bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe treatment-induced inflammatory polyarthritis in advanced melanoma patients: 2 case reports
Authors: Lauwyck Justine , Schreuer Max , Meric de Bellefon Laurent , Van Erps Joanna , Neyns Bart , Aspeslagh Sandrine
Published: April 2022

Immune checkpoint inhibitors (ICI) and targeted therapies form the therapeutic mainstay for v-Raf murine sarcoma viral oncogene homolog B V600-mutated metastatic melanoma. Both treatment regimens can cause inflammatory arthritis. The reported incidence of treatment-induced inflammatory arthritis is low, though presumably underestimated due to lack of awareness, clear definitions and uniform grading systems. Nevertheless, recognition is important as inflammatory arthritis can become chronic and thus affect the quality of life beyond treatment. In this short communication, we present two patients with metastatic melanoma treated with ICI and targeted therapies who develop severe polyarthritis. Based on their clinical discourse we describe standard inflammatory arthritis treatment modalities and more advanced immunomodulatory treatment options with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic DMARDs (bDMARDs). Long-term immunosuppressive treatment with glucocorticoids or DMARDs in this setting raises concerns about antitumour response and potential carcinogenic risk. Current literature on this topic is scarce, heterogeneous and retrospective. Prospective analysis of cancer patients treated with DMARDs is needed to clearly address these concerns.
Cardiovascular disease and malignant melanoma
Authors: Wang Charlie Yue , Zoungas Sophia , Voskoboynik Mark , Mar Victoria
Published: April 2022

In the last decade, systemic therapies such as immune checkpoint inhibitors and BRAF-MEK inhibitors have improved the prognosis of high-risk and advanced melanoma. With improved survival, melanoma survivorship is increasingly important, particularly in patients who have a good prognosis or are diagnosed at a younger age. It is increasingly recognized that cancer and its treatment is associated with increased cardiovascular morbidity and mortality. Indeed, data from observational studies and meta-analyses of randomized controls trials in melanoma show that systemic therapies may be associated with cardiac toxicities, such as myocardial infarction, heart failure, myocarditis and stroke. Our review will discuss cardiovascular disease and risk factors in the context of melanoma and outline the importance of cardiovascular risk modification in this population.
A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors
Authors: Awada Gil , Schwarze Julia Katharina , Tijtgat Jens , Fasolino Giuseppe , Kruse Vibeke , Neyns Bart
Published: April 2022

Patients with advanced BRAFV600
mutant melanoma who progressed on prior treatment with BRAF-/MEK-inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor (‘rechallenge’). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600
mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when ‘rechallenging’ BRAFV600
mutant melanoma patients, recruitment to the trial was closed prematurely.
Drivers and outcomes of between-group conflict in vervet monkeys
Authors: García Miguel Gareta , de Guinea Miguel , Bshary Redouan , van de Waal Erica
Published: April 2022

Neighbouring groups compete over access to resources and territories in between-group encounters, which can escalate into between-group conflicts (BGCs). Both the ecological characteristics of a territory and the rival's fighting ability shape the occurrence and outcome of such contests. What remains poorly understood, however, is how seasonal variability in the ecological value of a territory together with fighting ability related to the likelihood of between-group encounters and the extent to which these escalate into conflicts. To test this, we observed and followed four vervet monkey groups in the wild, and recorded the group structure (i.e. size, composition), the locations and the outcomes of 515 BGCs. We then assessed key ecological measures at these locations, such as vegetation availability (estimated from Copernicus Sentinel 2 satellite images) and the intensity of usage of these locations. We tested to what extent these factors together influenced the occurrence and outcomes of BGCs. We found that the occurrence of BGCs increased at locations with higher vegetation availability relative to the annual vegetation availability within the group's home territory. Also, groups engaging in a BGC at locations far away from their home territory were less likely to win a BGC. Regarding group structure, we found that smaller groups systematically won BGCs against larger groups, which can be explained by potentially higher rates of individual free-riding occurring in larger groups. This study sheds light on how the ecology of encounter locations in combination with a group's social characteristics can critically impact the dynamics of BGCs in a non-human primate species.

This article is part of the theme issue ‘Intergroup conflict across taxa’.
Parochial cooperation in wild chimpanzees: a model to explain the evolution of parochial altruism
Authors: Lemoine Sylvain R. T. , Samuni Liran , Crockford Catherine , Wittig Roman M.
Published: April 2022

Parochial altruism, taking individual costs to benefit the in-group and harm the out-group, has been proposed as one of the mechanisms underlying the human ability of large-scale cooperation. How parochial altruism has evolved remains unclear. In this review paper, we formulate a parochial cooperation model in small-scale groups and examine the model in wild chimpanzees. As suggested for human parochial altruism, we review evidence that the oxytocinergic system and in-group cooperation and cohesion during out-group threat are integral parts of chimpanzee collective action during intergroup competition. We expand this model by suggesting that chimpanzee parochial cooperation is supported by the social structure of chimpanzee groups which enables repeated interaction history and established social ties between co-operators. We discuss in detail the role of the oxytocinergic system in supporting parochial cooperation, a pathway that appears integral already in chimpanzees. The reviewed evidence suggests that prerequisites of human parochial altruism were probably present in the last common ancestor between
Pan
and
Homo
.

This article is part of the theme issue ‘Intergroup conflict across taxa’.
Kidnapping intergroup young: an alternative strategy to maintain group size in the group-living pied babbler (Turdoides bicolor)
Authors: Ridley Amanda R. , Nelson-Flower Martha J. , Wiley Elizabeth M. , Humphries David J. , Kokko Hanna
Published: April 2022

Both inter- and intragroup interactions can be important influences on behaviour, yet to date most research focuses on intragroup interactions. Here, we describe a hitherto relatively unknown behaviour that results from intergroup interaction in the cooperative breeding pied babbler: kidnapping. Kidnapping can result in the permanent removal of young from their natal group. Since raising young requires energetic investment and abductees are usually unrelated to their kidnappers, there appears no apparent evolutionary advantage to kidnapping. However, kidnapping may be beneficial in species where group size is a critically limiting factor (e.g. for reproductive success or territory defence). We found kidnapping was a highly predictable event in pied babblers: primarily groups that fail to raise their own young kidnap the young of others, and we show this to be the theoretical expectation in a model that predicts kidnapping to be facultative, only occurring in those cases where an additional group member has sufficient positive impact on group survival to compensate for the increase in reproductive competition. In babblers, groups that failed to raise young were also more likely to accept extragroup adults (hereafter rovers). Groups that fail to breed may either (i) kidnap intergroup young or (ii) accept rovers as an alternative strategy to maintain or increase group size.

This article is part of the theme issue ‘Intergroup conflict across taxa’.
From inter-group conflict to inter-group cooperation: insights from social insects
Authors: Rodrigues António M. M. , Barker Jessica L. , Robinson Elva J. H.
Published: April 2022

The conflict between social groups is widespread, often imposing significant costs across multiple groups. The social insects make an ideal system for investigating inter-group relationships, because their interaction types span the full harming–helping continuum, from aggressive conflict, to mutual tolerance, to cooperation between spatially separate groups. Here we review inter-group conflict in the social insects and the various means by which they reduce the costs of conflict, including individual or colony-level avoidance, ritualistic behaviours and even group fusion. At the opposite extreme of the harming–helping continuum, social insect groups may peacefully exchange resources and thus cooperate between groups in a manner rare outside human societies. We discuss the role of population viscosity in favouring inter-group cooperation. We present a model encompassing intra- and inter-group interactions, and local and long-distance dispersal. We show that in this multi-level population structure, the increased likelihood of cooperative partners being kin is balanced by increased kin competition, such that neither cooperation (helping) nor conflict (harming) is favoured. This model provides a baseline context in which other intra- and inter-group processes act, tipping the balance toward or away from conflict. We discuss future directions for research into the ecological factors shaping the evolution of inter-group interactions.

This article is part of the theme issue ‘Intergroup conflict across taxa’.
The FocA channel functions to maintain intracellular formate homeostasis during Escherichia coli fermentation
Authors: Kammel Michelle , Sawers R. Gary
Published: April 2022

FocA translocates formate/formic acid bi-directionally across the cytoplasmic membrane when

Escherichia coli

grows by fermentation. It remains unclear, however, what physiological benefit is imparted by FocA, because formic acid (pK
a=3.75) can diffuse passively across the membrane, especially at low pH. Here, we monitored changes in intra- and extracellular formate levels during batch-culture fermentation, comparing a parental

E. coli

K-12 strain with its isogenic focA mutant. Our results show that, regardless of the initial pH in the culture, FocA functions to maintain relatively constant intracellular formate levels during growth. Analysis of a strain synthesizing a FocAT91A variant with an exchange in a conserved threonine residue within the translocation pore revealed the strain accumulated formate intracellularly and imported formate poorly, but in a pH-dependent manner, which was different to uptake by native FocA. We conclude that FocA maintains formate homeostasis, using different mechanisms for efflux and uptake of the anion.
Unravelling the transcriptome of the human tuberculosis lesion and its clinical implications
Authors: Fonseca Kaori L. , Lozano Juan José , Despuig Albert , Habgood-Coote Dominic , Sidorova Julia , Arias Lilibeth , Del Río-Álvarez Álvaro , Carrillo-Reixach Juan , Goff Aaron , Wildner Leticia Muraro , Gogishvili Shota , Nikolaishvili Keti , Shubladze Natalia , Avaliani Zaza , Cardona Pere-Joan , Martinón-Torres Federico , Salas Antonio , Gómez-Carballa Alberto , Armengol Carolina , Waddell Simon J , Kaforou Myrsini , O’Garra Anne , Vashakidze Sergo , Vilaplana Cristina
Published: April 2022

The granuloma is a complex structure, contributing to the overall spectrum of tuberculosis (TB). We characterised 44 fresh human pulmonary TB lesion samples from 13 patients (drug-sensitive and multi-drug resistant TB) undergoing therapeutic surgery using RNA-Sequencing. We confirmed a clear separation between the granuloma and adjacent non-lesional tissue, with the granuloma samples consistently displaying increased inflammatory profile despite heterogeneity. Using weighted correlation network analysis, we identified 17 transcriptional modules associated with granulomata and demonstrated a gradient of immune-related transcript abundance according to the granuloma’s spatial organization. Furthermore, we associated the modular transcriptional signature of the TB granuloma with clinical surrogates of treatment efficacy and TB severity. We show that in patients with severe disease, the IFN/cytokine signalling and neutrophil degranulation modules were overabundant, while tissue organization and metabolism modules were under-represented. Our findings provide evidence of a relationship between clinical parameters, treatment response and immune signatures at the infection site.
Assessing the potential cost-effectiveness of centralized vs point-of-care testing for hepatitis C virus in Pakistan: a model-based comparison
Authors: Babigumira Joseph B. , Karichu James K. , Clark Samantha , Cheng Mindy M. , Garrison Louis P. , Maniecki Maciej B. , Hamid Saeed S.
Published: April 2022

Background

Pakistan has a hepatitis C virus (HCV) infection prevalence of 6–9% and aims to achieve World Health Organization (WHO) targets for elimination of HCV by the year 2030 through scaling HCV diagnosis and accelerating access to care. The clinical and economic benefits of various HCV testing strategies have not yet been evaluated in Pakistan.

Objective

To evaluate the potential cost-effectiveness of a reference laboratory-based (CEN) confirmatory testing approach vs a molecular near-patient point-of-care (POC) confirmatory approach to screen the general population for HCV in Pakistan.

Methods

We developed a decision-analytic model comparing HCV testing under two scenarios: screening with an anti-HCV antibody test (Anti-HCV) followed by either POC nucleic acid testing (NAT) (Anti-HCV-POC), or reference laboratory NAT (Anti-HCV-CEN), using data from published literature, the Pakistan Ministry of Health, and expert judgment. Outcome measures included: number of HCV infections identified per year, percentage of individuals correctly classified, total costs, average costs per individual tested, and cost-effectiveness. Sensitivity analysis was also performed.

Results

At a national level for a tested population of 25 million, the Anti-HCV-CEN strategy would identify 142,406 more HCV infections in one year and increase correct classification of individuals by 0.57% compared with the Anti-HCV-POC strategy. The total annual cost of HCV testing was reduced using the Anti-HCV-CEN strategy by $7.68 million ($0.31 per person). Thus, incrementally, the Anti-HCV-CEN strategy costs less and identifies more HCV infections than Anti-HCV-POC.

Conclusions

Anti-HCV-CEN would provide the best value for money when scaling up HCV testing in Pakistan.

Significance statement

Hepatitis C virus (HCV) infection constitutes a major medical and public health burden in Pakistan

Widespread testing is important to identify those that are chronically infected in order to link them to treatment services

The optimal and most cost-effective testing approach to scale up HCV testing to support elimination efforts in Pakistan has not been established

High throughput reference laboratory testing would provide the best value for money when scaling-up HCV testing in Pakistan
Epidemiological topology data analysis links severe COVID-19 to RAAS and hyperlipidemia associated metabolic syndrome conditions
Authors: Platt Daniel , Bose Aritra , Levovitz Chaya , Rhrissorrakrai Kahn , Parida Laxmi
Published: April 2022

The emergence of COVID19 created incredible worldwide challenges but offers unique opportunities to understand the physiology of its risk factors and their interactions with complex disease conditions, such as metabolic syndrome. Epidemiological analysis powered by topological data analysis (TDA) is a novel approach to uncover these clinically relevant interactions. Here TDA utilized Explorys data to discover associations among severe COVID19 and metabolic syndrome, and it explored the probative value of drug prescriptions to capture the involvement of RAAS and hypertension with COVID19 as well as modification of risk factor impact by hyperlipidemia on severe COVID19.
“Assessment of Referral System on Maternal Services in Cagayan De Oro City”
Authors: Laurito Arbeen Acosta
Published: April 2022

A retrospective document analysis study aimed to assess the referral system on maternal services based on the referral forms of referred women of reproductive age from the referral facilities to the receiving hospital from January to December 2019. The specific objectives of the study were to describe the use of standard referral forms, compliance of the healthcare workers in using the standard form based on 14 criteria, and the utilization of relevant data related to maternal services based on 16 criteria. There were 3330 referral forms received by the receiving facility on different formats of forms during the study period. A random sampling of 384 referral forms was used as study population. Among 384 referral forms (random sampling), only 126 (31.8%) used the standard referral forms. The compliance of these referral forms using 14 criteria showed that 116 (92.06%) referral forms complied with only 51-75% of the criteria, and none of the referral forms complied with all the 14 criteria. On assessing the data entries among 384 referral forms with different formats, there were six data entries consistently used more than 60% by the healthcare providers which were not part of the printed form: last menstrual period (67.87%), expected date of confinement (64.84%), fundic height (63.04%), fetal heart beat (60.76%), birthweight (62.59%), and age of gestation (60%). Based on the 16 criteria, majority of referral forms (210) utilized 51-75% of the 16 criteria, 122 referral forms utilized 76-99%, 51 forms utilized 26-50%, and 1 form utilized less than 25% of the data entries. Several studies documented that referral forms and functional referral systems are vital to an improved maternal mortality rate (MMR) and infant mortality rate (IMR). Therefore, as part of a continued quality referral system, it is highly recommended that the required referral forms be re-assessed, revised, and regularly monitored on its form compliance and utilization.
Transcriptional landscape in BRAF wild type metastatic melanoma
Authors: Lastraioli Elena , Ruffinatti Federico Alessandro , di Costanzo Francesco , Munaron Luca , Arcangeli Annarosa
Published: April 2022

Melanoma is a relative rare disease worldwide, nevertheless it has a great relevance in some countries such as in Europe. In order to shed some light upon the transcriptional profile of skin melanoma, we compared the gene expression of 6 independent tumours (all progressed towards metastatic disease and with wild type BRAF) to the expression profile of healthy melanocytes. Paraffin-embedded samples were manually microdissected to obtain enriched samples and then RNA was extracted and analysed through a microarray-based approach. An exhaustive bioinformatics analysis was performed to identify differentially expressed transcripts between the two groups as well as enriched functional terms. Overall, 50 up- and 19 down-regulated transcripts were found to be significantly changed in tumour compared to control tissue. Among the upregulated transcripts, the majority belonged to the immune response group and to proteasome, while most of the downregulated genes were related to cytosolic ribosomes. Interestingly, Gene Set Enrichment Analysis (GSEA), along with the analysis of the expression data retrieved from TCGA/GTEx databases, confirmed the general trend of downregulation affecting cytoribosome proteins. In contrast, transcripts coding for mitori-bosome proteins showed the opposite trend.
Pharmacokinetics/pharmacodynamics by Race: Analysis of a Peginterferon β-1a Phase I Study
Authors: Zhao Yuan , Mokliatchouk Oksana , Ramia Nancy F , Naylor Maria L , Butts Cherié L
Published: April 2022

Background

Black/African-American participants are underrepresented in clinical trials but can experience a greater burden of disease, such as multiple sclerosis, than other racial groups in the United States. A phase 1, open-label, 2-period crossover study that demonstrated bioequivalence of subcutaneous (SC) and intramuscular (IM) injection of peginterferon beta-1a in healthy volunteers enrolled a similar proportion of Black/African-American and White participants, enabling a subgroup analysis comparing these groups.

Methods

Peginterferon beta-1a 125 μg was administered by SC or IM (1:1) injection, followed by a 28-day washout period before a second injection using the alternate method. Primary endpoints were maximum observed concentration (Cmax) and area under the concentration-time curve from Hour 0 to infinity (AUCinf). Secondary endpoints included safety, tolerability, and additional pharmacokinetic and pharmacodynamic parameters.

Findings

This analysis included 70 (51.5%) Black and 59 (43.3%) White participants. Black participants exhibited a 29.8% higher geometric mean Cmax of peginterferon beta-1a than White participants following SC administration and demonstrated similar values following IM administration. Black participants displayed 31.0% versus 11.8% higher geometric mean AUCinf values than White participants with SC versus IM administration. Neopterin dynamics and safety signals were similar between groups, with numerically fewer adverse events reported among Black participants.

Conclusions

No clinically meaningful differences were identified between Black and White participants in pharmacokinetics/pharmacodynamics or safety related to peginterferon beta-1a administration, indicating that no change in dosing regimen is warranted for Black patients with MS.

Funding

Funding for medical writing support was provided by Biogen Inc. (Cambridge, MA, USA).
Multimodal Hypersensitivity Derived from Quantitative Sensory Testing Predicts Long-Term Pelvic Pain Outcome
Authors: Kmiecik Matthew J. , Tu Frank F. , Clauw Daniel J. , Hellman Kevin M.
Published: April 2022

Multimodal hypersensitivity (MMH)—greater sensitivity across multiple sensory modalities (e.g., light, sound, temperature, pressure)—is hypothesized to be responsible for the development of chronic pain and pelvic pain. However, previous studies of MMH are restricted given their reliance on biased self-report questionnaires, limited use of multimodal quantitative sensory testing (QST), or limited follow-up. Therefore, we conducted multimodal QST on a cohort of 200 reproductive age women at elevated risk for developing or maintaining chronic pelvic pain conditions and pain-free controls. Pelvic pain self-report was examined over a four-year follow-up period. Multimodal QST was comprised of visual, auditory, bodily pressure, pelvic pressure, thermal, and bladder testing. A principal component analysis of QST measures resulted in three orthogonal factors that explained 43% of the variance: MMH, pressure stimulus-response, and bladder hypersensitivity. MMH and bladder hypersensitivity factors correlated with baseline self-reported menstrual pain, genitourinary symptoms, depression, anxiety, and health. Baseline self-report pain ratings were significant predictors of pelvic pain up to three years after assessment but decreased in their predictive ability of pelvic pain outcome over time. In contrast, MMH increased its predictive ability of pelvic pain outcome over time and was the only factor to predict outcome up to four years later. These results suggest that a “centralized” component of MMH is an important long-term risk factor for pelvic pain. Further research on the modifiability of MMH could provide options for future treatment avenues for chronic pain.
Aberrant neurophysiological signaling underlies speech impairments in Parkinson’s disease
Authors: Wiesman Alex I. , Donhauser Peter W. , Degroot Clotilde , Diab Sabrina , Kousaie Shanna , Fon Edward A. , Klein Denise , Baillet Sylvain ,   PREVENT-AD Research Group,   Quebec Parkinson Network
Published: April 2022

Difficulty producing intelligible speech is a common and debilitating symptom of Parkinson’s disease (PD). Yet, both the robust evaluation of speech impairments and the identification of the affected brain systems are challenging. We examine the spectral and spatial definitions of the functional neuropathology underlying reduced speech quality in patients with PD using a new approach to characterize speech impairments and a novel brain-imaging marker. We found that the interactive scoring of speech impairments in PD (N=59) is reliable across non-expert raters, and better related to the hallmark motor and cognitive impairments of PD than automatically-extracted acoustical features. By relating these speech impairment ratings to neurophysiological deviations from healthy adults (N=65), we show that articulation impairments in patients with PD are robustly predicted from aberrant activity in the left inferior frontal cortex, and that functional connectivity of this region with somatomotor cortices mediates the influence of cognitive decline on speech deficits.
Cellular dynamics of endosperm development in Arabidopsis thaliana
Authors: Ali Mohammad Foteh , Shin Ji-Min , Fatema Umma , Kurihara Daisuke , Berger Frédéric , Yuan Ling , Kawashima Tomokazu
Published: April 2022

After double fertilization, the endosperm in the seeds of many flowering plants undergoes repeated mitotic nuclear divisions without cytokinesis, resulting in a large coenocytic endosperm that then cellularizes. Growth during the coenocytic phase is strongly associated with the final seed size; however, a detailed description of the cellular dynamics controlling the unique coenocytic development in flowering plants has remained elusive. By integrating confocal microscopy live-cell imaging and genetics, we have characterized the entire development of the coenocytic endosperm of Arabidopsis thaliana including nuclear divisions, their timing intervals, nuclear movement, and cytoskeleton dynamics. Around each nucleus, microtubules organize into aster-shaped structures that drive F-actin organization. Microtubules promote nuclear movement after division while F-actin restricts it. F-actin is also involved in controlling the size of both the coenocytic endosperm and mature seed. Characterization the of cytoskeleton dynamics in real-time throughout the entire coenocyte endosperm period provides foundational knowledge of plant coenocytic development, insights into the coordination of F-actin and microtubules in nuclear dynamics, and new opportunities to increase seed size and our food security.
Genomic regions associate with major axes of variation driven by gas exchange and leaf construction traits in cultivated sunflower (Helianthus annuusL.)
Authors: Earley Ashley M. , Temme Andries A. , Cotter Christopher R. , Burke John M.
Published: April 2022

Stomata and leaf veins play an essential role in transpiration and the movement of water throughout leaves. These traits are thus thought to play a key role in the adaptation of plants to drought and a better understanding of the genetic basis of their variation and coordination could inform efforts to improve drought tolerance. Here, we explore patterns of variation and covariation in leaf anatomical traits and analyze their genetic architecture via genome-wide association (GWA) analyses in cultivated sunflower (Helianthus annuusL.). Traits related to stomatal density and morphology as well as lower order veins were manually measured from digital images while the density of minor veins was estimated using a novel deep learning approach. Leaf, stomatal, and vein traits exhibited numerous significant correlations that generally followed expectations based on functional relationships. Correlated suites of traits could further be separated along three major principal component (PC) axes that were heavily influenced by variation in traits related to gas exchange, leaf hydraulics, and leaf construction. While there was limited evidence of colocalization when individual traits were subjected to GWA analyses, major multivariate PC axes that were most strongly influenced by several traits related to gas exchange or leaf construction did exhibit significant genomic associations. These results provide insight into the genetic basis of leaf trait covariation and showcase potential targets for future efforts aimed at modifying leaf anatomical traits in sunflower.

Significance Statement

Using traditional and automated/high-throughput (using a novel deep learning approach) phenotyping methods we studied leaf anatomical variation in sunflower. Genome-wide association (GWA) analyses identified numerous genomic regions underlying individual trait variation and regions underlying major multivariate axes of phenotypic variation. These results illustrate the value of employing a multivariate approach to GWA analyses and shed light on the extent to which leaf trait (co-)variation can be genetically decoupled to explore novel phenotypic space.
A scalable phenotyping approach for female floral organ development and senescence in the absence of pollination in wheat
Authors: Millan-Blanquez Marina , Hartley Matthew , Bird Nicholas , Manes Yann , Uauy Cristobal , Boden Scott
Published: April 2022

In the absence of pollination, female reproductive organs senesce leading to an irrevocable loss in the reproductive potential of the flower and directly affecting seed set. In self-pollinating crops like wheat (Triticum aestivum), the post-anthesis viability of the unpollinated carpel has been overlooked, despite its importance for hybrid seed production systems. To advance our knowledge of carpel development in the absence of pollination, we created a relatively high-throughput phenotyping approach to quantify stigma and ovary morphology. We demonstrate the suitability of the approach, which is based on light microscopy imaging and machine learning, for the detailed study of floral organ traits in field grown plants using both fresh and fixed samples. We show that the unpollinated carpel undergoes a well-defined initial growth phase, followed by a peak phase (in which stigma area reaches its maximum and the radial expansion of the ovary slows), and a final deterioration phase. These developmental dynamics were largely consistent across years and could be used to classify male sterile cultivars, however the absolute duration of each phase varied across years. This phenotyping approach provides a new tool for examining carpel morphology and development which we hope will help advance research into this field and increase our mechanistic understanding of female fertility in wheat.
Nonlethal effects of predation: Presence of insectivorous birds affects the behaviour and level of stress in insects
Authors: Kollross Jan , Jancuchova-Laskova Jitka , Kleckova Irena , Freiberga Inga , Kodrik Dalibor , Sam Katerina
Published: April 2022

Insect exposure to their predators can affect individuals and community processes, through direct consumption or nonlethal (i.e., nonconsumptive) effects. However, the links between behavioural and physiological responses and stimuli needed for development of the fear are not clear. We therefore subjected the desert locusts (Schistocerca gregaria) to three nonlethal treatments, using the great tits (Parus major) as a potential predator. The treatments involved: (1) bird - presence of a live great tit and its calls, (2) call - great tit calls only, (3) control - without any treatment. In the first behavioural laboratory experiment, hungry locusts were kept in an experimental cage with a shelter and food on opposite sides of the cage. The duration of hiding and feeding were considered as an indicator of fear responses. In the second laboratory experiment with the same three treatments, levels of the adipokinetic hormone (AKH) were evaluated in the central nervous system (CNS) and haemolymph. In the third experiment in an outdoor aviary, birds were free to fly in larger distances from locusts, before hormone levels were measured as response to bird and control treatments. In the first behavioural experiment, the presence of tits and their call resulted in significantly longer hiding time and significantly shorter feeding time than in the call/control treatments. The proximity of birds and locusts in the laboratory experiment elicited a significant increase in the AKH levels in the CNS and haemolymph as compared to the call/control treatments. In the outdoor experiment, the AKH levels were significantly higher in the CNS of locusts exposed to the bird than to control; no difference was recorded in their haemolymph. We showed that predator exposure quickly affected behavioural responses and physiological processes of locusts. Playback of the avian calls was not an appropriate stimulus to induce stress responses in desert locusts.
Prediction of designer-recombinases for DNA editing with generative deep learning
Authors: Schmitt Lukas Theo , Paszkowski-Rogacz Maciej , Jug Florian , Buchholz Frank
Published: April 2022

Site-specific tyrosine-type recombinases are effective tools for genome engineering, with the first engineered variants having demonstrated therapeutic potential. So far, adaptation to new DNA target site selectivity of designer-recombinases has been achieved mostly through iterative cycles of directed molecular evolution. While effective, directed molecular evolution methods are laborious and time consuming. Here we present RecGen (Recombinase Generator), an algorithm for the intelligent generation of designer-recombinases. We gathered the sequence information of over two million Cre-like recombinase sequences evolved for 89 different target sites with which we trained Conditional Variational Autoencoders for recombinase generation. Experimental validation demonstrated that the algorithm can predict recombinase sequences with activity on novel target-sites, indicating that RecGen is useful to accelerate the development of future designer-recombinases.

Abstract Figure

Teaser Figure:Recombinase prediction generates active recombinases for a desired target site, while existing libraries with a similar target site need to go through directed evolution to achieve activity on the new site. While evolution takes weeks, prediction and synthesis of recombinases can be done in days.
Population estimation of a cryptic moss frog using acoustic spatially explicit capture recapture
Authors: Stark Debra , Turner Andrew , van Rensburg Berndt J. , Measey John
Published: April 2022

Cryptic amphibians pose a problem for conservation managers as they are difficult to find to assess initial populations, and monitor changes during potentially threatening processes. The rough moss frog,Arthroleptella rugosa, is small and occurs in seepages on a single unprotected mountain in South Africa’s fire prone, biodiverse fynbos biome. The area is heavily impacted by invasive plants, which dry seepages and increase the frequency and intensity of fires, leading to the assessment of this species as Critically Endangered. We aimed to test the efficacy of acoustic spatially explicit capture recapture (aSCR) to estimate the entire population of calling adultA. rugosa, and assess the impacts by invasive plants. Using aSCR, our estimates suggest that the population ofA. rugosais more than five times that previously estimated using aural calling surveys on the mountain, at ∼2000 individuals. This despite an intense fire over the entire area three years earlier that reduced the calling population to a few tens of individuals. Our vegetation surveys suggest that the ongoing removal of invasive plants from the mountain is successful in areas occupied byA. rugosa, but that adjacent areas invaded by pines and hakea have a negative impact on calling density. The private public conservancy partnership on Klein Swartberg Mountain, is conserving this frog but will require ongoing management and monitoring to ensure conservation in the future.
Combined drought resistance strategies and the hydraulic limit in co-existing Mediterranean woody species
Authors: Alon Asaf , Cohen Shabtai , Burlett Regis , Hochberg Uri , Lukyanov Victor , Rog Ido , Klein Tamir , Cochard Herve , Delzon Sylvain , David-Schwartz Rakefet
Published: April 2022

Woody species employ various strategies to cope with drought stress. We investigated similarities and differences in response to chronic drought to understand resistance strategies in co-occurring Mediterranean species.

We studied five predominant Mediterranean species;Quercus calliprinos, Pistacia palaestina, Pistacia lentiscus, Rhamnus lycioides, andPhillyrea latifoliaover two summers at three sites with different aridities. We measured key hydraulic and osmotic traits related to drought resistance, including resistance to embolism (Ψ50), carbon isotope signature (δ13C), pre-dawn (ΨPD) and mid-day (ΨMD) water potentials, and native (Ψs) and full turgor (П0) osmotic potentials.

Significant differences among species appeared in resistance to embolism. The species also showed differences in the water potential plastic response over the dry season. This interspecific variation increased at the end of the dry season and resulted in very narrow hydraulic safety margins (HSM). Consequently, predicted loss of hydraulic conductivity revealed species with significant native embolism. Two of the species also had seasonal changes in osmotic adjustment.

Our detailed analysis indicates that co-existing Mediterranean woody species combine various drought resistance strategies to minimize mortality risk. However, all of them risk mortality as they approach their hydraulic limit near the dry margin of their distribution.
Single-cell profiling of lncRNAs in human germ cells and molecular analysis reveals transcriptional regulation of LNC1845 on LHX8
Authors: Wang Nan , He Jing , Feng Xiaoyu , Liao Shengyou , Zhao Yi , Tang Fuchou , Kee Kehkooi
Published: April 2022

Non-coding RNAs exert diverse functions in many cell types. In addition to transcription factors from coding genes, non-coding RNAs may also play essential roles in shaping and directing the fate of germ cells. Here, we report the presence of many long non-coding RNAs (lncRNAs) which were specifically expressed in the germ cells during human gonadal development by single-cell profiling of the reported datasets, and the functional characterization of one divergent lncRNA, LNC1845. Comprehensive bioinformatic analysis of these lncRNAs indicates that divergent lncRNAs occupied the majority of female and male germ cells. Integrating lncRNA expression into the bioinformatic analysis also enhances the cell-type classification of female germ cells. Functional dissection using in vitro differentiation of human pluripotent stem cells to germ cells revealed the regulatory role of LNC1845 on a transcription factor essential for ovarian follicle development, LHX8, by modulating the levels of histone modifications, H3K4me3 and H3K27Ac. Hence, this study provides a comprehensive analysis of lncRNAs in developing germ cells and elucidates how a lncRNA function as a cis regulator during human germ cell development.

GRAPHICAL ABSTRACT

HIGHLIGHTS

lncRNAs are expressed at significantly higher levels in both male and female germ cells than in somatic cells during human gonadal development.

Divergent lncRNAs are enriched in the female meiotically and male mitotically arrested germ cells.

LNC1845 regulates the transcriptional expression of LHX8 by modulating H3K4me3 and H3K27Ac levels.
Combining GWAS and TWAS to identify candidate causal genes for tocochromanol levels in maize grain
Authors: Wu Di , Li Xiaowei , Tanaka Ryokei , Wood Joshua C. , Tibbs-Cortes Laura E. , Magallanes-Lundback Maria , Bornowski Nolan , Hamilton John P. , Vaillancourt Brieanne , Diepenbrock Christine H. , Li Xianran , Deason Nicholas T. , Schoenbaum Gregory R. , Yu Jianming , Robin Buell C. , DellaPenna Dean , Gore Michael A.
Published: April 2022

Tocochromanols (tocopherols and tocotrienols, collectively vitamin E) are lipid-soluble antioxidants important for both plant fitness and human health. The main dietary sources of vitamin E are seed oils that often accumulate high levels of tocopherol isoforms with lower vitamin E activity. The tocochromanol biosynthetic pathway is conserved across plant species but an integrated view of the genes and mechanisms underlying natural variation of tocochromanol levels in seed of most cereal crops remains limited. To address this issue, we utilized the high mapping resolution of the maize Ames panel of ∼1,500 inbred lines scored with 12.2 million single-nucleotide polymorphisms to generate metabolomic (mature grain tocochromanols) and transcriptomic (developing grain) data sets for genetic mapping. By combining results from genome- and transcriptome-wide association studies, we identified a total of 13 candidate causal gene loci, including five that had not been previously associated with maize grain tocochromanols: four biosynthetic genes (arodeH2paralog,dxs1,vte5, andvte7) and a plastid S-adenosyl methionine transporter (samt1). Expression quantitative trait locus (eQTL) mapping of these 13 gene loci revealed that they are predominantly regulated bycis-eQTL. Through a joint statistical analysis, we implicatedcis-acting variants as responsible for co-localized eQTL and GWAS association signals. Our multi-omics approach provided increased statistical power and mapping resolution to enable a detailed characterization of the genetic and regulatory architecture underlying tocochromanol accumulation in maize grain and provided insights for ongoing biofortification efforts to breed and/or engineer vitamin E and antioxidant levels in maize and other cereals.
Farnesyltransferase inhibition overcomes the adaptive resistance to osimertinib in EGFR-mutant NSCLC
Authors: Figarol Sarah , Delahaye Célia , Gence Rémi , Asslan Raghda , Pagano Sandra , Tardy Claudine , Colinge Jacques , Villemin Jean-Philippe , Maraver Antonio , Ferrer Irene , Paz-Ares Luis , Lajoie-Mazenc Isabelle , Clermont Estelle , Casanova Anne , Pradines Anne , Mazières Julien , Calvayrac Olivier , Favre Gilles
Published: April 2022

Drug-tolerant “dormant” cells (DTC) have emerged as one of the major non-genetic mechanisms driving resistance to targeted therapy in lung cancer, although the sequence of events leading to entry and exit from dormancy remain poorly described. Here, we performed real-time monitoring of the cell cycle dynamics during the adaptive response to Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKi) in a panel of EGFR-mutated lung cancer cell lines. We identified a rare population of S/G2 cycling cells (referred to as early escapers) that emerged in the first hours of treatment amongst stably arrested and progressively dying G1 cells. We determined that early escapers evolved from a non-proliferative differentiated alveolar type 1 (AT1) phenotype which was invariably associated with cytoskeletal remodeling through Rho/ROCK pathway activation. Using a panel of Rho-pathway inhibitors, we found that the farnesyltransferase inhibitor tipifarnib induced a complete clearance of EGFR-TKi-induced DTC thus fully preventing relapse in vitro. Using a xenograft model and a PDX model of EGFRL858R/T790M lung cancer, co-treatment with tipifarnib prevented relapse to osimertinib for up to 6 months with no evidence of toxicity. Among the farnesylated proteins regulated during osimertinib treatment, concomitant inhibition of RHOE and LaminB1 was sufficient to recapitulated FTIs’ effect. Osimertinib and tipifarnib co-treatment completely suppressed the emergence of AT1 phenotype, prevented mitosis of S/G2-treated cells and increased the apoptotic response through activation of ATF4-CHOP-dependent Integrated Stress Response (ISR) pathway. Our data strongly support the use of tipifarnib in combination with osimertinib in patients to effectively and durably prevent relapse.
Allele mining, evolutionary genetic analysis of TaHKT1;5 gene and evaluation of salinity stress in selected lines of wheat
Authors: Thiyagarajan Karthikeyan , Mathur Prem Narain , Vikram Prashant , Sehgal Deepmala , Valluru Ravi , Govindan Velu , Rahman Hifzur , Thapa Dhruba Bahadur , Pantha Sumitra , Galeffi Patrizia , Latini Arianna , Cantale Cristina , Porceddu Enrico , Joshi Arun Kumar
Published: April 2022

This study reports the novel allelic diversity in HKT 1;5 gene (High Affinity Potassium Transporter) in bread wheat and its phylogenetic relationship among the paralogs/orthologs of in Triticum aestivum and its wild relatives. HKT 1;5 gene is a known and pivotal gene associated with the salinity tolerance in plants upon the discrimination of K+ over Na+ in leaves without change in Na+ concentration in root. This gene was sequenced in a diverse collection of bread wheat, durum wheat, wild relatives, and ditelosomic lines. Sequence analysis in bread wheat led to the identification of four alleles, which could be distinguished by number of SNPs. Sequence comparison between monocot bread wheat and dicot Arabidopsis thaliana revealed that the HKT1;5 gene is conserved at level of exonic regions; however, the presence of transposable elements especially in intronic regions is further intriguing towards evolutionary relatedness. Two paralogous or major alleles observed in Triticum monoccum and Aegilops tauschii were further categorized as sub-alleles based on their SNPs comparison. This gene was absent in T. urartu in accordance with existing evidence, while it was found in A. speltoides (an allelic variant) with a few base pairs insertion in the exon1 region causing a frameshift mutation with an altered amino acids and genomic database mining unveiled additional alleles in this species. Ditelosomic lines with 4DL and 4DS chromosomes revealed a higher similarity with bread and durum wheat respectively. Phylogenetic studies of HKT1;5 orthologs from different Poaceae species revealed the occurrence of five different ortholog groups with taxonomic consistency. Phenotyping based salinity stress experiment distinguished the unknown lines for salinity tolerance and sensitiveness in comparison with known reference lines and possible allelic comparison was made. The salinity stress analysis further revealed that some known drought/heat tolerance lines showed slightly better salinity tolerance with mean values and variability of traits than known saline tolerant wheat line at controlled ambient.