosure in a cross-sectional design study. Results: PMIE dimensions and self-disclosure significantly contributed to current SI. Notably, the moderating model indicated that self-disclosure moderated the link between PMIE-Self and current SI, as PMIE-Self and current SI demonstrated a stronger association among veterans with low self-disclosure than among those with high self-disclosure. Limitations: Cross-sectional design of volunteers, the findings may not be directly generalizable to veterans' population. Conclusion: Self-disclosure, as a factor promoting a sense of belongingness, interpersonal bonding, and support, might diminish SI risk following PMIE exposure. Various mechanisms accounting for these associations are suggested, and the clinical implications of these interactions are discussed.
Perfectionism and Suicidal Ideation
Authors: Moscardini Emma H. , Robinson Anthony , Calamia Matthew , Tucker Raymond P.
Published: February 2022

Abstract. Background: The integrated motivational–volitional (IMV) model of suicidal behavior posits that defeat leads to suicidal ideation through increased vulnerability for feelings of entrapment. One potentially important vulnerability factor for the development of feelings of defeat is socially prescribed perfectionism. Aims: The current study investigated these relationships in a sample of 313 US adults. Method: Mediation and parallel mediation analyses were conducted to determine the relationships between defeat, entrapment, social prescribed perfectionism, negative social comparison, and rejection sensitivity. Results: Findings indicated that socially prescribed perfectionism was significantly related to defeat through both negative social comparison and rejection sensitivity even when controlling for depression symptoms. Negative social comparison and rejection sensitivity were related to entrapment through feelings of defeat. This relationship was strongest when analyzing externalized (vs. internalized) entrapment. Limitations: The findings were limited by the cross-sectional study design as well as the relatively homogeneous sample. Implications and future directions are discussed.
Status of Debtor Registration at an Enforcement Authority and Risk of Nonfatal Suicide Attempt
Authors: Rojas Yerko
Published: February 2022

Abstract. Background: Not much is known about whether paying unpaid debt is related to a reduced risk of suicidal behavior. Aims: To examine whether nonfatal suicide attempt varied by status of nonpayment of debt as registered at the Swedish Enforcement Authority (SEA). Method: People aged between 20 and 64 years with a registration date for an unpaid debt at the SEA during 2016 ( n = 57,039) and registered as either active or inactive for a debt and/or a decision of debt reconstruction in the register in 2018 were followed up for a 2-year period for suicide attempt and compared with a sample from the general Swedish population ( n = 301,714). Results: Those who were still active for a debt and/or a decision of debt reconstruction were about twice ( Odds Ratio = 2.21) as likely to attempt suicide than those who no longer had an active debt in the SEA register. Limitations: The study was limited to suicide attempts that were registered as such in the National Patient Register. Conclusion: The results, based on unique nationwide register data, reinforce the importance of making tackling debt and financial distress part of current suicide prevention strategies. Professionals and others who interact with indebted people may be important gatekeepers in preventing suicide attempts.
Simulated Future Trends in Marine Nitrogen Fixation Are Sensitive to Model Iron Implementation
Authors: Yao Wanxuan , Kvale Karin F. , Koeve Wolfgang , Landolfi Angela , Achterberg Eric , Bertrand Erin M. , Oschlies Andreas
Published: February 2022

Biological nitrogen fixation is an important oceanic nitrogen source, potentially stabilizing marine fertility in an increasingly stratified and nutrient‐depleted ocean. Iron limitation of low latitude primary producers has been previously demonstrated to affect simulated regional ecosystem responses to climate warming or nitrogen cycle perturbation. Here we use three biogeochemical models that vary in their representation of the iron cycle to estimate change in the marine nitrogen cycle under a high CO2 emissions future scenario (RCP8.5). The first model neglects explicit iron effects on biology (NoFe), the second utilizes prescribed, seasonally cyclic iron concentrations and associated limitation factors (FeMask), and the third contains a fully dynamic iron cycle (FeDyn). Models were calibrated using observed fields to produce near‐equivalent nutrient and oxygen fits, with productivity ranging from 49 to 75 Pg C yr−1. Global marine nitrogen fixation increases by 71.1% with respect to the preindustrial value by the year 2100 in NoFe, while it remains stable (0.7% decrease in FeMask and 0.3% increase in FeDyn) in explicit iron models. The mitigation of global nitrogen fixation trend in the models that include a representation of iron originates in the Eastern boundary upwelling zones, where the bottom‐up control of iron limitation reduces export production with warming, which shrinks the oxygen deficient volume, and reduces denitrification. Warming‐induced trends in the oxygen deficient volume in the upwelling zones have a cascading effect on the global nitrogen cycle, just as they have previously been shown to affect tropical net primary production.
Effects of Drought on Mortality in Macro Urban Areas of Brazil Between 2000 and 2019
Authors: Salvador C. , Vicedo‐Cabrera A. M. , Libonati R. , Russo A. , Garcia B. N. , Belem L. B. C. , Gimeno L. , Nieto R.
Published: February 2022

A significant fraction of Brazil's population has been exposed to drought in recent years, a situation that is expected to worsen in frequency and intensity due to climate change. This constitutes a current key environmental health concern, especially in densely urban areas such as several big cities and suburbs. For the first time, a comprehensive assessment of the short‐term drought effects on weekly non‐external, circulatory, and respiratory mortality was conducted in 13 major Brazilian macro‐urban areas across 2000–2019. We applied quasi‐Poisson regression models adjusted by temperature to explore the association between drought (defined by the Standardized Precipitation‐Evapotranspiration Index) and the different mortality causes by location, sex, and age groups. We next conducted multivariate meta‐analytical models separated by cause and population groups to pool individual estimates. Impact measures were expressed as the attributable fractions among the exposed population, from the relative risks (RRs). Overall, a positive association between drought exposure and mortality was evidenced in the total population, with RRs varying from 1.003 [95% CI: 0.999–1.007] to 1.010 [0.996–1.025] for non‐external mortality related to moderate and extreme drought conditions, from 1.002 [0.997–1.007] to 1.008 [0.991–1.026] for circulatory mortality, and from 1.004 [0.995–1.013] to 1.013 [0.983–1.044] for respiratory mortality. Females, children, and the elderly population were the most affected groups, for whom a robust positive association was found. The study also revealed high heterogeneity between locations. We suggest that policies and action plans should pay special attention to vulnerable populations to promote efficient measures to reduce vulnerability and risks associated with droughts.
Forecasting GICs and Geoelectric Fields From Solar Wind Data Using LSTMs: Application in Austria
Authors: Bailey R. L. , Leonhardt R. , Möstl C. , Beggan C. , Reiss M. A. , Bhaskar A. , Weiss A. J.
Published: February 2022

The forecasting of local GIC effects has largely relied on the forecasting of dB/dt as a proxy and, to date, little attention has been paid to directly forecasting the geoelectric field or GICs themselves. We approach this problem with machine learning tools, specifically recurrent neural networks or LSTMs by taking solar wind observations as input and training the models to predict two different kinds of output: first, the geoelectric field components Ex and Ey; and second, the GICs in specific substations in Austria. The training is carried out on the geoelectric field and GICs modeled from 26 years of one‐minute geomagnetic field measurements, and results are compared to GIC measurements from recent years. The GICs are generally predicted better by an LSTM trained on values from a specific substation, but only a fraction of the largest GICs are correctly predicted. This model has a correlation with measurements of around 0.6, and a root‐mean‐square error of 0.7 A. The probability of detecting mild activity in GICs is around 50%, and 15% for larger GICs.
Interactions between nocturnal melatonin secretion, metabolism, and sleeping behavior in adolescents with obesity
Authors: Overberg Johanna , Kalveram Laura , Keller Theresa , Krude Heiko , Kühnen Peter , Wiegand Susanna
Published: February 2022

Background/objectives

Sleeping behavior and individual prospensity in sleep timing during a 24 h period, known as chronotypes, are underestimated factors, which may favor the development of obesity and metabolic diseases. Furthermore, melatonin is known to play an important role in circadian rhythm, but was also suggested to directly influence metabolism and bodyweight regulation. Since disturbed and shifted sleep rhythms have been observed in adolescents with obesity, this study aimed to investigate potential interactions between melatonin secretion, chronobiology, and metabolism. In addition, the influence of artificial light especially emitted by electronic devices on these parameters was of further interest.

Subjects/methods

We performed a cross-sectional study including 149 adolescents (mean age 14.7 ± 2.1 years) with obesity. Metabolic blood parameters (e.g., cholesterol, triglycerides, uric acid, and insulin) were obtained from patients and correlated with nocturnal melatonin secretion. Melatonin secretion was determined by measuring 6-sulfatoxymelatonin (MT6s), the major metabolite of melatonin in the first-morning urine, and normalized to urinary creatinine levels to account for the urinary concentration. Chronobiologic parameters were further assessed using theMunich ChronoType Questionnaire.

Results

Subjects with insulin resistance (n = 101) showed significantly lower nocturnal melatonin levels compared to those with unimpaired insulin secretion (p = 0.006). Furthermore, triglyceride (p = 0.012) and elevated uric acid levels (p = 0.029) showed significant associations with melatonin secretion. Patients with late chronotype showed a higher incidence of insulin resistance (p = 0.018). Moreover, late chronotype and social jetlag were associated with the time and duration of media consumption.

Conclusion

We identified an association of impaired energy metabolism and lower nocturnal melatonin secretion in addition to late chronotype and increased social jetlag (misalignment of biological and social clocks) in adolescents with obesity. This might point towards a crucial role of chronotype and melatonin secretion as risk factors for the development of pediatric and adolescent obesity.
Opioid-blunted cortisol response to stress is associated with increased negative mood and wanting of social reward
Authors: Massaccesi Claudia , Willeit Matthaeus , Quednow Boris B. , Nater Urs M. , Lamm Claus , Müller Daniel , Silani Giorgia
Published: February 2022

Animal research suggests a central role of the μ-opioid receptor (MOR) system in regulating affiliative behaviors and in mediating the stress-buffering function of social contact. However, the neurochemistry of stress-related social contact seeking in humans is still poorly understood. In a randomized, double-blind, between-subjects design, healthy female volunteers (N = 80) received either 10 mg of the µ-opioid agonist morphine sulfate, or a placebo. Following a standardized psychosocial stress induction, participants engaged in a social reward task, in which the motivation to obtain skin-to-skin social touch and the hedonic reactions elicited by such touch were assessed. Morphine prevented the increase of salivary cortisol typically observed following acute stress exposure. Notably, this altered HPA axis responsivity was associated with increased negative affect in response to psychosocial stress, and with enhanced subjective wanting of highly rewarding social contact. These findings provide novel evidence on the effect of exogenous opioids administration on the reactions to psychosocial stress and point to a state-dependent regulation of social motivation.
An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants
Authors: Chi Xiaojing , Zhang Xinhui , Pan Shengnan , Yu Yanying , Shi Yujin , Lin Tianli , Duan Huarui , Liu Xiuying , Chen Wenfang , Yang Xuehua , Chen Lan , Dong Xiaoqian , Ren Lili , Ding Qiang , Wang Jianwei , Yang Wei
Published: February 2022

The wide transmission and host adaptation of SARS-CoV-2 have led to the rapid accumulation of mutations, posing significant challenges to the effectiveness of vaccines and therapeutic antibodies. Although several neutralizing antibodies were authorized for emergency clinical use, convalescent patients derived natural antibodies are vulnerable to SARS-CoV-2 Spike mutation. Here, we describe the screen of a panel of SARS-CoV-2 receptor-binding domain (RBD) targeted nanobodies (Nbs) from a synthetic library and the design of a biparatopic Nb, named Nb1–Nb2, with tight affinity and super-wide neutralization breadth against multiple SARS-CoV-2 variants of concern. Deep-mutational scanning experiments identify the potential binding epitopes of the Nbs on the RBD and demonstrate that biparatopic Nb1–Nb2 has a strong escape-resistant feature against more than 60 tested RBD amino acid substitutions. Using pseudovirion-based and trans-complementation SARS-CoV-2 tools, we determine that the Nb1–Nb2 broadly neutralizes multiple SARS-CoV-2 variants at sub-nanomolar levels, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Kappa (B.1.617.1), and Mu (B.1.621). Furthermore, a heavy-chain antibody is constructed by fusing the human IgG1 Fc to Nb1–Nb2 (designated as Nb1–Nb2-Fc) to improve its neutralization potency, yield, stability, and potential half-life extension. For the new Omicron variant (B.1.1.529) that harbors unprecedented multiple RBD mutations, Nb1–Nb2-Fc keeps a firm affinity (KD < 1.0 × 10−12 M) and strong neutralizing activity (IC50 = 1.46 nM for authentic Omicron virus). Together, we developed a tetravalent biparatopic human heavy-chain antibody with ultrapotent and broad-spectrum SARS-CoV-2 neutralization activity which highlights the potential clinical applications.
The collagen receptor, discoidin domain receptor 2, functions in Gli1-positive skeletal progenitors and chondrocytes to control bone development
Authors: Mohamed Fatma F. , Ge Chunxi , Cowling Randy T. , Lucas Daniel , Hallett Shawn A. , Ono Noriaki , Binrayes Abdul-Aziz , Greenberg Barry , Franceschi Renny T.
Published: February 2022

Discoidin Domain Receptor 2 (DDR2) is a collagen-activated receptor kinase that, together with integrins, is required for cells to respond to the extracellular matrix. Ddr2 loss-of-function mutations in humans and mice cause severe defects in skeletal growth and development. However, the cellular functions of Ddr2 in bone are not understood. Expression and lineage analysis showed selective expression of Ddr2 at early stages of bone formation in the resting zone and proliferating chondrocytes and periosteum. Consistent with these findings, Ddr2+ cells could differentiate into hypertrophic chondrocytes, osteoblasts, and osteocytes and showed a high degree of colocalization with the skeletal progenitor marker, Gli1. A conditional deletion approach showed a requirement for Ddr2 in Gli1-positive skeletal progenitors and chondrocytes but not mature osteoblasts. Furthermore, Ddr2 knockout in limb bud chondroprogenitors or purified marrow-derived skeletal progenitors inhibited chondrogenic or osteogenic differentiation, respectively. This work establishes a cell-autonomous function for Ddr2 in skeletal progenitors and cartilage and emphasizes the critical role of this collagen receptor in bone development.
A diencephalic circuit in rats for opioid analgesia but not positive reinforcement
Authors: Waung Maggie W. , Maanum Kayla A. , Cirino Thomas J. , Driscoll Joseph R. , O’Brien Chris , Bryant Svetlana , Mansourian Kasra A. , Morales Marisela , Barker David J. , Margolis Elyssa B.
Published: February 2022

Mu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain.
A platform for oncogenomic reporting and interpretation
Authors: Reisle Caralyn , Williamson Laura M. , Pleasance Erin , Davies Anna , Pellegrini Brayden , Bleile Dustin W. , Mungall Karen L. , Chuah Eric , Jones Martin R. , Ma Yussanne , Lewis Eleanor , Beckie Isaac , Pham David , Matiello Pletz Raphael , Muhammadzadeh Amir , Pierce Brandon M. , Li Jacky , Stevenson Ross , Wong Hansen , Bailey Lance , Reisle Abbey , Douglas Matthew , Bonakdar Melika , Nelson Jessica M. T. , Grisdale Cameron J. , Krzywinski Martin , Fisic Ana , Mitchell Teresa , Renouf Daniel J. , Yip Stephen , Laskin Janessa , Marra Marco A. , Jones Steven J. M.
Published: February 2022

Manual interpretation of variants remains rate limiting in precision oncology. The increasing scale and complexity of molecular data generated from comprehensive sequencing of cancer samples requires advanced interpretative platforms as precision oncology expands beyond individual patients to entire populations. To address this unmet need, we introduce a Platform for Oncogenomic Reporting and Interpretation (PORI), comprising an analytic framework that facilitates the interpretation and reporting of somatic variants in cancer. PORI integrates reporting and graph knowledge base tools combined with support for manual curation at the reporting stage. PORI represents an open-source platform alternative to commercial reporting solutions suitable for comprehensive genomic data sets in precision oncology. We demonstrate the utility of PORI by matching 9,961 pan-cancer genome atlas tumours to the graph knowledge base, calculating therapeutically informative alterations, and making available reports describing select individual samples.
The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression
Authors: Geller Anne E. , Shrestha Rejeena , Woeste Matthew R. , Guo Haixun , Hu Xiaoling , Ding Chuanlin , Andreeva Kalina , Chariker Julia H. , Zhou Mingqian , Tieri David , Watson Corey T. , Mitchell Robert A. , Zhang Huang-ge , Li Yan , Martin II Robert C. G. , Rouchka Eric C. , Yan Jun
Published: February 2022

Despite the remarkable success of immunotherapy in many types of cancer, pancreatic ductal adenocarcinoma has yet to benefit. Innate immune cells are critical to anti-tumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Here we demonstrate that yeast-derived particulate β-glucan, an inducer of trained immunity, traffics to the pancreas, which causes a CCR2-dependent influx of monocytes/macrophages to the pancreas that display features of trained immunity. These cells can be activated upon exposure to tumor cells and tumor-derived factors, and show enhanced cytotoxicity against pancreatic tumor cells. In orthotopic models of pancreatic ductal adenocarcinoma, β-glucan treated mice show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with immunotherapy. These findings characterize the dynamic mechanisms and localization of peripheral trained immunity and identify an application of trained immunity to cancer.
Chemically Induced Chromosomal Interaction (CICI) method to study chromosome dynamics and its biological roles
Authors: Du Manyu , Zou Fan , Li Yi , Yan Yujie , Bai Lu
Published: February 2022

Numerous intra- and inter-chromosomal contacts have been mapped in eukaryotic genomes, but it remains challenging to link these 3D structures to their regulatory functions. To establish the causal relationships between chromosome conformation and genome functions, we  develop a method, Chemically Induced Chromosomal Interaction (CICI), to selectively perturb the chromosome conformation at targeted loci. Using this method, long-distance chromosomal interactions can be induced dynamically between intra- or inter-chromosomal loci pairs, including the ones with very low Hi-C contact frequencies. Measurement of CICI formation time allows us to probe chromosome encounter dynamics between different loci pairs across the cell cycle. We also conduct two functional tests of CICI. We perturb the chromosome conformation near a DNA double-strand break and observe altered donor preference in homologous recombination; we force interactions between early and late-firing DNA replication origins and find no significant changes in replication timing. These results suggest that chromosome conformation plays a deterministic role in homology-directed DNA repair, but not in the establishment of replication timing. Overall, our study demonstrates that CICI is a powerful tool to study chromosome dynamics and 3D genome function.
Neutralization against Omicron SARS-CoV-2 from previous non-Omicron infection
Authors: Zou Jing , Xia Hongjie , Xie Xuping , Kurhade Chaitanya , Machado Rafael R. G. , Weaver Scott C. , Ren Ping , Shi Pei-Yong
Published: February 2022

The spread of the Omicron SARS-CoV-2 variant underscores the importance of analyzing the cross-protection from previous non-Omicron infection. We have developed a high-throughput neutralization assay for Omicron SARS-CoV-2 by engineering the Omicron spike gene into an mNeonGreen USA-WA1/2020 SARS-CoV-2 (isolated in January 2020). Using this assay, we determine the neutralization titers (defined as the maximal serum dilution that inhibited 50% of infectious virus) of patient sera collected at 1- or 6-months after infection with non-Omicron SARS-CoV-2. From 1- to 6-month post-infection, the neutralization titers against USA-WA1/2020 decrease from 601 to 142 (a 4.2-fold reduction), while the neutralization titers against Omicron-spike SARS-CoV-2 remain low at 38 and 32, respectively. Thus, at 1- and 6-months after non-Omicron SARS-CoV-2 infection, the neutralization titers against Omicron are 15.8- and 4.4-fold lower than those against USA-WA1/2020, respectively. The low cross-neutralization against Omicron from previous non-Omicron infection supports vaccination of formerly infected individuals to mitigate the health impact of the ongoing Omicron surge.
Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA
Authors: Bergstrom Erik N. , Luebeck Jens , Petljak Mia , Khandekar Azhar , Barnes Mark , Zhang Tongwu , Steele Christopher D. , Pillay Nischalan , Landi Maria Teresa , Bafna Vineet , Mischel Paul S. , Harris Reuben S. , Alexandrov Ludmil B.
Published: February 2022

Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1–5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7–9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.
Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors
Authors: Kasaragod Vikram Babu , Mortensen Martin , Hardwick Steven W. , Wahid Ayla A. , Dorovykh Valentina , Chirgadze Dimitri Y. , Smart Trevor G. , Miller Paul S.
Published: February 2022

Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, β-, γ-, δ-, ε-, ρ-, θ- and π-subunits1. αβ, α4βδ, α6βδ and α5βγ receptors favour extrasynaptic localization, and mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain1,2. Mutations of these receptors in humans are linked to epilepsy and insomnia3,4. Altered extrasynaptic receptor function is implicated in insomnia, stroke and Angelman and Fragile X syndromes1,5, and drugs targeting these receptors are used to treat postpartum depression6. Tonic GABAergic responses are moderated to avoid excessive suppression of neuronal communication, and can exhibit high sensitivity to Zn2+ blockade, in contrast to synapse-preferring α1βγ, α2βγ and α3βγ receptor responses5,7–12. Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic αβ GABAA receptor class. An inhibited state bound by both the lethal paralysing agent α-cobratoxin13 and Zn2+ was used in comparisons with GABA–Zn2+ and GABA-bound structures. Zn2+ nullifies the GABA response by non-competitively plugging the extracellular end of the pore to block chloride conductance. In the absence of Zn2+, the GABA signalling response initially follows the canonical route until it reaches the pore. In contrast to synaptic GABAA receptors, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterizes the extrasynaptic receptor. Overall, this study explains distinct traits adopted by αβ receptors that adapt them to a role in tonic signalling.
Vaccine effectiveness of heterologous CoronaVac plus BNT162b2 in Brazil
Authors: Cerqueira-Silva Thiago , Katikireddi Srinivasa Vittal , de Araujo Oliveira Vinicius , Flores-Ortiz Renzo , Júnior Juracy Bertoldo , Paixão Enny S. , Robertson Chris , Penna Gerson O. , Werneck Guilherme L. , Barreto Maurício L. , Pearce Neil , Sheikh Aziz , Barral-Netto Manoel , Boaventura Viviane S.
Published: February 2022

There is considerable interest in the waning of effectiveness of coronavirus disease 2019 (COVID-19) vaccines and vaccine effectiveness (VE) of booster doses. Using linked national Brazilian databases, we undertook a test-negative design study involving almost 14 million people (~16 million tests) to estimate VE of CoronaVac over time and VE of BNT162b2 booster vaccination against RT–PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes (hospitalization or death). Compared with unvaccinated individuals, CoronaVac VE at 14–30 d after the second dose was 55.0% (95% confidence interval (CI): 54.3–55.7) against confirmed infection and 82.1% (95% CI: 81.4–82.8) against severe outcomes. VE decreased to 34.7% (95% CI: 33.1–36.2) against infection and 72.5% (95% CI: 70.9–74.0) against severe outcomes over 180 d after the second dose. A BNT162b2 booster, 6 months after the second dose of CoronaVac, improved VE against infection to 92.7% (95% CI: 91.0−94.0) and VE against severe outcomes to 97.3% (95% CI: 96.1−98.1) 14–30 d after the booster. Compared with younger age groups, individuals 80 years of age or older had lower protection after the second dose but similar protection after the booster. Our findings support a BNT162b2 booster vaccine dose after two doses of CoronaVac, particularly for the elderly.