bluuebunny/crossref_metadata_2025 huggingface dataset:
A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function
Authors: Meister Toni Luise , Brüggemann Yannick , Nocke Maximilian K. , Ulrich Rainer G. , Schuhenn Jonas , Sutter Kathrin , Gömer André , Bader Verian , Winklhofer Konstanze F. , Broering Ruth , Verhoye Lieven , Meuleman Philip , Vondran Florian W. R. , Camuzet Charline , Cocquerel Laurence , Todt Daniel , Steinmann Eike
Published: August 2022

Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and is the leading cause of enterically transmitted viral hepatitis worldwide. Ribavirin (RBV) is currently the only treatment option for many patients; however, cases of treatment failures or posttreatment relapses have been frequently reported. RBV therapy was shown to be associated with an increase in HEV genome heterogeneity and the emergence of distinct HEV variants. In this study, we analyzed the impact of eight patient-derived open reading frame 2 (ORF2) single-nucleotide variants (SNVs), which occurred under RBV treatment, on the replication cycle and pathogenesis of HEV. The parental HEV strain and seven ORF2 variants showed comparable levels of RNA replication in human hepatoma cells and primary human hepatocytes. However, a P79S ORF2 variant demonstrated reduced RNA copy numbers released in the supernatant and an impairment in the production of infectious particles. Biophysical and biochemical characterization revealed that this SNV caused defective, smaller HEV particles with a loss of infectiousness. Furthermore, the P79S variant displayed an altered subcellular distribution of the ORF2 protein and was able to interfere with antibody-mediated neutralization of HEV in a competition assay. In conclusion, an SNV in the HEV ORF2 could be identified that resulted in altered virus particles that were noninfectious in vitro and in vivo, but could potentially serve as immune decoys. These findings provide insights in understanding the biology of circulating HEV variants and may guide development of personalized antiviral strategies in the future.
Chromatin structure undergoes global and local reorganization during murine dendritic cell development and activation
Authors: Kurotaki Daisuke , Kikuchi Kenta , Cui Kairong , Kawase Wataru , Saeki Keita , Fukumoto Junpei , Nishiyama Akira , Nagamune Kisaburo , Zhao Keji , Ozato Keiko , Rocha Pedro P. , Tamura Tomohiko
Published: August 2022

Classical dendritic cells (cDCs) are essential for immune responses and differentiate from hematopoietic stem cells via intermediate progenitors, such as monocyte−DC progenitors (MDPs) and common DC progenitors (CDPs). Upon infection, cDCs are activated and rapidly express host defense-related genes, such as those encoding cytokines and chemokines. Chromatin structures, including nuclear compartments and topologically associating domains (TADs), have been implicated in gene regulation. However, the extent and dynamics of their reorganization during cDC development and activation remain unknown. In this study, we comprehensively determined higher-order chromatin structures by Hi-C in DC progenitors and cDC subpopulations. During cDC differentiation, chromatin activation was initially induced at the MDP stage. Subsequently, a shift from inactive to active nuclear compartments occurred at the cDC gene loci in CDPs, which was followed by increased intra-TAD interactions and loop formation. Mechanistically, the transcription factor IRF8, indispensable for cDC differentiation, mediated chromatin activation and changes into the active compartments in DC progenitors, thereby possibly leading to cDC-specific gene induction. Using an infection model, we found that the chromatin structures of host defense-related gene loci were preestablished in unstimulated cDCs, indicating that the formation of higher-order chromatin structures prior to infection may contribute to the rapid responses to pathogens. Overall, these results suggest that chromatin structure reorganization is closely related to the establishment of cDC-specific gene expression and immune functions. This study advances the fundamental understanding of chromatin reorganization in cDC differentiation and activation.
Inferring gene regulation from stochastic transcriptional variation across single cells at steady state
Authors: Gupta Anika , Martin-Rufino Jorge D. , Jones Thouis R. , Subramanian Vidya , Qiu Xiaojie , Grody Emanuelle I. , Bloemendal Alex , Weng Chen , Niu Sheng-Yong , Min Kyung Hoi , Mehta Arnav , Zhang Kaite , Siraj Layla , Al' Khafaji Aziz , Sankaran Vijay G. , Raychaudhuri Soumya , Cleary Brian , Grossman Sharon , Lander Eric S.
Published: August 2022

Regulatory relationships between transcription factors (TFs) and their target genes lie at the heart of cellular identity and function; however, uncovering these relationships is often labor-intensive and requires perturbations. Here, we propose a principled framework to systematically infer gene regulation for all TFs simultaneously in cells at steady state by leveraging the intrinsic variation in the transcriptional abundance across single cells. Through modeling and simulations, we characterize how transcriptional bursts of a TF gene are propagated to its target genes, including the expected ranges of time delay and magnitude of maximum covariation. We distinguish these temporal trends from the time-invariant covariation arising from cell states, and we delineate the experimental and technical requirements for leveraging these small but meaningful cofluctuations in the presence of measurement noise. While current technology does not yet allow adequate power for definitively detecting regulatory relationships for all TFs simultaneously in cells at steady state, we investigate a small-scale dataset to inform future experimental design. This study supports the potential value of mapping regulatory connections through stochastic variation, and it motivates further technological development to achieve its full potential.
ORP5 and ORP8 orchestrate lipid droplet biogenesis and maintenance at ER–mitochondria contact sites
Authors: Guyard Valentin , Monteiro-Cardoso Vera Filipa , Omrane Mohyeddine , Sauvanet Cécile , Houcine Audrey , Boulogne Claire , Ben Mbarek Kalthoum , Vitale Nicolas , Faklaris Orestis , El Khallouki Naima , Thiam Abdou Rachid , Giordano Francesca
Published: August 2022

Lipid droplets (LDs) are the primary organelles of lipid storage, buffering energy fluctuations of the cell. They store neutral lipids in their core that is surrounded by a protein-decorated phospholipid monolayer. LDs arise from the endoplasmic reticulum (ER). The ER protein seipin, localizing at ER-LD junctions, controls LD nucleation and growth. However, how LD biogenesis is spatially and temporally coordinated remains elusive. Here, we show that the lipid transfer proteins ORP5 and ORP8 control LD biogenesis at mitochondria-associated ER membrane (MAM) subdomains, enriched in phosphatidic acid. We found that ORP5/8 regulates seipin recruitment to these MAM–LD contacts, and their loss impairs LD biogenesis. Importantly, the integrity of ER–mitochondria contact sites is crucial for ORP5/8 function in regulating seipin-mediated LD biogenesis. Our study uncovers an unprecedented ORP5/8 role in orchestrating LD biogenesis and maturation at MAMs and brings novel insights into the metabolic crosstalk between mitochondria, ER, and LDs at the membrane contact sites.
Research Spotlight—Insect Polarization Vision: Peripheral And Central Mechanisms
Authors: Warrant Eric , Homberg U.
Published: August 2022

The ability to detect linearly polarized light is used by insects for spatial orientation, object identification and, in a few cases, sexual signalling. The use of polarization vision for sky compass orientation has received particular attention. Scattering of sunlight by air molecules generates a pattern of skylight polarization, which insects can use, just like the sun itself, as a visual celestial compass. Polarized skylight is detected by specialized ommatidia in the so-called dorsal rim area of the eye. In this eye region, ommatidial photoreceptors have highly aligned rhodopsin-bearing microvilli, resulting in high polarization sensitivity. Photoreceptors are homochromatic and occur in each ommatidium as sets of receptors with orthogonal microvillar orientations. Antagonistic input from these photoreceptors likely results in polarization-opponency in neurons of the polarization vision pathway in the brain. Studies in locusts, monarch butterflies, and a few other species have shown that convergence of signals from both eyes occurs in the central complex, a group of midline-spanning neuropils in the brain. Here, bilateral integration results in a compass-like topographic representation of zenithal E-vectors, which may be used as a frame of reference for spatial memory, path integration, and other spatial tasks. Integration of other celestial cues, such as the sky chromatic contrast, occurs at central stages of the polarization vision system, presumably to increase the robustness of the sky compass signal.
Exploring Ageism as a Structure of Consciousness Across the Female Life Course Through the Work of Simone de Beauvoir
Authors: Pickard Susan
Published: August 2022

Drawing on the work of Simone de Beauvoir, this paper considers ageism as a structure of consciousness, with important convergences with, as well as departures from, those associated with gender. Specifically, it explores the double consciousness through which the self is experienced negatively as old, at 2 points in a woman’s life course, namely midlife and “old age.” The first kind of ageism works through the double standard of aging and the gender hierarchy, whereby women can no longer successfully comply with the objectification of the male gaze. This is a moment of intense age consciousness, tainted by a gendered narrative of decline, working jointly from the outside in and from the inside out. The second form of ageism has its source in the social world, in the reactions of other people to old age, resulting in an uneasy dialectic between one’s own sense of an ageless or youthful self and the alien view of self as old. The paper proceeds as follows. After a brief account of Beauvoir’s general philosophical approach, I compare and contrast the doubled consciousness associated with aging as a woman and with aging in a more general sense as described in The Second Sex and The Coming of Age, respectively. I then flesh out this conceptual framework by drawing on fiction and autofiction written by Beauvoir herself. Together, this approach vividly illuminates the important interconnections and intersections between ageism and sexism, the way they work together, as well as separately, across the female life course.
Expected Impact of Universal Immunization With Nirsevimab Against RSV-Related Outcomes and Costs Among All US Infants in Their First RSV Season: A Static Model
Authors: Kieffer Alexia , Beuvelet Matthieu , Sardesai Aditya , Musci Robert , Milev Sandra , Roiz Julie , Lee Jason K H
Published: August 2022

Background

Respiratory syncytial virus (RSV) is associated with substantial morbidity in the United States, especially among infants. Nirsevimab, an investigational long-acting monoclonal antibody, was evaluated as an immunoprophylactic strategy for infants in their first RSV season and for its potential impact on RSV-associated, medically attended lower respiratory tract illness (RSV-MALRTI) and associated costs.

Methods

A static decision-analytic model of the US birth cohort during its first RSV season was developed to estimate nirsevimab’s impact on RSV-related health events and costs; model inputs included US-specific costs and epidemiological data. Modelled RSV-related outcomes included primary care and emergency room visits, hospitalizations including intensive care unit admission and mechanical ventilations, and RSV-related mortality.

Results

Under current standard of care, RSV caused 529 915 RSV-MALRTIs and 47 281 hospitalizations annually, representing $1.2 billion (2021 US dollars [USD]) in costs. Universal immunization of all infants with nirsevimab is expected to reduce 290 174 RSV-MALRTI, 24 986 hospitalizations, and expenditures of $612 million 2021 USD.

Conclusions

An all-infant immunization strategy with nirsevimab could substantially reduce the health and economic burden for US infants during their first RSV season. While this reduction is driven by term infants, all infants, including palivizumab-eligible and preterm infants, would benefit from this strategy.
Magnetic Resonance Imaging Is Inadequate to Assess Cervical Sagittal Alignment Parameters
Authors: Goh Brian C. , Lightsey Harry M. , Lopez Wylie Y. , Tobert Daniel G. , Fogel Harold A. , Cha Thomas D. , Schwab Joseph H. , Bono Christopher M. , Hershman Stuart H.
Published: August 2022

Study Design:

Retrospective radiographic study.

Objective:

To evaluate cervical sagittal alignment measurement reliability and correlation between upright radiographs and magnetic resonance imaging (MRI).

Summary of Background Data:

Cervical sagittal alignment (CSA) helps determine the surgical technique employed to treat cervical spondylotic myelopathy. Traditionally, upright lateral radiographs are used to measure CSA, but obtaining adequate imaging can be challenging. Utilizing MRI to evaluate sagittal parameters has been explored; however, the impact of positional change on these parameters has not been determined.

Methods:

One hundred seventeen adult patients were identified who underwent laminoplasty or laminectomy and fusion for cervical spondylotic myelopathy from 2017 to 2019. Two clinicians independently measured the C2–C7 sagittal angle, C2–C7 sagittal vertical axis (SVA), and the T1 tilt. Interobserver and intraobserver reliability were assessed by intraclass correlation coefficient.

Results:

Intraobserver and interobserver reliabilities were highly correlated, with correlations greater than 0.85 across all permutations; intraclass correlation coefficients were highest with MRI measurements. The C2–C7 sagittal angle was highly correlated between x-ray and MRI at 0.76 with no significant difference (P=0.46). There was a weaker correlation with regard to C2–C7 SVA (0.48) and T1 tilt (0.62) with significant differences observed in the mean values between the 2 modalities (P<0.01).

Conclusions:

The C2–C7 sagittal angle is highly correlated and not significantly different between upright x-ray and supine MRIs. However, cervical SVA and T1 tilt change with patient position. Since MRI does not accurately reflect the CSA in the upright position, upright lateral radiographs should be obtained to assess global sagittal alignment when planning a posterior-based cervical procedure.
Risk factors for future osteoporosis in perimenopausal Japanese women
Authors: Kanto Akiko , Kotani Yasushi , Murakami Kosuke , Tamaki Junko , Sato Yuho , Kagamimori Sadanobu , Matsumura Noriomi , Iki Masayuki
Published: August 2022

Objective

The aims of this study were to investigate trends in bone mineral density (BMD) loss and related factors in early postmenopausal women in Japan, identify risk factors for future osteoporosis, and predict osteoporosis before it occurs.

Methods

The study population consisted of women who were 50 to 54 years old at the time of the survey in 2002 or 2006. The study included a questionnaire and physical measurement findings (BMD, height, body weight [WT], body mass index [BMI], and handgrip strength). One hundred sixty-seven women continued to participate in the study and had BMD measurements at the 9- or 10-year follow-up of the Japanese Population-based Osteoporosis study. Statistical analyses were performed using Pearson correlation to examine each factor of physical measurement and BMD for lumbar spine (LS) and femoral neck (FN). The receiver operating characteristic curve of this data was also predictive of osteoporosis in 2011 for 2002 data; BMD at the age of 50 to 54 years was then used to predict the likelihood of being diagnosed with osteoporosis 9 and 10 years later.

Results

At the baseline in 2002 and 2006, WT, BMI, height, and handgrip strength were positively correlated with BMD. The optimal cutoff values for BMD in 2006 to predict osteoporosis in 2016 were LS less than 0.834 g/cm2 and FN less than 0.702 g/cm2. These data were also predictive of osteoporosis in 2011 for 2002 data; applying this to the 2002 data, LS/FN had a sensitivity of 92%/100%, a specificity of 87%/81%, a positive predictive value of 55%/48%, and a negative predictive value of 98%/100%. The larger WT and BMI also resulted in a greater decrease in BMD of FN after 9 or 10 years.

Conclusions

We have identified a cutoff value for BMD to predict future osteoporosis in menopausal women and found a negative correlation between WT and BMI in menopausal women and changes in BMD of the FN over the next 10 years.
Association between equol production and metabolic syndrome in Japanese women in their 50s-60s
Authors: Takahashi Atsushi , Kokubun Masae , Anzai Yukio , Kogre Atsuko , Ogata Takashi , Imaizumi Hiromichi , Fujita Masashi , Hayashi Manabu , Abe Kazumichi , Ohira Hiromasa
Published: August 2022

Objective

Equol is an active metabolite of soy isoflavone. As a phytoestrogen, equol has the potential to prevent metabolic disorders such as hyperglycemia, hyperlipidemia, and obesity. This study aimed to determine the association between equol production and metabolic syndrome (METS) in postmenopausal women.

Methods

This cross-sectional study included 1,345 women aged 50 to 69 years who underwent health checkups from February 2018 to November 2021 at four health centers in Fukushima, Japan. Equol producers were defined as those with a urinary equol concentration of 1.0 μM or more. METS was defined based on Japanese diagnostic criteria including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and glucose intolerance. The association between equol production and METS was estimated by logistic regression analysis, with adjustments for age, exercise, physical activity, and fast walking.

Results

Of the 1,345 women, 378 (28.1%) were equol producers. The proportion of women who had METS (6.6% vs 10.9%) was significantly lower in the equol-producing group than in the nonproducing group. Multivariable logistic regression analysis revealed that equol production was significantly associated with METS (odds ratio, 0.60; 95% CI, 0.38-0.95).

Conclusions

Equol production was associated with a lower prevalence of METS among women aged 50 to 69 years.
Pleural Pustule—a Novel Thoracoscopic Appearance of Pleural Tuberculosis
Authors: Maturu Venkata Nagarjuna , Prasad Virender Pratibh , Biradar Mahendra , Narahari Narendra Kumar
Published: August 2022

Background:

Thoracoscopic pleural biopsy is the gold standard for diagnosing tubercular pleural effusion (TPE). Various thoracoscopic appearances like sago grain nodules, caseous necrosis, and adhesions have been described in TPE. However, none of these have high specificity for diagnosing TPE. In this study we evaluate a novel finding on thoracoscopy, the “Pleural Pustule.”

Methods:

This is a retrospective analysis of patients who underwent thoracoscopy for undiagnosed pleural effusion. Visual inspection of the pleura was performed to identify abnormalities. Biopsies were obtained from those areas and sent for histopathology, acid fast bacillus (AFB) smear, culture, and Xpert MTB/Rif assay. Pleural pustule was defined as a pus filled nodule on the pleural surface.

Results:

Of the 259 patients included, 92 were diagnosed with TPE. Pleural pustule(s) were identified in 16 patients with TPE. Presence of pleural pustule had a sensitivity, specificity, positive predictive value, and negative predictive value of 17.4%, 100%, 100% and 68.7%, respectively, for diagnosing TPE. Histopathology of pleural pustule demonstrated necrotizing granulomas in all. In patients with pleural pustule, a microbiological diagnosis of tuberculosis was achieved in 93.7% patients (AFB smear, Xpert MTB/Rif assay, and MTB culture positive in 31.3%, 93.7%, and 43.7% cases, respectively). There is a strong association between pleural pustule and positive Xpert MTB/Rif assay (P=0.002) and microbiologic confirmation of diagnosis (P=0.017).

Conclusion:

The presence of pleural pustule on thoracoscopy has a high positive predictive value for TPE. In tuberculosis-endemic countries, this can be considered suggestive for TPE. When identified, a biopsy from the pleural pustule should be performed as it will likely yield a positive microbiologic diagnosis.
Toward Personalized Diagnosis and Therapy for Hearing Loss: Insights From Cochlear Implants
Authors: Sagi Varun , Stankovic Konstantina M.
Published: August 2022

Sensorineural hearing loss (SNHL) is the most common sensory deficit, disabling nearly half a billion people worldwide. The cochlear implant (CI) has transformed the treatment of patients with SNHL, having restored hearing to more than 800,000 people. The success of CIs has inspired multidisciplinary efforts to address the unmet need for personalized, cellular-level diagnosis, and treatment of patients with SNHL. Current limitations include an inability to safely and accurately image at high resolution and biopsy the inner ear, precluding the use of key structural and molecular information during diagnostic and treatment decisions. Furthermore, there remains a lack of pharmacological therapies for hearing loss, which can partially be attributed to challenges associated with new drug development. We highlight advances in diagnostic and therapeutic strategies for SNHL that will help accelerate the push toward precision medicine. In addition, we discuss technological improvements for the CI that will further enhance its functionality for future patients. This report highlights work that was originally presented by Dr. Stankovic as part of the Dr. John Niparko Memorial Lecture during the 2021 American Cochlear Implant Alliance annual meeting.
Tympanoplasty With and Without Mastoidectomy for Chronic Otitis Media Without Cholesteatoma: A Systematic Review and Meta-analysis
Authors: Poupore Nicolas S. , Gordis Tamar M. , Nguyen Shaun A. , Meyer Ted A. , Carroll William W. , Lambert Paul R.
Published: August 2022

Objective

This study aimed to compare surgical and audiometric outcomes of tympanoplasty alone (T) to tympanoplasty and mastoidectomy (T&M) in patients without cholesteatoma.

Databases Reviewed

According to PRISMA guidelines, English articles in PubMed, Scopus, CINAHL, and Cochrane Library databases from inception to 7/29/2021 were searched.

Methods

Studies describing a comparison of patients who underwent T to patients who underwent T&M were included. Studies describing patients with cholesteatoma were excluded. Patient demographics, graft failure rates, and preoperative and postoperative audiological findings were collected. Mean differences (MD) and risk difference (RD) were calculated using RevMan 5.4. Heterogeneity was assessed using Q test and I
2 statistic. Risk of bias was assessed using both version 2 of the Cochrane risk-of-bias tool for randomized trials and Risk of Bias in Non-randomized Studies of Interventions.

Results

A total of 27 studies fulfilled eligibility with T (n = 1,711) and T&M (n = 1,186). When pooling the data, mean differences between T versus T&M for air bone gap (−0.3 dB: 95% CI = −1.9 to 1.3, p = 0.730) and pure tone average (1.9 dB: 95% CI = −0.3 to 4.2, p = 0.090) were not statistically significant. Graft failure was higher with T only (16.4% versus 14.2%) than T&M (RD = −0.04, 95% CI = −0.07 to −0.00, p = 0.030, I
2 = 35%].

Conclusion

This study endorses clinically similar audiological outcomes and a reduced risk difference of graft failure with mastoidectomy. Although these data suggest that adding a mastoidectomy could decrease the risk of graft failure, the risk reduction is minimal. More research on the cost-effectiveness and the specific patient clinical characteristics and comorbidities that would benefit from adding a mastoidectomy is warranted.
Refining epidemiological forecasts with simple scoring rules
Authors: Moore Robert E. , Rosato Conor , Maskell Simon
Published: August 2022

Estimates from infectious disease models have constituted a significant part of the scientific evidence used to inform the response to the COVID-19 pandemic in the UK. These estimates can vary strikingly in their bias and variability. Epidemiological forecasts should be consistent with the observations that eventually materialize. We use simple scoring rules to refine the forecasts of a novel statistical model for multisource COVID-19 surveillance data by tuning its smoothness hyperparameter.

This article is part of the theme issue ‘Technical challenges of modelling real-life epidemics and examples of overcoming these’.
The Royal Society RAMP modelling initiative
Authors: Ackland G. J. , Panovska-Griffiths J. , Waites W. , Cates M. E.
Published: August 2022

Normally, science proceeds following a well-established set of principles. Studies are done with an emphasis on correctness, are submitted to a journal editor who evaluates their relevance, and then undergo anonymous peer review by experts before publication in a journal and acceptance by the scientific community via the open literature. This process is slow, but its accuracy has served all fields of science well. In an emergency situation, different priorities come to the fore. Research and review need to be conducted quickly, and the target audience consists of policymakers. Scientists must jostle for the attention of non-specialists without sacrificing rigour, and must deal not only with peer assessment but also with media scrutiny by journalists who may have agendas other than ensuring scientific correctness. Here, we describe how the Royal Society coordinated efforts of diverse scientists to help model the coronavirus epidemic.

This article is part of the theme issue ‘Technical challenges of modelling real-life epidemics and examples of overcoming these’.
When should bees be flower constant? An agent-based model highlights the importance of social information and foraging conditions
Authors: Hayes Lucy , Grüter Christoph
Published: August 2022

Many bee species show flower constancy,i.e. a tendency to visit flowers of one type during a foraging trip. Flower constancy is important for plant reproduction, but whether bees also benefit from flower constancy remains unclear. Social bees, which often use communication about food sources, show particularly strong flower constancy.

We hypothesised that the sharing of social information increases the benefits of flower constancy because foragers share information selectively about high-quality food sources, thereby reducing the need to sample alternatives. We also asked if foraging landscapes affect flower constancy. We developed an agent-based model that allowed us to simulate bee colonies with and without communication and flower constancy in different foraging environments.

Flower constancy alone performed poorly in all environments, while indiscriminate flower choice was often the most successful strategy. However, communication improved the performance of flower constant colonies in nearly all tested environments. This combination was particularly successful when high-quality food sources were abundant and competition was weak.

Our findings help explain why social bees tend to be more flower constant than solitary bees and suggest that flower constancy can be an adaptive strategy in social bees. Simulations suggest that anthropogenic changes of foraging landscapes will have different effects on the foraging performance of bees that vary in flower constancy.
An antibody-drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer
Authors: Jacob Joan , Francisco Liezl E. , Chatterjee Treena , Liang Zhengdong , Subramanian Shraddha , Liu Qingyun J. , Rowe Julie H. , Carmon Kendra S.
Published: August 2022

Antibody-drug conjugates (ADCs) have become an increasingly successful class of anticancer therapy, particularly within the past few years. Though ADCs are in clinical trials for colorectal cancer (CRC), a candidate has yet to be approved. CRC continues to be a leading cause of cancer-related death, emphasizing the need to identify novel target antigens for ADC development. GPR56, a member of the 7TM receptor family, is upregulated in colorectal tumors compared to normal tissues and located on the surface of CRC cells, making it a promising ADC target. Furthermore, high GPR56 expression occurs in tumors that are microsatellite stable, negative for the CpG methylator phenotype, and show chromosomal instability. We previously reported the generation of a high affinity GPR56-specific monoclonal antibody, 10C7, and we have now mapped the epitope to the C-terminal end of the extracellular domain, proximal to the GPCR proteolysis site. Here, we describe the development of a duocarmycin-conjugated 10C7 ADC. 10C7 co-internalized with GPR56 and trafficked to the lysosomes of CRC cells, which is critical for efficient ADC payload release. Evaluation of the ADC in a panel of CRC cell lines and tumor organoids with different levels of GPR56 expression showed the ADC selectively induced cytotoxicity at low nanomolar concentrations in a GPR56-dependent manner. A nontargeting control ADC showed minimal to no activity. Furthermore, GPR56 ADC exhibited significant antitumor efficacy against GPR56-expressing patient-derived xenograft models of CRC. This study provides rationale for the development of a GPR56-targeted ADC approach to potentially treat a large fraction of CRC patients.
Spike desensitisation as a mechanism for high-contrast selectivity in retinal ganglion cells
Authors: Chang Le , Ran Yanli , Auferkorte Olivia , Butz Elisabeth , Hüser Laura , Haverkamp Silke , Euler Thomas , Schubert Timm
Published: August 2022

In the vertebrate retina, several dozens of parallel channels relay information about the visual world to the brain. These channels are represented by the different types of retinal ganglion cells (RGCs), whose responses are rendered selective for distinct sets of visual features by various mechanisms. These mechanisms can be roughly grouped into synaptic interactions and cell-intrinsic mechanisms, with the latter including dendritic morphology as well as ion channel complement and distribution. Here, we investigate how strongly ion channel complement can shape RGC output by comparing two mouse RGC types, the well-described ON alpha cell and a little-studied ON cell that is EGFP-labelled in the Igfbp5 mouse line and displays an unusual selectivity for high-contrast stimuli. Using patch-clamp recordings and computational modelling we show that in ON Igfbp5 cells – but not in the ON alpha cells – a higher activation threshold and a pronounced slow inactivation of the voltage-gated Na+ channels are responsible for the distinct contrast tuning and transient responses of ON Igfbp5 RGCs, respectively. This study provides an example for the powerful role that the last stage of retinal processing can play in shaping RGC responses.

SIGNIFICANCE STATEMENT

Here, we investigated, how voltage-gated sodium channels contribute to shaping the light responses of mouse retinal ganglion cells. Using single-cell electrophysiology and computational modelling, we studied a ganglion cell type that displays highly transient responses and an unusual selectivity for visual high-contrast stimuli. We found that the cell’s characteristic responses were largely determined by intrinsic mechanisms, notably, a high activation threshold and a pronounced slow inactivation of its voltage-gated sodium channels. Therefore, our study demonstrates how sodium channels at the last stage of retinal signal processing can contribute to shape retinal output to higher visual areas the brain; it also adds a rare example for how channel complement can be directly linked to feature selectivity.
Spectral brain signatures of aesthetic natural perception in the alpha and beta frequency bands
Authors: Kaiser Daniel
Published: August 2022

During our everyday lives, visual beauty is often conveyed by sustained and dynamic visual stimulation, such as when we walk through an enchanting forest or watch our pets playing. Here, I devised an MEG experiment that mimics such situations: Participants viewed 8s videos of everyday situations and rated their beauty. Using multivariate analysis, I linked aesthetic ratings to (1) sustained MEG broadband responses and (2) spectral MEG responses in the alpha and beta frequency bands. These effects were not accounted for by a set of high- and low-level visual descriptors of the videos, suggesting that they are genuinely related to aesthetic perception. My findings provide a first characterization of spectral brain signatures linked to aesthetic experiences in the real world.
Impact of population size on early adaptation in rugged fitness landscapes
Authors: Servajean Richard , Bitbol Anne-Florence
Published: August 2022

Due to stochastic fluctuations arising from finite population size, known as genetic drift, the ability of a population to explore a rugged fitness landscape depends on its size. In the weak mutation regime, while the mean steady-state fitness increases with population size, we find that the height of the first fitness peak encountered when starting from a random genotype displays various behaviors versus population size, even among small and simple rugged landscapes. We show that the accessibility of the different fitness peaks is key to determining whether this height overall increases or decreases with population size. Furthermore, there is often a finite population size that maximizes the height of the first fitness peak encountered when starting from a random genotype. This holds across various classes of model rugged landscapes with sparse peaks, and in some experimental and experimentally-inspired ones. Thus, early adaptation in rugged fitness landscapes can be more efficient and predictable for relatively small population sizes than in the large-size limit.
Through the Random Forest: Ontogeny as a study system to connect prediction to explanation
Authors: Simon Sophia , Glaum Paul , Valdovinos Fernanda S.
Published: August 2022

As modeling tools and approaches become more advanced, ecological models are becoming more complex and must be investigated with novel methods of analysis. Machine learning approaches are a powerful toolset for exploring such complexity. While these approaches are powerful, results may suffer from well-known trade-offs between predictive and explanatory power. We employ an empirically rooted ontogenetically stage-structured consumer-resource model to investigate how machine learning can be used as a tool to root model analysis in mechanistic ecological principles. Applying random forest models to model output using simulation parameters as feature inputs, we extended established feature analysis into a simple graphical analysis. We used this graphical analysis to reduce model behavior to a linear function of three ecologically based mechanisms. From this model, we find that stability depends on the interaction between internal plant demographics that control the distribution of plant density across ontogenetic stages and the distribution of consumer pressure across ontogenetic stages. Predicted outcomes from these linear models rival accuracy achieved by our random forests, while explaining results as a function of ecological interactions.
TRIAC disrupts cerebral thyroid hormone action via a negative feedback loop and heterogenous distribution among organs
Authors: Yamauchi Ichiro , Hakata Takuro , Ueda Yohei , Sugawa Taku , Omagari Ryo , Teramoto Yasuo , Nakayama Shoji F , Nakajima Daisuke , Kubo Takuya , Inagaki Nobuya
Published: August 2022

3,3’,5-triiodothyroacetic acid (TRIAC) is a metabolite of endogenous thyroid hormones (THs) that can bind to and activate TH receptors. As TRIAC was previously detected in sewage effluent, we aimed to investigate exogenous TRIAC’s potential for endocrine disruption. We administered either TRIAC or 3,3’,5-triiodo-L-thyronine (LT3) to both euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC alleviated growth retardation, suppressed the hypothalamus-pituitary-thyroid (HPT) axis, and upregulated TH-responsive genes in the pituitary gland, liver, and heart. We observed that, unlike LT3, TRIAC does not upregulate the expression of TH-responsive genes in the cerebrum. Measurement of organ-specific TRIAC levels suggested that TRIAC was not efficiently trafficked into the cerebrum. Furthermore, by analyzing euthyroid mice, we found that cerebral TRIAC levels did not increase despite TRIAC administration at higher concentrations, whereas serum and cerebral TH levels were substantially decreased. Hence, TH-responsive genes in the cerebrum appear to be downregulated by TRIAC. In summary, TRIAC administration decreases circulating TH levels by suppressing the HPT axis, while the consequent attenuation of TH actions was compensated by TRIAC in peripheral tissues but not in the cerebrum due to the relative impermeability of the blood–brain barrier towards TRIAC. We verified that exogenous TRIAC disrupts TH actions in the cerebrum. This disruption is apparently due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogenous distribution of TRIAC among different organs. Our findings indicate that environmental TRIAC poses a potential neurodevelopmental risk.
Unsupervised learning reveals interpretable latent representations for translucency perception
Authors: Liao Chenxi , Sawayama Masataka , Xiao Bei
Published: August 2022

Humans constantly assess the appearance of materials to plan actions, such as stepping on icy roads without slipping. Visual inference of materials is challenging because a given material can appear dramatically different in various scenes. This problem especially stands out for translucent materials (e.g., skin, soap), whose appearance strongly depends on lighting, geometry, and viewpoint. Despite this, humans can still distinguish between different materials, and it remains unsolved how to systematically discover visual features pertinent to material inference. Here, we developed an unsupervised style-based image generation model to identify perceptually relevant dimensions for material appearances from natural photographs. We find the model can synthesize images of convincing material appearances. Importantly, without supervision, human-understandable scene attributes, including object’s shape, material, and body color, spontaneously emerge in the model’s layer-wise latent space in a scale-specific manner. Crucially, the middle-layers of the latent space selectively encode translucency features correlated with perception, suggesting that translucent impressions are established in mid-to-low spatial scale features. Our findings indicate that humans may use the scale-specific statistical structure of natural images to efficiently represent material properties across contexts, and our approach is widely applicable in discovering perceptually relevant features from complex stimuli for many visual inference tasks.
The Arabidopsis INNER NO OUTER (INO) gene acts exclusively and quantitatively in regulation of ovule outer integument development
Authors: Skinner Debra J. , Dang Trang , Gasser Charles S.
Published: August 2022

The INNER NO OUTER (INO) gene is essential for formation of the outer integument of ovules in Arabidopsis thaliana. Initially described lesions in INO were missense mutations resulting in aberrant mRNA splicing. To determine the null mutant phenotype we used CRISPR to induce frame-shift mutations and found, in confirmation of results on another recently identified frame-shift mutation (Vijayan et al., 2021), that such mutants have a phenotype identical to the most severe splicing mutant (ino-1), with effects specific to outer integument development. We show that the altered protein of an ino mRNA splicing mutant with a less severe phenotype (ino-4) does not have INO activity, and the mutant is partial because it produces a small amount of correctly spliced INO mRNA. Screening for suppressors of ino-4 in a fast-neutron mutagenized population identified a genetic duplication of the ino-4 gene leading to an increase in the amount of this mRNA. The increased expression led to a decrease in the severity of the mutant effects, indicating that the amount of INO activity quantitatively regulates outer integument growth. The results further confirm that the role of INO in Arabidopsis development is specific to the outer integument of ovules where it quantitatively affects the growth of this structure.
Evolutionary dynamics of genome size and content during the adaptive radiation of Heliconiini butterflies
Authors: Cicconardi Francesco , Milanetti Edoardo , de Castro Erika C. Pinheiro , Mazo-Vargas Anyi , Van Belleghem Steven M. , Ruggieri Angelo Alberto , Rastas Pasi , Hanly Joseph , Evans Elizabeth , Jiggins Chris D , McMillan W Owen , Papa Riccardo , Di Marino Daniele , Martin Arnaud , Montgomery Stephen H
Published: August 2022

Heliconiusbutterflies, a speciose genus of Müllerian mimics, represent a classic example of an adaptive radiation that includes a range of derived dietary, life history, physiological and neural traits. However, key lineages within the genus, and across the broader Heliconiini tribe, lack genomic resources, limiting our understanding of how adaptive and neutral processes shaped genome evolution during their radiation. We have generated highly contiguous genome assemblies for nine new Heliconiini, 29 additional reference-assembled genomes, and improve 10 existing assemblies. Altogether, we provide a major new dataset of annotated genomes for a total of 63 species, including 58 species within the Heliconiini tribe. We use this extensive dataset to generate a robust and dated heliconiine phylogeny, describe major patterns of introgression, explore the evolution of genome architecture, and the genomic basis of key innovations in this enigmatic group, including an assessment of the evolution of putative regulatory regions at theHeliconiusstem. Our work illustrates how the increased resolution provided by such dense genomic sampling improves our power to generate and test gene-phenotype hypotheses, and precisely characterize how genomes evolve.
The K-mer Antibiotic Resistance Gene Variant Analyzer (KARGVA)
Authors: Marini Simone , Boucher Christina , Noyes Noelle , Prosperi Mattia
Published: August 2022

Characterization of antibiotic resistance genes (ARGs) from high-throughput sequencing data of metagenomics and cultured bacterial samples is a challenging task, with the need to account for both computational (e.g., string algorithms) and biological (e.g., gene transfers, rearrangements) aspects. Curated ARG databases exist together with assorted ARG classification approaches (e.g., database alignment, machine learning). Besides ARGs that naturally occur in bacterial strains or are acquired through mobile elements, there are chromosomal genes that can render a bacterium resistant to antibiotics through point mutations, i.e., ARG variants (ARGVs). While ARG repositories also collect ARGVs, there are only a few tools that are able to identify ARGVs from metagenomics and high throughput sequencing data, with a number of limitations (e.g., pre-assembly, a posteriori verification of mutations, or specification of species). In this work we present the k-mer, i.e., strings of fixed length k, ARGV analyzer –KARGVA– an open-source, multi-platform tool that provides: (i) an ad hoc, large ARGV database derived from multiple sources; (ii) input capability for various types of high-throughput sequencing data; (iii) a three-way, hash-based, k-mer search setup to process data efficiently, linking k-mers to ARGVs, k-mers to point mutations, and ARGVs to k-mers, respectively; (iv) a statistical filter on sequence classification to reduce type I and II errors. On semi-synthetic data, KARGVA provides very high accuracy even in presence of high sequencing errors or mutations (99.2% and 86.6% accuracy within 1% and 5% base change rates, respectively), and genome rearrangements (98.2% accuracy), with robust performance on ad hoc false positive sets. On data from the worldwide MetaSUB consortium, comprising 3,700+ metagenomics experiments, KARGVA identifies more ARGVs than Resistance Gene Identifier (4.8x) and PointFinder (6.8x), yet all predictions are below the expected false positive estimates. The prevalence of ARGVs is correlated to ARGs but ecological characteristics do not explain well ARGV variance. KARGVA is publicly available at https://github.com/DataIntellSystLab/KARGVA under MIT license.
Development and validation of PainFace, a software platform that simplifies and standardizes mouse grimace analyses
Authors: McCoy Eric S. , Park Sang Kyoon , Patel Rahul P. , Ryan Dan F. , Mullen Zachary J. , Nesbitt Jacob J. , Lopez Josh E. , Taylor-Blake Bonnie , Krantz James L. , Hu Wenxin , Garris Rosanna L. , Lima Lucas V. , Sotocinal Susana G. , Austin Jean-Sebastien , Kashlan Adam D. , Jimenez Jessica A. , Shah Sanya , Trocinski Abigail K. , Vanden Kelly A. , Major Rami M. , Bazick Hannah O. , Klein Morgan R. , Mogil Jeffrey S. , Wu Guorong , Zylka Mark J.
Published: August 2022

Facial grimaces are now commonly used to quantify spontaneous pain in mice and other mammalian species, but scoring remains subjective and relies on humans with very different levels of proficiency. Here, we developed a Mouse Grimace Scale (MGS) for black-coated (C57BL/6) mice consisting of four facial action units (orbitals, nose, ears, whiskers). We used this scale to generate ground truth data from over 70,000 images of black mice in different settings. With this large data set, we developed a deep neural network and cloud-based software platform called PainFace (http://painface.net) that accurately scores facial grimaces of black mice on a 0–8 scale. PainFace generates over two orders of magnitude more MGS data than humans can realistically achieve, and at superhuman speed. By analyzing the frequency distribution of grimace scores, we found that mice spent >7x more time in a high grimace state following laparotomy surgery relative to sham surgery controls. The analgesic carprofen reduced the amount of time animals spent in this high grimace state after surgery. Specific facial action unit score combinations were overrepresented following laparotomy surgery, suggesting that characteristic facial expressions are associated with a high grimace state. We performed validation experiments in two labs located in different countries to demonstrate reproducibility of the PainFace platform. To further enhance rigor and reproducibility, we will invite pain researchers to beta test PainFace and then incorporate their feedback into the software and manuscript prior to peer review. While this study is focused on mice, PainFace was designed to simplify, standardize, and scale up grimace analyses with many other mammalian species, including humans.
Parasitoid pressures and silence evolution
Authors: Suswaram Megha R. , Yeakel Justin D. , Gokhale Chaitanya S.
Published: August 2022

Acoustic signals used by organisms to attract mates are known to attract parasitoid flies. The parasitoid flies lay their eggs inside the host signaler, eventually killing the host. We build a host-parasitoid acoustic model to investigate the effect of parasitoid flies on the signalling host’s eco-evolutionary dynamics. We used field crickets as a system to build the framework of the model. We explore how the sex ratio and the female parasitoid fecundity impact the evolution of the acoustic signal and population density of the signalling hosts. We also explore the stability of the host populations with an increase in parasitoid load. We find that up to a threshold value, an increase in parasitoid load leads to a thriving yet silent host population. Consistent with field observations, we show how this emergence of silence as an evolutionary strategy is immediate. Our results show that a drastic increase in the parasitoid load can rapidly push the signalling host population towards instability and extinction.