bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Interventions and Outcomes in Civilian and Military Isolated Gunshot Wounds to the Head
Authors: Benjamin Elizabeth R. , Demetriades Demetrios , Owattanapanich Natthida , Shackelford Stacy A. , Roedel Erik , Polk Travis M. , Biswas Subarna , Rasmussen Todd
Published: July 2022

Objective:

The purpose of this study was to compare therapeutic strategies and outcomes, following isolated gunshot wounds of the head, between military and civilian populations.

Background:

Recent military conflicts introduced new concepts in trauma care, including aggressive surgical intervention in severe head trauma.

Methods:

This was a cohort-matched study, using the civilian Trauma Quality Improvement Program (TQIP) database of the American College of Surgeons (ACS) and the Department of Defense Trauma Registry (DoDTR), during the period 2013 to 2016. Included in the study were patients with isolated gunshots to the head. Exclusion criteria were dead on arrival, civilians transferred from other hospitals, and patients with major extracranial associated injuries (body area Abbreviated Injury Scale >3). Patients in the military database were propensity score–matched 1:3 with patients in the civilian database.

Results:

A total of 136 patients in the DoDTR database were matched for age, sex, year of injury, and head Abbreviated Injury Scale with 408 patients from TQIP. Utilization of blood products was significantly higher in the military population (P<0.001). In the military group, patients were significantly more likely to have intracranial pressure monitoring (17% vs 6%, P<0.001) and more likely to undergo craniotomy or craniectomy (34% vs 13%, P<0.001) than in the civilian group. Mortality in the military population was significantly lower (27% vs 38%, P=0.013).

Conclusions:

Military patients are more likely to receive blood products, have intracranial pressure monitoring and undergo craniectomy or craniotomy than their civilian counterparts after isolated head gunshot wounds. Mortality is significantly lower in the military population.

Level of Evidence:

Level III—therapeutic.
Operative and Nonoperative Outcomes of Emergency General Surgery Conditions
Authors: Kaufman Elinore J. , Keele Luke J. , Wirtalla Christopher J. , Rosen Claire B. , Roberts Sanford E. , Mavroudis Catherine L. , Reilly Patrick M. , Holena Daniel N. , McHugh Matthew D. , Small Dylan , Kelz Rachel R.
Published: July 2022

Objective:

To determine the effect of operative versus nonoperative management of emergency general surgery conditions on short-term and long-term outcomes.

Background:

Many emergency general surgery conditions can be managed either operatively or nonoperatively, but high-quality evidence to guide management decisions is scarce.

Methods:

We included 507,677 Medicare patients treated for an emergency general surgery condition between July 1, 2015, and June 30, 2018. Operative management was compared with nonoperative management using a preference-based instrumental variable analysis and near-far matching to minimize selection bias and unmeasured confounding. Outcomes were mortality, complications, and readmissions.

Results:

For hepatopancreaticobiliary conditions, operative management was associated with lower risk of mortality at 30 days [−2.6% (95% confidence interval: −4.0, −1.3)], 90 days [−4.7% (−6.50, −2.8)], and 180 days [−6.4% (−8.5, −4.2)]. Among 56,582 intestinal obstruction patients, operative management was associated with a higher risk of inpatient mortality [2.8% (0.7, 4.9)] but no significant difference thereafter. For upper gastrointestinal conditions, operative management was associated with a 9.7% higher risk of in-hospital mortality (6.4, 13.1), which increased over time. There was a 6.9% higher risk of inpatient mortality (3.6, 10.2) with operative management for colorectal conditions, which increased over time. For general abdominal conditions, operative management was associated with 12.2% increased risk of inpatient mortality (8.7, 15.8). This effect was attenuated at 30 days [8.5% (3.8, 13.2)] and nonsignificant thereafter.

Conclusions:

The effect of operative emergency general surgery management varied across conditions and over time. For colorectal and upper gastrointestinal conditions, outcomes are superior with nonoperative management, whereas surgery is favored for patients with hepatopancreaticobiliary conditions. For obstructions and general abdominal conditions, results were equivalent overall. These findings may support patients, clinicians, and families making these challenging decisions.
Cardiovascular disease risk in people with severe mental disorders: an update and call for action
Authors: Rødevand Linn , Tesli Martin , Andreassen Ole A.
Published: July 2022

Purpose of review

Cardiovascular disease (CVD) is a major cause of premature death in people with severe mental disorders (SMDs). This review provides an update on the level of CVD mortality and morbidity, as well as the socioeconomic, psychosocial and genetic factors associated with the comorbidity, and offer directions for improved interventions to reduce CVD in SMDs.

Recent findings

The level of CVD mortality and morbidity has sustained high in people with SMDs during the past decades, but the causal mechanism must be further elucidated. Psychosocial and socioeconomic challenges are frequent in SMDs as well as in CVD. Further, recent studies have revealed genetic variants jointly associated with SMDs, CVD risk and social factors. These findings highlight the need for more targeted interventions, prediction tools and psychosocial approaches to comorbid CVD in SMDs.

The level of CVD comorbidity remains high in SMDs, indicating that most people with SMDs have not benefitted from recent medical advances. A complex interplay between genetic and social vulnerability to CVD, which differs across subgroups of patients, seems to be involved. Further research is required to meet the urgent need for earlier, more efficient intervention approaches and preventive strategies for comorbid CVD in SMD.
Amisulpride steady-state plasma concentration and adverse reactions in patients with schizophrenia: a study based on therapeutic drug monitoring data
Authors: Qu Kankan , Zhou Qin , Tian Lin , Shen Yuan , Zhou Zhenhe
Published: July 2022

The aim of the study was to evaluate the reference range of amisulpride for Chinese patients with schizophrenia and to assess its possible influencing factors based on therapeutic drug monitoring information. The relative adverse reactions of patients induced by amisulpride were also systematically investigated. A total of 425 patients with schizophrenia were assessed, including Positive and Negative Syndrome Scales, Treatment Emergent Symptom Scale, blood routine examination, hepatorenal function, lipids, hormones, as well as myocardial enzymes at baseline, and following treatment with amisulpride for 8 weeks. The steady-state plasma concentration of amisulpride was assayed using two-dimensional liquid chromatography. At the same dose, the amisulpride plasma concentration of patients combined with clozapine was higher than that without clozapine. The therapeutic reference range of amisulpride can be defined as 230.3–527.1 ng/ml for Chinese patients with schizophrenia. The potential side effects appear to be associated with significantly increased levels of LDH, CK, creatine kinase isoenzyme (CK-MB), TC and decreased level of E2, relative to the amisulpride plasma concentration. These findings could provide individualized medication and reduce the adverse effects of amisulpride for Chinese patients with schizophrenia.
The cosmological constant problem and running vacuum in the expanding universe
Authors: Solà Peracaula Joan
Published: July 2022

It is well known that quantum field theory (QFT) induces a huge value of the cosmological constant (CC),

Λ

, which is outrageously inconsistent with cosmological observations. We review here some aspects of this fundamental theoretical conundrum (the cosmological constant problem, CCP) and strongly argue in favour of the possibility that the cosmic vacuum density

ρ

vac

may be mildly evolving with the expansion rate

H

. Such a ‘running vacuum model’ (RVM) proposal predicts an effective dynamical dark energy without postulating new ad hoc fields (quintessence and the like). Using the method of adiabatic renormalization within QFT in curved space–time, we find that

ρ

vac

(
H
)

acquires a dynamical component

O

(

H
2

)

caused by the quantum matter effects. There are also

O

(

H
n

)

(

n
=
4
,
6
,
…

) contributions, some of which may trigger inflation in the early universe. Remarkably, the evolution of the adiabatically renormalized

ρ

vac

(
H
)

is not affected by dangerous terms proportional to the quartic power of the masses (

∼

m
4

) of the quantized matter fields. Traditionally, these terms have been the main source of trouble as they are responsible for the extreme fine-tuning feature of the CCP. In the context under study, however, the late time

ρ

vac

(
H
)

around

H
0

is given by a dominant term (

ρ

vac

0

) plus the aforementioned mild dynamical component

∝
ν
(

H
2

−

H
0
2

)

(with

|

ν

|

≪
1

), which makes the RVM to mimic quintessence. Finally, on the phenomenological side, we show that the RVM may be instrumental in alleviating some of the most challenging problems (so-called ‘tensions’) afflicting nowadays the observational consistency of the ‘concordance’

Λ

CDM model, such as the

H
0

and

σ
8

tensions.

This article is part of the theme issue ‘The future of mathematical cosmology, Volume 2’.
The autism-associated Neuroligin-3 R451C mutation alters mucus density and the spatial distribution of bacteria in the mouse gastrointestinal tract
Authors: Herath Madushani , Bornstein Joel C , Hill-Yardin Elisa L , Franks Ashley E
Published: July 2022

The intestinal mucus layer protects the host from invading pathogens and is essential for maintaining a healthy mucosal microbial community. Alterations in the mucus layer and composition of mucus-residing microbiota in people diagnosed with Autism Spectrum Disorder (ASD; autism) may contribute to dysbiosis and gastrointestinal (GI) dysfunction. Although microbial dysbiosis based on sequencing data is frequently reported in autism, spatial profiling of microbes adjacent to the mucosa is needed to identify changes in bacterial subtypes in close contact with host tissues. Here, we analysed the spatial distribution of the MUC-2 protein using immunofluorescence as well as total bacteria, Bacteroidetes, Firmicutes phyla and Akkermansia muciniphila (A. muciniphila) using fluorescent in situ hybridization in mice expressing the autism-associated R451C mutation in the Neuroligin-3 (Nlgn3) gene. We show that the Nlgn3 R451C mutation increases mucus density adjacent to the distal ileal epithelium in mice. The relative density of total bacteria, Firmicutes and A. muciniphila was increased whereas the density of Bacteroidetes was decreased closer to the epithelium in Nlgn3R451C mice. In summary, this study suggests that increased mucus density could contribute to mucosal microbial dysbiosis in ASD.
Rodent perirhinal cortex, but not ventral hippocampus, inhibition induces approach bias under object-based approach-avoidance conflict
Authors: Dhawan Sandeep S. , Pinter Carl , Lee Andy C. H. , Ito Rutsuko
Published: July 2022

Neural models of approach-avoidance (AA) conflict behavior and its dysfunction have focused traditionally on the hippocampus, with the assumption that this medial temporal lobe (MTL) structure plays a ubiquitous role in arbitrating AA conflict. We challenge this perspective by using three different AA behavioural tasks in conjunction with optogenetics, to demonstrate that a neighbouring region in rats, perirhinal cortex, is also critically involved but only when conflicting motivational values are associated with objects and not contextual information. The ventral hippocampus, in contrast, was found not to be essential for object-associated AA conflict, suggesting its preferential involvement in context-associated conflict. We propose that stimulus type can impact MTL involvement during AA conflict and that a more nuanced understanding of MTL contributions to impaired AA behaviour (e.g., anxiety) is required. These findings serve to expand upon the established functions of the perirhinal cortex while concurrently presenting innovative behavioural paradigms that permit the assessment of different facets of AA conflict behaviour.
Benchmarking freely available human leukocyte antigen typing algorithms across varying genes, coverages and typing resolutions
Authors: Thuesen Nikolas Hallberg , Klausen Michael Shantz , Gopalakrishnan Shyam , Trolle Thomas , Renaud Gabriel
Published: July 2022

The human leukocyte antigen (HLA) system is a group of genes coding for proteins that are central to the adaptive immune system and identifying the specific HLA allele combination of a patient is relevant in organ donation, risk assessment of autoimmune and infectious diseases and cancer immunotherapy. However, due to the high genetic polymorphism in this region, HLA typing requires specialized methods.

We investigated the performance of five next-generation-sequencing (NGS) based HLA typing tools with a non-restricted license namely HLA*LA, Optitype, HISAT-genotype, Kourami and STC-Seq. This evaluation was done for the five HLA loci, HLA-A, -B, -C, -DRB1 and -DQB1 using whole-exome sequencing (WES) samples from 829 individuals. The robustness of the tools to lower coverage was evaluated by subsampling and HLA typing 230 WES samples at coverages ranging from 1X to 100X. The typing accuracy was measured across four typing resolutions. Among these, we present two clinically-relevant typing resolutions, which specifically focus on the peptide binding region.

On average, across the five HLA genes, HLA*LA was found to have the highest typing accuracy. For the individual genes, HLA-A, -B and -C, Optitype’s typing accuracy was highest and HLA*LA had the highest typing accuracy for HLA-DRB1 and -DQB1.

The tools’ robustness to lower coverage data varied widely and further depended on the specific HLA locus. For all class I loci, Optitype had a typing accuracy above 95% (according to the modification of the amino acids in the functionally relevant portion of the protein) at 50X, but increasing the depth of coverage beyond even 100X could still improve the typing accuracy of HISAT-genotype, Kourami, and STC-seq across all five HLA genes as well as HLA*LA’s typing accuracy for HLA-DQB1. HLA typing is also used in studies of ancient DNA (aDNA), which often is based on lower quality sequencing data. Interestingly, we found that Optitype’s typing accuracy is not notably impaired by short read length or by DNA damage, which is typical of aDNA, as long as the depth of coverage is sufficiently high.
Sensitivity of bipartite network analyses to incomplete sampling and taxonomic uncertainty
Authors: Llopis-Belenguer Cristina , Balbuena Juan Antonio , Blasco-Costa Isabel , Karvonen Anssi , Sarabeev Volodimir , Jokela Jukka
Published: July 2022

Bipartite network analysis is a powerful tool to study the processes structuring interactions in antagonistic ecological communities. In applying the method, we assume that the sampled interactions provide an accurate representation of the actual community. However, acquiring a representative sample may be difficult as not all species are equally abundant or easily identifiable. Two potential sampling issues can compromise the conclusions of bipartite network analyses: failure to capture the full range of interactions of species (sampling completeness) and failure to identify species correctly (taxonomic resolution). These sampling issues are likely to co-occur in community ecology studies. We asked how commonly used descriptors (modularity, nestedness, connectance and specialisation (H2′)) of bipartite communities are affected by reduced host sampling completeness, parasite taxonomic resolution and their crossed effect. We used a quantitative niche model to generate replicates of simulated weighted bipartite networks that resembled natural host-parasite communities. The combination of both sampling issues had an additive effect on modularity and nestedness. The descriptors were more sensitive to uncertainty in parasite taxonomic resolution than to host sampling completeness. All descriptors in communities capturing less than 70% of correct taxonomic resolution strongly differed from correctly identified communities. When only 10% of parasite taxonomic resolution was retained, modularity and specialisation decreased ∼0.3 and ∼0.1-fold respectively, and nestedness and connectance changed ∼0.7 and ∼3.2-fold respectively. The loss of taxonomic resolution made the confidence intervals of estimates wider. Reduced taxonomic resolution led to smaller size of the communities, which emphasised the larger relative effect of taxonomic resolution on smaller communities. With regards to host sampling completeness, connectance and specialisation were robust, nestedness was reasonably robust (∼0.2-fold overestimation), and modularity was sensitive (∼0.5-fold underestimation). Nonetheless, most of the communities with low resolution for both sampling issues were structurally equivalent to correctly sampled communities (i.e., more modular and less nested than random assemblages). Therefore, modularity and nestedness were useful as categorical rather than quantitative descriptors of communities affected by sampling issues. We recommend evaluating both sampling completeness and taxonomic certainty when conducting bipartite network analyses. We also advise to apply the most robust descriptors in circumstances of unavoidable sampling issues.

Open Research statement

we provide permanent and open access links to data sources and replication code in Appendix S1.
Individual reflectance of solar radiation confers a thermoregulatory benefit to dimorphic males bees (Centris pallida) using distinct microclimates
Authors: Barrett Meghan , O’Donnell Sean
Published: July 2022

Incoming solar radiation (wavelengths 290 – 2500 nm) significantly affects an organism’s thermal balance via radiative heat gain. Species adapted to different environments can differ in solar reflectance profiles. We hypothesized that conspecific individuals using thermally distinct microhabitats to engage in fitness-relevant behaviors would show intraspecific differences in reflectance: we predicted individuals that use hot microclimates (where radiative heat gain represents a greater thermoregulatory challenge) would be more reflective across the entire solar spectrum than those using cooler microclimates. Differences in near-infrared (NIR) reflectance (700 - 2500 nm) are strongly indicative of thermoregulatory adaptation as, unlike differences in visible reflectance (400 - 700 nm), they are not perceived by ecological or social partners. We tested these predictions in maleCentris pallida(Hymenoptera: Apidae) bees from the Sonoran Desert. MaleC. pallidause alternative reproductive tactics that are associated with distinct microclimates: Large-morph males, with paler visible coloration, behave in an extremely hot microclimate close to the ground, while small-morph males, with a dark brown dorsal coloration, frequently use cooler microclimates above the ground near vegetation. We found that large-morph males had higher reflectance of solar radiation (UV through NIR) resulting in lower solar absorption coefficients. This thermoregulatory adaptation was specific to the dorsal surface, and produced by differences in hair, not cuticle, characteristics. Our results showed that intraspecific variation in behavior, particular in relation to microclimate use, can generate unique thermal adaptations that changes the reflectance of shortwave radiation among individuals within the same population.
Assessing jugular venous compliance with optical hemodynamic imaging by modulating intrathoracic pressure
Authors: Amelard Robert , Flannigan Nyan , Patterson Courtney A , Heigold Hannah , Hughson Richard L , Robertson Andrew D
Published: July 2022

Significance

The internal jugular veins are critical cerebral venous drainage pathways that are affected by right heart function. Cardiovascular disease and microgravity can alter central venous pressure (CVP) and venous return, which may contribute to increased intracranial pressure and decreased cardiac output. Assessing jugular venous compliance may provide insight into cerebral drainage and right heart function, but monitoring changes in vessel volume is challenging.

Aim

We investigated the feasibility of quantifying jugular venous compliance from jugular venous attenuation (JVA), a non-contact optical measurement of blood volume, alongside CVP from antecubital vein cannulation.

Approach

CVP was progressively increased through a guided graded Valsalva maneuver, increasing mouth pressure by 2 mmHg every 2 s until a maximum expiratory pressure of 20 mmHg. JVA was extracted from a 1 cm segment between the clavicle and mid-neck. Contralateral internal jugular vein cross-sectional area (CSA) was measured with ultrasound to validate changes in vessel size. Compliance was calculated using both JVA and CSA between four-beat averages over the duration of the maneuver.

Results

JVA and CSA were strongly correlated (median, interquartile range) over the Valsalva maneuver across participants (r=0.986, [0.983, 0.987]). CVP more than doubled on average between baseline and peak strain (10.7 ± 4.4 vs 25.8 ± 5.4 cmH2O; p<.01). JVA and CSA increased non-linearly with CVP, and both JVA- and CSA-derived compliance decreased progressively from baseline to peak strain (49% and 56% median reduction, respectively), with no significant difference in compliance reduction between the two measures (Z=–1.24, p=.21). Pressure-volume curves showed a logarithmic relationship in both CSA and JVA.

Conclusions

Optical jugular vein assessment may provide new ways to assess jugular distention and cardiac function.
Endosymbiont strategic shifts inhibit cooperation during coral bleaching recovery
Authors: Allen-Waller Luella , Barott Katie L.
Published: July 2022

The future of coral reefs in a warming world depends on corals’ ability to resist or recover from losing their photosynthetic algal endosymbionts (coral bleaching) during marine heatwaves. Heat-tolerant algal species can confer bleaching resistance by remaining in symbiosis during heat stress but tend to provide less photosynthate to the host than heat-sensitive species. Understanding this potential nutritional tradeoff is crucial for predicting coral success under climate change, but the energetic dynamics of corals hosting different algal species during bleaching recovery are poorly understood. To test how algal energetics affects coral recovery, we heat-stressed corals (Montipora capitata) hosting either heat-sensitive Cladocopium sp. or heat-tolerant Durusdinium glynni algae for two weeks, followed by a one-month recovery period. We found that while thermotolerant D. glynni regained density and photochemical efficiency faster after bleaching than Cladocopium, this algal recovery did not correspond with host physiological recovery, and D. glynni populations still contributed less photosynthate to the host relative to Cladocopium. Further, high-density algal populations of both species translocated a smaller proportion of their photosynthate than low-density populations, and corals receiving less photosynthate suffered reduced calcification rates and lower intracellular pH. This is the first evidence of a direct negative relationship between symbiont population size and ‘selfishness,’ and the first to establish a connection between Symbiodiniaceae carbon translocation and coral cellular homeostasis. Together, these results suggest that algal energy reallocation towards regrowth after bleaching can harm coral physiology, and that reestablishing a beneficial endosymbiosis can pose a secondary challenge for holobionts surviving stress.
Text mining and portal development for gene-specific publications on Alzheimer’s disease and other neurodegenerative diseases
Authors: Liu Jiannan , Wu Huanmei , Robertson Daniel H. , Zhang Jie
Published: July 2022

Background

Tremendous research efforts have been made in the Alzheimer’s disease (AD) field to understand the disease etiology, progression and discover treatments for AD. Many mechanistic hypotheses, therapeutic targets and treatment strategies have been proposed in the last few decades. Reviewing previous work and staying current on this ever-growing body of AD publications is an essential yet difficult task for AD researchers.

Methods

In this study, we designed and implemented a natural language processing (NLP) pipeline to extract gene-specific neurodegenerative disease (ND) -focused information from the PubMed database. The collected publication information was filtered and cleaned to construct AD-related gene-specific publication profiles. Six categories of AD-related information are extracted from the processed publication data: publication trend by year, dementia type occurrence, brain region occurrence, mouse model information, keywords occurrence, and co-occurring genes. A user-friendly web portal is then developed using Django framework to provide gene query functions and data visualizations for the generalized and summarized publication information.

Results

By implementing the NLP pipeline, we extracted gene-specific ND-related publication information from the abstracts of the publications in the PubMed database. The results are summarized and visualized through an interactive web query portal. Multiple visualization windows display the ND publication trends, mouse models used, dementia types, involved brain regions, keywords to major AD-related biological processes, and co-occurring genes. Direct links to PubMed sites are provided for all recorded publications on the query result page of the web portal.

Conclusion

The resulting portal is a valuable tool and data source for quick querying and displaying AD publications tailored to users’ interested research areas and gene targets, which is especially convenient for users without informatic mining skills. Our study will not only keep AD field researchers updated with the progress of AD research, assist them in conducting preliminary examinations efficiently, but also offers additional support for hypothesis generation and validation which will contribute significantly to the communication, dissimilation and progress of AD research.
GLT8D1 mutations cause amyotrophic lateral sclerosis via disruption of neurotrophin signalling within membrane lipid rafts
Authors: Moll Tobias , Graves Emily , Urbanek Agnieszka , Soni Nikita , Ranganathan Ramya , Higginbottom Adrian , Wang Shanshan , Head Brian P , Cooper-Knock Johnathan , Shaw Pamela J
Published: July 2022

Mutations within GLT8D1 contribute to familial amyotrophic lateral sclerosis. Pathogenic mutations impair GLT8D1 glycosyltransferase enzymatic function via a dominant negative mechanism, yet the downstream mechanism leading to neurotoxicity is unclear. Here we show that a p.R92C mutation causes fragmentation of the Golgi network and reduces ganglioside expression within membrane lipid rafts (MLRs), leading to impaired neurotrophin signalling. Expression of p.R92C-GLT8D1 in HEK293 cells and mouse primary neurons reduces expression of GM1 gangliosides within the cell plasma membrane leading to disruption of MLRs. Furthermore, p.R92C-GLT8D1 reduces TrkB-mediated pro-survival signalling in MLRs isolated from primary neurons. Interestingly, up-regulation of wild-type GLT8D1 enhances MLRs and promotes pro-survival signalling through TrkB. This closely mirrors findings for another ALS gene, CAV1, suggesting convergence on a common pathogenic pathway. Other ALS genes have been associated with Golgi dysfunction and may disrupt the same pathway, suggesting a potential new therapeutic approach via upregulation of GLT8D1.

Graphical Abstract
Microwell-Based Flow Culture Increases Viability and Restores Drug Response in Prostate Cancer Spheroids
Authors: Payne Marie C. , Ho Sum Yat , Hashimoto Takao , Imboden Sara , Diaz Johnny A. , Lee Brandon S. , Rupert Melissa J. , Cai Nathan Y. , Goldstein Andrew S. , Lin Neil Y.C.
Published: July 2022

3D cancer spheroids represent a highly promising model for study of cancer progression and therapeutic development. Wide-scale adoption of cancer spheroids, however, remains a challenge due to the lack of control over hypoxic gradients that may cloud the assessment of cell morphology and drug response. Here, we present a Microwell Flow Device (MFD) that generates in-well laminar flow around 3D tissues via repetitive tissue sedimentation. Using a prostate cancer cell line, we demonstrate the spheroids in the MFD exhibit improved cell growth, reduced necrotic core formation, enhanced structural integrity, and down-regulated expression of cell stress genes. The flow-cultured spheroids also exhibit an improved sensitivity to chemotherapy with greater transcriptional response. These results demonstrate how fluidic stimuli reveal the cellular phenotype previously masked by severe necrosis. Our platform advances 3D cellular models and enables study into hypoxia modulation, cancer metabolism, and drug screening within pathophysiological conditions.
BinaRena: a dedicated interactive platform for human-guided exploration and binning of metagenomes
Authors: Pavia Michael J. , Chede Abhinav , Wu Zijun , Cadillo-Quiroz Hinsby , Zhu Qiyun
Published: July 2022

Exploring metagenomic contigs and “binning” them are essential for delineating functional and evolutionary guilds within microbial communities. Despite available automated binners, researchers often find human involvement necessary to achieve representative results. We present BinaRena, an interactive graphic interface dedicated to aiding human operators to explore contigs via customizable visualization and to associate them with bins based on various data types, including sequence metrics, coverage profiles, taxonomic assignments and functional annotations. Binning plans can be edited, inspected and compared visually or using algorithms. Completeness and redundancy of user-selected contigs can be calculated real-time. We show that BinaRena facilitated biological pattern discovery, hypothesis generation and bin refinement in a tropical peatland metagenome. It enabled isolation of pathogenic genomes within closely-related populations from human gut samples. It significantly improved overall binning quality after curation using a simulated marine dataset. BinaRena is an installation-free, client-end web application for researchers of all levels.
Was fishing village of Lepenski Vir built by Europe’s first farmers?
Authors: Brami Maxime , Winkelbach Laura , Schulz Ilektra , Schreiber Mona , Blöcher Jens , Diekmann Yoan , Burger Joachim
Published: July 2022

Today, it is widely accepted that agriculture and settled village life arrived in Europe as a cultural package, carried by people migrating from Anatolia and the Aegean Basin. The putative fisher-forager site of Lepenski Vir in Serbia has long been acknowledged as an exception to this model. Here, the Mesolithic-Neolithic transition - possibly inspired by interaction with the new arrivals - was thought to have taken place autochthonously on site. Our reinterpretation, based on ancient genomes, as well as archaeological and isotopic evidence, revisits this conclusion, indicating that here too, house construction, early village society and agriculture were primarily associated with Europe’s first farmers, thus challenging the long-held interpretation of Lepenski Vir as a Mesolithic community that adopted Neolithic practices. A detailed timeline of population changes at the site suggests that Aegean incomers did not simply integrate into an established Mesolithic society, rather founded new lineages and households. Iron Gates foragers and their admixed descendants appear to have been buried largely separately, on the fringes of the settlement, their diet showing no major shift from aquatic to terrestrial food resources.
Accelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection
Authors: Chaguza Chrispin , Hahn Anne M. , Petrone Mary E. , Zhou Shuntai , Ferguson David , Breban Mallery I. , Pham Kien , Peña-Hernández Mario A. , Castaldi Christopher , Hill Verity ,   Yale SARS-CoV-2 Genomic Surveillance Initiative, Schulz Wade , Swanstrom Ronald I. , Roberts Scott C. , Grubaugh Nathan D.
Published: July 2022

The chronic infection hypothesis for novel SARS-CoV-2 variant emergence is increasingly gaining credence following the appearance of Omicron. Here we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral loads. During the infection, we found an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately two-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution led to the emergence and persistence of at least three genetically distinct genotypes suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, using unique molecular indexes for accurate intrahost viral sequencing, we tracked the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, ultimately providing opportunity for the emergence of genetically divergent and potentially highly transmissible variants as seen with Delta and Omicron.
Interpretable Radiomics Method for Predicting Human Papillomavirus Status in Oropharyngeal Cancer using Bayesian Networks
Authors: Altinok Oya , Guvenis Albert
Published: July 2022

Objectives

To develop a simple interpretable Bayesian Network (BN) to classify HPV status in patients with oropharyngeal cancer.

Methods

Two hundred forty-six patients, 216 of whom were HPV positive, were used in this study. We extracted 851 radiomics markers from patients’ contrast-enhanced Computed Tomography (CT) images. Mens eX Machina (MXM) approach selected two most relevant predictors: sphericity and max2DDiameterRow. The area under the curve (AUC) demonstrated BN model performance in 30% of the data reserved for testing. A Support Vector Machine (SVM) based method was also implemented for comparison purposes.

Results

The Mens eX Machina (MXM) approach selected two most relevant predictors: sphericity and max2DDiameterRow. Areas under the Curves (AUC) were found 0.78 and 0.72 on the training and test data, respectively. When using support vector machine (SVM) and 25 features, the AUC was found 0.83 on the test data.

Conclusions

The straightforward structure and power of interpretability of our BN model will help clinicians make treatment decisions and enable the non-invasive detection of HPV status from contrast-enhanced CT images. Higher accuracy can be obtained using more complex structures at the expense of lower interpretability.

Advances in Knowledge

Determination of HPV status can be done by invasive laboratory techniques, which poses a potential risk to patients. Radiomics-based methods are non-invasive but are usually difficult to use because they are generally not interpretable. Therefore, there is a growing need to develop a non-invasive radiomics method that is simple and interpretable. This work accomplishes this objective while pointing out the limitations.
Modelling the contributions to hyperexcitability in a mouse model of Alzheimer’s disease
Authors: Mittag Martin , Mediavilla Laura , Remy Stefan , Cuntz Hermann , Jedlicka Peter
Published: July 2022

Neuronal hyperexcitability is a feature of Alzheimer’s disease (AD). Three main mechanisms have been proposed to explain it: i), dendritic degeneration leading to increased input resistance, ii), ion channel changes leading to enhanced intrinsic excitability, and iii), synaptic changes leading to excitation-inhibition (E/I) imbalance. However, the relative contribution of these mechanisms is not fully understood. Therefore, we performed biophysically realistic multi-compartmental modelling of excitability in reconstructed CA1 pyramidal neurons of wild-type and APP/PS1 mice, a well-established animal model of AD. We show that, for synaptic activation, the excitability promoting effects of dendritic degeneration are cancelled out by excitability decreasing effects of synaptic loss. We find an interesting balance of excitability regulation with enhanced degeneration in the basal dendrites of APP/PS1 cells potentially leading to increased excitation by the apical but decreased excitation by the basal Schaffer collateral pathway. Furthermore, our simulations reveal that three additional pathomechanistic scenarios can account for the experimentally observed increase in firing and bursting of CA1 pyramidal neurons in APP/PS1 mice. Scenario 1: increased excitatory burst input; scenario 2: enhanced E/I ratio and scenario 3: alteration of intrinsic ion channels (IAHP down-regulated; INap, INa and ICaT up-regulated) in addition to enhanced E/I ratio. Our work supports the hypothesis that pathological network and ion channel changes are major contributors to neuronal hyperexcitability in AD. Overall, our results are in line with the concept of multi-causality and degeneracy according to which multiple different disruptions are separately sufficient but no single disruption is necessary for neuronal hyperexcitability.

In brief

Using a computational model, we find that changes in the extrinsic network and intrinsic biophysical neuronal properties rather than dendritic degeneration alone explain the altered firing behaviour observed in Alzheimer’s disease (AD).

Highlights

Simulations of synaptically driven responses in PCs with AD-related dendritic degeneration.

Dendritic degeneration alone alters PC responses to layer-specific input but additional pathomechanistic scenarios are required to explain neuronal hyperexcitability in AD.

Possible scenario 1: Burst hyperactivity of the surrounding network can explain hyper-excitability of PCs during AD.

Possible scenario 2: AD-related increased excitatory input together with decreased inhibitory input (E/I imbalance) can lead to hyperexcitability in PCs.

Possible scenario 3: Changes in E/I balance combined with altered ion channel properties can account for hyperexcitability in AD.
Loss of MYB34 transcription factor that controls feedback loop in indole glucosinolate biosynthesis supports backward evolution of this pathway within Camelineae tribe
Authors: Czerniawski Paweł , Piślewska-Bednarek Mariola , Piasecka Anna , Kułak Karolina , Bednarek Paweł
Published: July 2022

Glucosinolates are specialized defensive metabolites characteristic for the Brassicales order. Among them aliphatic and indolic glucosinolates (IGs) are usually highly abundant in the species from Brassicaceae family. The exception from this trend is constituted by species representing a subclade of Camelineae tribe, including Capsella and Camelina genera, which have reduced capacity to produce and metabolize IGs. Our study addresses contribution of specific glucosinolate-related MYB transcription factors to this unprecedented backward evolution of IG biosynthesis. To this end we performed phylogenomic and functional studies of respective MYB proteins. Obtained results revealed weakened conservation of glucosinolate-related MYB transcription factors, including loss of functional MYB34 protein, in the investigated species. We showed that introduction of functional MYB34 from Arabidopsis thaliana partially restores IG biosynthesis in Capsella rubella indicating that loss of this transcription factor contributes to the backward evolution of this metabolic pathway. Finally, we performed analysis of the impact of particular myb mutations on the feedback loop in IG biosynthesis, which drives auxin overproduction, metabolic dysregulation and strong growth retardation caused by mutations in IG biosynthetic genes. This uncovered unique function of MYB34 among IG-related MYBs in this feedback regulation and consequently in IG conservation in Brassicaceae plants.
Comparing the speed of action initiation and action inhibition
Authors: Du Yue , Forrence Alexander D. , Metcalf Delaney M. , Haith Adrian M.
Published: July 2022

Much work has examined the process of canceling or inhibiting an impending action. However, the converse process of initiating a movement has, comparatively, been much less studied. Action initiation and action inhibition are generally considered to be independent and qualitatively distinct processes, while the exact relationship between these processes remains unclear. One respect in which action initiation and action inhibition are often thought to differ is in their speed; action inhibition is typically considered to be faster than action initiation, which allows for impending actions to be inhibited before they are initiated. This apparent contrast is, however, largely observed in tasks in which there is much greater urgency to inhibit an action that there is to initiate an action. This asymmetry in the urgency between action initiation and action inhibition, as well as other asymmetries in how action initiation and inhibition are cued, make it impossible to compare their relative time courses. Here, we demonstrate that, when action initiation and action inhibition are measured under conditions that are matched as closely as possible, their speed is the same. In light of this, we suggest that action initiation and action inhibition may not necessarily be qualitatively distinct processes, but may instead reflect two opposing states of a single process supporting a decision about whether to act or not. This perspective carries significant implications for computational models and presumed neural mechanisms of action control.
The impact of ants and vertebrate predators on arthropods and plants: a meta-analysis
Authors: Sam Katerina , Tahadlova Marketa , Freiberga Inga , Mrazova Anna , Toszogyova Anna , Sreekar Rachakonda
Published: July 2022

The trophic interactions between plants, insect herbivores and their predators are complex and prone to trophic cascades. Theory predicts that predators increase plant biomass by feeding on herbivores. However, it remains unclear whether different types of predators regulate herbivores to the same degree, and how intraguild predation impacts these trophic interactions. Specifically, we lack a more comprehensive look at the effects of various groups of predators on a global scale. Here we report a meta-analysis of 486 experiments gathered from 157 publications reporting the effect of insectivorous vertebrates (birds and bats) and ants on abundances of predatory (spiders, ants, others) and herbivorous (chewers and others) arthropods; on arthropod richness and plant damage. Generally, the absence of vertebrate predators led to the increase of predatory arthropods by 18%, herbivorous arthropods by 75%, and plant damage by 47%. In contrast, after the removal of ants, the increase in the abundances of other predatory arthropods did not compensate for missing ants, herbivore arthropods increased their abundances by 53%, and plant damage increased by 146%. The effects of ant exclosures were stronger in communities at lower elevations and latitudes, while we did not detect any clear geographical patterns in the effect of vertebrate exclosures. Neither precipitation nor NDVI had a significant impact on most of the measured effects, and the effect of exclosures was robust for both plant growth forms and different habitat types. We found vertebrate insectivores to be the more dominant predators of arthropods, but we detected that the strength of their trophic cascades was weakened by intraguild predation. On the other hand, we found that although ants were relatively less dominant as predators, and their influence was detectable only in the most productive sites, the effect of trophic cascades on plants they caused was stronger than that of vertebrate insectivores.
OSCAR: Optimal subset cardinality regression using the L0-pseudonorm with applications to prognostic modelling of prostate cancer
Authors: Halkola Anni S. , Joki Kaisa , Mirtti Tuomas , Mäkelä Marko M. , Aittokallio Tero , Laajala Teemu D.
Published: July 2022

In many real-world applications, such as those based on patient electronic health records, prognostic prediction of patient survival is based on heterogeneous sets of clinical laboratory measurements. To address the trade-off between the predictive accuracy of a prognostic model and the costs related to its clinical implementation, we propose an optimized L0-pseudonorm approach to learn sparse solutions in multivariable regression. The model sparsity is maintained by restricting the number of nonzero coefficients in the model with a cardinality constraint, which makes the optimization problem NP-hard. In addition, we generalize the cardinality constraint for grouped feature selection, hence making it possible to identify key sets of predictors that may be measured together in a kit in clinical practice. We demonstrate the operation of our cardinality constraint-based feature subset selection method, named OSCAR, in the context of prognostic modelling of prostate cancer, where it enabled one to determine the key explanatory predictors at different levels of model sparsity, and to explore how the model sparsity affects the model accuracy and implementation cost.

Author summary

Feature selection has become a crucial part in building biomedical models, due to the abundance of available predictors in many applications, yet there remains an uncertainty of their importance and generalization ability. Regularized regression methods have become popular approaches to tackle this challenge by balancing the model goodness-of-fit against the increasing complexity of the model in terms of coefficients that deviate from zero. Regularization norms are pivotal in formulating the model complexity, and currently L1 (LASSO), L2 (Ridge Regression) and their hybrid (Elastic Net) norms dominate the field. In this paper, we present a novel methodology using the L0-pseudonorm, also known as the best subset selection, which has largely gone overlooked due to its challenging discrete nature. Our methodology makes use of a continuous transformation of the discrete optimization problem, and provides effective solvers implemented in a user friendly R software package. We exemplify the use of oscar-package in the context of prostate cancer prognostic prediction using both real-world hospital registry and clinical cohort data. By benchmarking the methodology against related regularization methods, we illustrate the advantages of the L0-pseudonorm for better clinical applicability and selection of grouped features.