bluuebunny/crossref_metadata_2025 huggingface dataset:
Scots pine trees react to drought by increasing xylem and phloem conductivities
Authors: Kiorapostolou Natasa , Camarero J Julio , Carrer Marco , Sterck Frank , Brigita Brigita , Sangüesa-Barreda Gabriel , Petit Giai
Published: March 2020

Drought limits the long-distance transport of water in the xylem due to the reduced leaf-to-soil water potential difference and possible embolism-related losses of conductance and of sugars in the phloem due to the higher viscosity of the dehydrated sugary solution. This condition can have cascading effects in water and carbon (C) fluxes that may ultimately cause tree death. We hypothesize that the maintenance of xylem and phloem conductances is fundamental for survival also under reduced resource availability, when trees may produce effective and low C cost anatomical adjustments in the xylem and phloem close to the treetop where most of the hydraulic resistance is concentrated. We analyzed the treetop xylem and phloem anatomical characteristics in coexisting Scots pine trees, symptomatic and non-symptomatic of drought-induced dieback. We selected the topmost 55 cm of the main stem and selected several sampling positions at different distances from the stem apex to test for differences in the axial patterns between the two groups of trees. We measured the annual ring area, the tracheid hydraulic diameter (Dh) and cell wall thickness (CWT), the conductive phloem area and the average lumen diameter of the 20 largest phloem sieve cells (Dph). Declining trees grew less than the non-declining ones, and despite the similar axial scaling of anatomical traits, had larger Dh and lower CWT. Moreover, declining trees had wider Dph. Our results demonstrate that even under drought stress, maintenance of xylem and phloem efficiencies is of primary importance for survival, even if producing fewer larger tracheids may lead to a xylem more vulnerable to embolism formation.
Analysis of spatial clustering, time trend, social vulnerability and risk of human visceral leishmaniasis in an endemic area in Brazil: an ecological study
Authors: Andrade Acácio W F , Souza Carlos D F , Carmo Rodrigo F
Published: March 2020

Background

More than 95% of visceral leishmaniasis (VL) cases in Latin America occur in Brazil, most of them in the northeast. The objective of this study was to identify spatial clusters with the highest risks of VL and to analyse the temporal behaviour of the incidence and the effects of social vulnerability on the disease transmission dynamic in northeastern Brazil.

Methods

All confirmed cases registered as residents in the state of Pernambuco during the period from 2007 to 2017 were analysed. The local empirical Bayesian method was applied and the association -between the VL incidence rate and municipal social vulnerability was tested via classic multivariate regression.

Results

A total of 1186 new cases were registered during the study period. Spatial analysis showed heterogeneous distribution, with the highest rates observed in the São Francisco and Sertão mesoregions. Moreover, the main factors associated with VL were urban infrastructure, income and work.

Conclusions

It was observed that spatial and temporal techniques are important tools for defining risk areas for VL, in conjunction with the evaluation of indexes of social vulnerability, which was shown to be an important factor for comprehending associations with VL in the state of Pernambuco.
Opportunistic sampling of wild native and invasive birds reveals a rich diversity of adenoviruses in Australia
Authors: Vaz Frederico F , Raso Tânia F , Agius Jessica E , Hunt Tony , Leishman Alan , Eden John-Sebastian , Phalen David N
Published: March 2020

Little is known about the diversity of adenoviruses in wild birds and how they have evolved and are maintained in complex ecosystems. In this study, 409 samples were collected from woodland birds caught for banding (droppings), birds submitted to a wildlife hospital (droppings and tissues), silver gulls (droppings or tissues), and feral pigeons (Columbia livia; oral, cloacal swabs, or tissues) from the Greater Sydney area in NSW, Australia. Additional samples were from native pigeons and doves (swabs) presented to the Healesville Sanctuary, VIC, Australia. Samples were screened for adenovirus DNA using degenerate primers and polymerase chain reaction. Adenovirus sequences were detected in eighty-three samples representing thirty-five novel amino acid sequences. Fourteen novel sequences were atadenoviruses, seven were aviadenoviruses, twelve were siadenoviruses, and one was a mastadenovirus. Sequences from passerine birds were predominately found to form a single lineage within the atadenoviruses, a second lineage in the siadenoviruses, and a third smaller aviadenovirus lineage. These viruses appeared to have co-evolved with a diverse group of woodland birds that share similar habitat. Evidence for host/virus co-evolution in some viruses and a wide host range in others was observed. A high prevalence of adenovirus infection was found in rainbow lorikeets (Trichoglossus haematodus), galahs (Eolophus roseicapilla), and sulphur-crested cockatoos (Cacatua galerita). Sequences were either identical to or mapped to already established lineages in the Aviadenovirus, Siadenovirus, and Atadenovirus genera, suggesting a possible origin of the psittacine adenoviruses in ancestral Australian psittacine birds. The sequences of passerine and psittacine origin provided insight into diversity and structure of the Atadenovirus genus and demonstrated for the first-time viruses of passerine origin in the Aviadenovirus genus. Four unrelated adenovirus sequences were found in silver gull samples (Chroicocephalus novaehollandiae), including one of pigeon origin, suggesting environmental virus exposure. Three pigeon adenovirus types were detected in feral pigeons and infection prevalence was high. Evidence for host switching between invasive species and native species and native species and invasive species was documented. A variant of a murine adenovirus was detected in kidney tissue from two bird species suggesting mouse to bird transmission.
Breeding systems and genetic diversity in tropical carpenter ant colonies: different strategies for similar outcomes in Brazilian Cerrado savanna
Authors: Azevedo-Silva Marianne , Mori Gustavo M , Carvalho Carolina S , Côrtes Marina C , Souza Anete P , Oliveira Paulo S
Published: March 2020

Eusocial insects tend to present low genetic diversity (GD) within colonies, which can increase with the co-occurrence of multiple queens (polygyny) or with multiple mating by a single queen (polyandry). Therefore, it is important to elucidate how these strategies influence GD, which in turn mediate population ecology and how organisms respond to their environment. We studied two carpenter ant species from the Brazilian savanna, Camponotus renggeri and C. rufipes. Using microsatellites, we evaluated the number of breeders, the genetic relatedness and the contribution of polygyny and polyandry to GD within colonies. Both species exhibited facultative polygyny. In C. renggeri, low related queens formed colonies jointly and present low mating frequency. In this species, colony GD increased with the number of queens. Contrastingly, closely related queens of C. rufipes formed polygynous colonies, exhibiting high mating frequency. In C. rufipes, both queens and males contributed to colony GD. Despite the differences, the two species have similar GD at the colony scale. Under low mating frequency, our data support that polygyny has evolutionary importance for increasing GD in ant colonies, a mechanism mainly conferred to polyandry. Although the impact of GD in variable ecological and adaptive contexts remains uncertain, this study highlights how distinct reproductive strategies may generate similar patterns of GD in ants.
The analysis of the role of MexAB-OprM on quorum sensing homeostasis shows that the apparent redundancy of Pseudomonasaeruginosamultidrug efflux pumps allows keeping the robustness and the plasticity of this intercellular signaling network
Authors: Alcalde-Rico Manuel , Olivares-Pacheco Jorge , Halliday Nigel , Cámara Miguel , Martínez José Luis
Published: March 2020

Multidrug efflux pumps are key determinants for antibiotic resistance. Besides contributing to intrinsic resistance, their overexpression is frequently a cause of the increased resistance acquired during therapy. In addition to their role in resistance to antimicrobials, efflux pumps are ancient and conserved elements with relevant roles in different aspects of the bacterial physiology. It is then conceivable that their overexpression might cause a burden that will be translated into a fitness cost associated with the acquisition of resistance. In the case ofPseudomonas aeruginosa, it has been stated that overexpression of different efflux pumps is linked to the impairment of the quorum sensing (QS) response. Nevertheless, the causes of such impairment are different for each analyzed efflux pump. In this study, we performed an in-depth analysis of the QS-mediated response of aP. aeruginosaantibiotic resistant mutant that overexpresses MexAB-OprM. Although previous work claimed that this efflux pump extrudes the QS signal 3-oxo-C12-HSL, we show otherwise. Our results suggest that the observed attenuation in the QS response when overexpressing this pump is related to a reduced availability of intracellular octanoate, one of the precursors of the biosynthesis of alkyl quinolone QS signals. The overexpression of otherP. aeruginosaefflux pumps has been shown to also cause a reduction in intracellular levels of QS signals or their precursors impacting on these signaling mechanisms. However, the molecules involved are distinct for each efflux pump, indicating that they can differentially contribute to theP. aeruginosaquorum sensing homeostasis.

Importance

The success of bacterial pathogens to cause disease relies on their virulence capabilities as well as in their resistance to antibiotic interventions. In the case of the important nosocomial pathogenPseudomonas aeruginosa, multidrug efflux pumps participate in the resistance/virulence crosstalk since, besides contributing to antibiotic resistance, they can also modulate the quorum sensing (QS) response. We show that mutants overexpressing the MexAB-OprM efflux pump, present an impaired QS response due to the reduced availability of the QS signal precursor octanoate, not because they extrude, as previously stated, the QS signal 3-oxo-C12-HSL. Together with previous studies, this indicates that, although the consequences of overexpressing efflux pumps are similar (impaired QS response), the mechanisms are different. This ‘apparent redundancy’ of RND efflux systems can be understood as aP. aeruginosastrategy to keep the robustness of the QS regulatory network and modulate its output in response to different signals.
β-catenin Signaling Regulates Cell Fate Decisions at the Transition Zone of the Chondro-Osseous Junction During Fracture Healing
Authors: Wong Sarah Anne , Hu Diane , Shao Tiffany , Niemi Erene , Barruet Emilie , Morales Blanca M , Boozarpour Omid , Miclau Theodore , Hsiao Edward C , Nakamura Mary , Bahney Chelsea S , Marcucio Ralph S
Published: March 2020

Chondrocytes within the fracture callus transform into osteoblasts during bone regeneration, but the molecular mechanisms regulating this process are unknown. Wnt ligands are expressed within the fracture callus, and hypertrophic chondrocytes undergoing transformation to osteoblasts exhibit nuclear localization of β-catenin, indicating active Wnt signaling in these cells. Here, we show that conditional knock out (cKO) of β-catenin in chondrocytes inhibits the transformation of chondrocytes to osteoblasts, while stabilization of β-catenin in chondrocytes accelerates this process. After cKO, chondrocyte-derived cells were located in the bone marrow cavity and upon re-fracture formed cartilage. Lineage tracing in wild type mice revealed that in addition to osteoblasts, chondrocytes give rise to stem cells that contribute to repair of subsequent fractures. These data indicate that Wnt signaling directs cell fate choices of chondrocytes during fracture healing by stimulating transformation of chondrocytes to osteoblasts, and provide a framework for developing Wnt-therapies to stimulate repair.
Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome
Authors: Shaashua Lee , Eckerling Anabel , Israeli Boaz , Yanovich Gali , Rosenne Ella , Fichman-Horn Suzana , Ben Zvi Ido , Sorski Liat , Satchi-Fainaro Ronit , Geiger Tamar , Sloan Erica K. , Ben-Eliyahu Shamgar
Published: March 2020

Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor (PT) excision, but underlying mechanisms are elusive. Here we present a model of metastases regression and latency following PT excision, and identify potential underlying mechanisms. Using MDA-MB-231HMhuman breast cancer cells that express highly sensitive luciferase, we were able to monitor early stages of spontaneous metastases development in BALB/c nu/nu mice. Removal of the PT caused marked regression of the smallest micro-metastases, but not of larger metastases, andin vivosupplementation of tumor secretome diminished this regression, suggesting that PT-secreted factors promote early metastatic growth. Correspondingly, cancer cell conditioned medium reduced apoptosis and enhanced MDA-MB-231HMadhesionin vitro. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HMsecretome were conducted. Results identified significant enrichment of angiogenesis, growth factors binding and activity, focal adhesion, metalloprotease regulation, and apoptosis regulation processes. Simultaneousin vivoblockade of four secreted key potential mediators of these processes, IL-8, PDGFaa, Serpin E1 (PAI-1), and MIF, arrested development of micro-metastases in the presence of the PT. Interestingly, using the public TCGA provisional dataset, high protein levels of these four factors were correlated with poor survival in a cohort of lung adenocarcinoma patients. These results demonstrate regression and latency of micro-metastases following PT excision, and a crucial role for PT-secretome in promoting early metastatic stages in MDA-MB-231HMxenografts. If generalized, such findings can suggest novel approaches to control minimal residual disease during and following PT excision.
TGF-Β Family Inhibitors Blunt Adipogenesis Via Non-Canonical Regulation Of SMAD Pathways
Authors: Aykul Senem , Maust Jordan , Floer Monique , Martinez-Hackert Erik
Published: March 2020

Adipose tissues (AT) expand in response to energy surplus through adipocyte hypertrophy and hyperplasia (i.e., adipogenesis). The latter is a process by which multipotent precursors differentiate into mature adipocytes. This process is directed by growth factors and cytokines, including members of the TGF-β family, which regulate intracellular signaling pathways that control adipogenic transcriptional programs. As ectopic adipogenesis has been linked with metabolic syndrome and other pathological conditions, we undertook to establish how TGF-β family growth factors and their inhibitors regulate this process in a 3T3-L1 adipogenesis model. We found that intracellular SMAD1/5/8 signaling pathways are activated while SMAD2/3 pathways are suppressed in differentiating cells. Addition of SMAD1/5/8 pathway activating ligands promoted cell proliferation, while SMAD2/3 pathway activating ligands suppressed adipocyte formation. We identified several ligand traps that blunted 3T3-L1 adipogenesis. Strikingly, anti-adipogenic traps and ligands exploited the same mechanism of regulation involving a negative feedback loop that links SMAD2/3 activation with SMAD1/5/8 hyper-phosphorylation, cytoplasmic retention, and reduced signaling. The identified anti-adipogenic traps could be used to control hyperplastic AT expansion and its associated pathological conditions.
PtenandDicer1loss causes poorly-differentiated endometrial adenocarcinoma in mice
Authors: Wang Xiyin , Wendel Jillian R. H. , Emerson Robert E. , Broaddus Russell R. , Creighton Chad , Rusch Douglas B. , Buechlein Aaron , DeMayo Francesco J. , Lydon John P. , Hawkins Shannon M.
Published: March 2020

Endometrial cancer remains the most common gynecological malignancy in the United States. While the loss of the tumor suppressor, PTEN (phosphatase and tensin homolog), is well studied in endometrial cancer, recent studies suggest thatDICER1, the endoribonuclease responsible for miRNA genesis, also plays a significant role in endometrial adenocarcinoma. In an endometrial adenocarcinoma mouse model, which has a conditional uterine deletion ofPten, Dicer1was also conditionally deleted. Conditional uterine deletion ofDicer1andPtenresulted in high-penetrance, poorly-differentiated endometrial adenocarcinomas. Poorly-differentiated endometrial adenocarcinomas expressed known markers of clear-cell adenocarcinoma, including Napsin A and HNF1B (hepatocyte nuclear factor 1 homeobox B). Adenocarcinomas were hormone-independent, and treatment with long-term progesterone did not mitigate poorly-differentiated adenocarcinoma, nor did it affect adnexal metastasis. Transcriptomic analyses of uteri or Ishikawa cells with deletion ofDICER1revealed unique transcriptomic profiles and global downregulation of miRNAs. Integration of downregulated miRNAs with upregulated mRNA targets revealed deregulated let-7 and miR-16 target genes, similar to published humanDICER1-mutant endometrial cancers from TCGA (The Cancer Genome Atlas). Importantly, these miRNA-target genes, involved in ephrin-receptor and transforming growth factor-beta signaling, represent potential clinical targets for rare, yet deadly, poorly-differentiated endometrial adenocarcinomas in women. This mouse model represents poorly-differentiated endometrial adenocarcinoma and will allow for the discovery of novel mechanisms of hormone-independent endometrial adenocarcinoma from atrophic endometrium.

Significance Statement

Endometrial cancer is one of the few cancers with an increasing death rate in the United States. The most significant risk factor associated with death is high tumor grade, which occurs most frequently in postmenopausal women, where it develops within an atrophic endometrium. Here, we present a mouse model with conditional deletion ofDicer1, a key enzyme in miRNA genesis, andPten, a tumor suppressor, that develops poorly-differentiated, steroid hormone-independent, endometrial adenocarcinoma with adnexal metastasis. These high-grade adenocarcinomas develop from an atrophic endometrium and share molecular features withDICER1-mutant human endometrial adenocarcinomas. We anticipate that this preclinical model represents a move toward the discovery of novel mechanisms of hormone-independent development of endometrial adenocarcinoma from atrophic endometrium.
RAB6 GTPase is a crucial regulator of the mammary secretory function controlling STAT5 activation
Authors: Cayre Surya , Faraldo Marisa M. , Bardin Sabine , Miserey-Lenkei Stéphanie , Deugnier Marie-Ange , Goud Bruno
Published: March 2020

The Golgi-associated RAB GTPases, RAB6A and RAB6A’, regulate anterograde and retrograde transport pathways from and to the Golgi.In vitro, RAB6A/A’ have been reported to be involved in several cellular functions, including, in addition to transport, cell division, migration, adhesion and polarity. However, their role remains poorly describedin vivo, in particular in epithelial tissues. Here, we generated BlgCre;Rab6aF/Fmouse presenting a specific deletion ofRab6ain the mammary luminal secretory lineage during gestation and lactation.Rab6aloss severely impaired the differentiation, maturation and maintenance of the secretory tissue, compromising lactation. It led to a decreased activation of STAT5, a key regulator of the lactogenic process primarily governed by prolactin. Data obtained with a human mammary epithelial cell line suggested that defective STAT5 activation might originate from a perturbed transport of the prolactin receptor, altering its membrane expression and signaling cascade. Despite the major functional defects observed uponRab6adeletion, the polarized organization of the mammary epithelial bilayer was preserved. Altogether, our data reveal a crucial role for RAB6A/A’ in the lactogenic function of the mammary gland. They also suggest that the trafficking pathways controlled by RAB6A/A’ depend on cell type specialization and tissue context.

SUMMARY STATEMENT

This study reveals a role for the Golgi-associated RAB GTPases, RAB6A/A’, in the lactogenic function of the mammary gland.
An inability to maintain the ribonucleoprotein genomic structure is responsible for host detection of negative-sense RNA viruses
Authors: Blanco-Melo Daniel , Nilsson-Payant Benjamin E. , Uhl Skyler , Escudero-Pèrez Beatriz , Olschewski Silke , Thibault Patricia , Panis Maryline , Rosenthal Maria , Muñoz-Fontela César , Lee Benhur , tenOever Benjamin R.
Published: March 2020

Cellular biology has a uniformity not shared amongst viruses. This is perhaps best exemplified by negative-sense RNA viruses that encode their genetic material as a ribonucleoprotein complex composed of genome, RNA-dependent RNA polymerase, and the nucleoprotein. Here we demonstrate that limiting nucleoprotein availability not only universally culminates in a replicative catastrophe for negative-sense RNA viruses, but it results in the production of aberrant genomic material and induction of the interferon-based host defenses. This dynamic illustrates the tremendous stress imposed on negative-sense RNA viruses during replication as genomic products accumulate in an environment that requires an increasing demand on nucleoprotein availability. We show that limiting NP by RNA interference or drug targeting blocks replication and primes neighboring cells through the production of interferon. Together, these results demonstrate that the nucleoprotein represents the Achilles heel of the entire phylum of negative-sense RNA viruses. Here we establish this principle for a diverse collection of human pathogens and propose that the nucleoprotein should be a primary target for the development of future antiviral drugs.

HIGHLIGHTS

Limited levels of NP result in production of defective viral genomes

Defective viral genomes and viral antagonists are key determinants of the host antiviral response

The host response and defective viral genome generation further exasperate NP availability

NP is an optimal drug target for the whole phylum of negative-sense RNA viruses
Tumor Necrosis Factor Receptor Signaling Modulates Carcinogenesis in a Mouse Model of Breast Cancer
Authors: He Ling , Bhat Kruttika , Duhacheck-Muggy Sara , Ioannidis Angeliki , Zhang Le , Nguyen Nhan T. , Moatamed Neda A. , Pajonk Frank
Published: March 2020

Proinflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both, obesity and in the response of tissues to radiation, two known risk factors for the development of breast cancer. Using the MMTV-Wnt1 mouse model for spontaneous breast cancer and knockout mice for TNFR1 and TNFR2 we report that loss of a TNFR2 allele leads to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal endbuds. Furthermore, that loss of one TNFR2 allele increases the incidence of breast cancers in MMTV-Wnt1 mice and results in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-κB signaling pathways and autocrine production of TNFα. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression.

We conclude, that imbalances in TNFR signaling promote the development and progression of breast cancer, indicating that selective agonists of TNFR2 could potentially modulate the risk for breast cancer in high-risk populations.

Significance Statement

Over the past four decades the treatment results for patients suffering from breast cancer have constantly improved, leaving breast cancer prevention as an important frontier against the second leading cause of cancer death in the United States. Obesity has become a national health crisis and is a known proinflammatory risk factor for breast cancer. Our study describes a previously unknown aspect of proinflammatory signaling on breast cancer development and progression, thus suggesting novel potential targets to modulate the incidence of the disease.
Global impact of phosphorylation on protein endurance
Authors: Wu Chongde , Ba Qian , Li Wenxue , Salovska Barbora , Hou Pingfu , Mueller Torsten , Rosenberger George , Gao Erli , Di Yi , Liu Yansheng
Published: March 2020

Post-translational modifications such as phosphorylation can have profound effects on the physicochemical and biological properties of proteins. However, high-throughput and systematic approaches have not yet been developed to assess the effects of specific modification types and sites on protein lifetime, which represents a key parameter for understanding signaling rewiring and drug development. Here we describe a proteomic method, DeltaSILAC, to quantify the impact of site-specific phosphorylation on the endurance of thousands of proteins in live cells. Being configured on the reproducible data-independent acquisition mass spectrometry (DIA-MS), the pulse labeling approach using stable isotope-labeled amino acids in cells (SILAC), together with a novel peptide-level matching strategy, this multiplexed assay revealed the global delaying effect of phosphorylation on protein turnover in growing cancer cells. Further, we identified local sequence and structural features in proximity to the phosphorylated sites that could be associated with protein endurance alterations. We found that phosphorylated sites accelerating protein turnover are functionally selected for cell fitness and evolutionarily conserved. DeltaSILAC provides a generalizable approach for prioritizing the effects of phosphorylation sites on protein lifetime in the context of cell signaling and disease biology, which is highly complementary to existing methods. Finally, DeltaSILAC is widely applicable to diverse post-translational modification types and different cell systems.
Serial sarcomere number is substantially decreased within the paretic biceps brachii in individuals with chronic hemiparetic stroke
Authors: Adkins Amy N. , Dewald Julius P.A. , Garmirian Lindsay , Nelson Christa M. , Murray Wendy M.
Published: March 2020

A muscle’s structure, or architecture, is indicative of its function and is plastic; changes in input to or use of the muscle alter its architecture. Stroke-induced neural deficits substantially alter both input to and usage of individual muscles. Here, we combined novelin vivoimaging methods (second harmonic generation microendoscopy, extended field-of-view ultrasound, and fat-supression MRI) to quantify functionally meaningful muscle architecture parameters in the biceps brachii of both limbs of individuals with chronic hemiparetic stroke and in age-matched, unimpaired controls. Specifically, serial sarcomere number and physiological cross-sectional area were calculated from data collected at three anatomical scales: sarcomere length, fascicle length, and muscle volume. Our data indicate that the paretic biceps brachii had ~8,500 fewer serial sarcomeres compared to the contralateral limb (p=0.0044). In the single joint posture tested, the decreased serial sarcomere number was manifested by significantly shorter fascicles (10.7cm vs 13.6cm; p<0.0001) without significant differences in sarcomere lengths (3.58μm vs. 3.54μm; p=0.6787) in the paretic compared to the contralateral biceps. No interlimb differences were observed in unimpaired controls, suggesting we observed muscle adaptations associated with stroke rather than natural interlimb variability. This study provides the first direct evidence of the loss of serial sarcomeres in human muscle, observed in a population with neural impairments that lead to disuse and chronically place the affected muscle at a shortened position. This adaptation is consistent with functional consequences (increased passive resistance to elbow extension) that would amplify already problematic, neurally driven motor impairments.

SIGNIFICANCE STATEMENT

Serial sarcomere number determines a muscle’s length during maximum force production and its available length range for active force generation. Skeletal muscle length adapts to functional demands; for example, animal studies demonstrate that chronically shortened muscles decrease length by losing serial sarcomeres. This phenomenon has never been demonstrated in humans. Integrating multi-scale imaging techniques, including two photon microendoscopy, an innovative advance from traditional, invasive measurement methods at the sarcomere scale, we establish that chronic impairments that place a muscle in a shortened position are associated with the loss of serial sarcomeres in humans. Understanding how muscle adapts following impairment is critical to the design of more effective clinical interventions to mitigate such adaptations and to improve function following motor impairments.
RNA binding domains of heterologous viral proteins substituted for basic residues in the RSV Gag NC domain restore specific packaging of genomic RNA
Authors: Rice Breanna L. , Lochmann Timothy L. , Parent Leslie J.
Published: March 2020

The Rous sarcoma virus Gag polyprotein transiently traffics through the nucleus, which is required for efficient incorporation of the viral genomic RNA (gRNA) into virus particles. Packaging of gRNA is mediated by two zinc knuckles and basic residues located in the nucleocapsid (NC) domain in Gag. To further examine the role of basic residues located downstream of the zinc knuckles in gRNA encapsidation, we used a gain-of-function approach. We replaced a basic residue cluster essential for gRNA packaging with heterologous basic residue motif (BR) with RNA binding activity from either the HIV-1 Rev protein (Rev BR) or the HSV ICP27 protein (ICP27 BR). Compared to wild type Gag, the mutant ICP27 BR and Rev BR Gag proteins were much more strongly localized to the nucleus and released significantly lower levels of virus particles. Surprisingly, both the ICP27 BR and Rev BR mutants packaged normal levels of gRNA per virus particle when examined in the context of a proviral vector, yet both mutants were noninfectious. These results support the hypothesis that basic residues located in the C-terminal region of NC are required for selective gRNA packaging, potentially via initial electrostatic interactions that facilitate specific binding.
Behavioural choice emerges from nonlinear all-to-all interactions between drives
Authors: Thornquist Stephen C. , Crickmore Michael A.
Published: March 2020

Under the right conditions any drive can overcome nearly any other, yet studies of behavioural selection predominantly focus on only one, or occasionally two behaviours. We present an experimental and computational framework that captures and explains the resolution of conflicts between several competing motivations. We characterize neurons that integrate information from all rival drives to generate an aggregate signal that urges male Drosophila to transition out of mating. Experimental investigation of these Drive Integrating Neurons (DINs) revealed time-varying, supralinear interactions among competing drives that stimulate the DINs and induce a change in behaviour. Extending these findings to model the interactions between all of an animal’s motivations led to the surprising prediction that, under many conditions, all-to-all interactions actually buffer the dominant drive against challengers. We experimentally validated this prediction, showing that weak drives for a variety of tertiary goals can have a profound stabilizing effect on the ongoing behaviour. These results emerge only if non-linear integration of other motivations occurs for each of an animal’s drives, suggesting the potential universality of this mechanism. Our findings emphasize the interconnectedness of motivational systems and the consequent importance of considering the full motivational state of an animal to understand its behaviour.
The Carbon Dioxide-induced Bioluminescence Increase inArachnocampaLarvae
Authors: Charlton Hamish Richard , Merritt David John
Published: March 2020

Arachnocampalarvae utilise bioluminescence to lure small arthropod prey into their web-like silk snares. The luciferin-luciferase light-producing reaction occurs in a specialised light organ composed of Malpighian tubule cells in association with a tracheal mass. The accepted model for bioluminescence regulation is that light is actively repressed during the non-glowing period and released when glowing through the night. The model is based upon foregoing observations that carbon dioxide (CO2) – a commonly-used insect anaesthetic – produces elevated light output in whole, live larvae as well as isolated light organs. Alternative anaesthetics were reported to have a similar light-releasing effect. We set out to test this model inArachnocampa flavalarvae by exposing them to a range of anaesthetics and gas mixtures. The anaesthetics isoflurane, ethyl acetate, and diethyl ether did not produce high bioluminescence responses in the same way as CO2. Ligation and dissection experiments localised the CO2response to the light organ rather than it being a response to general anaesthesia. Exposure to hypoxia through the introduction of nitrogen gas combined with CO2exposures highlighted that continuity between the longitudinal tracheal trunks and the light organ tracheal mass is necessary for recovery of the CO2-induced light response. The physiological basis of the CO2-induced bioluminescence increase remains unresolved but is most likely related to access of oxygen to the photocytes. The results suggest that the repression model for bioluminescence control can be rejected. An alternative is proposed based on neural upregulation modulating bioluminescence intensity.

Summary Statement

CO2was thought to act as an anaesthetic producing elevated bioluminescence inArachnocampa. Here we show it acts directly on the light organ and does not act as an anaesthetic.
Lipogenesis and innate immunity in hepatocellular carcinoma cells reprogrammed by an isoenzyme switch of hexokinases
Authors: Perrin-Cocon Laure , Vidalain Pierre-Olivier , Jacquemin Clémence , Aublin-Gex Anne , Olmstead Keedrian , Panthu Baptiste , Rautureau Gilles J. P. , André Patrice , Nyczka Piotr , Hütt Marc-Thorsten , Amoedo Nivea , Rossignol Rodrigue , Filipp Fabian Volker , Lotteau Vincent , Diaz Olivier
Published: March 2020

During the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). The transcriptomic analysis of HCC tumors shows that highest expression level ofHK2in tumor lesions is inversely correlated toGCKexpression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis,HK2was knocked-out in the HCC cell line Huh7 and replaced byGCK, to generate the Huh7-GCK+/HK2−cell line. HK2 knockdown and GCK expression rewired central carbon metabolism, stimulated mitochondrial respiration and restored essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion, glycogen storage. It also reactivated innate immune responses and sensitivity to natural killer cells, showing that consequences of the HK switch extend beyond metabolic reprogramming.
Synchronised oscillations in growing cell populations are explained by demographic noise
Authors: Gavagnin Enrico , Vittadello Sean T. , Gunasingh Gency , Haass Nikolas K. , Simpson Matthew J. , Rogers Tim , Yates Christian A.
Published: March 2020

Understanding synchrony in growing populations is important for applications as diverse as epidemiology and cancer treatment. Recent experiments employing fluorescent reporters in melanoma cell lines have uncovered growing subpopulations exhibiting sustained oscillations, with nearby cells appearing to synchronise their cycles. In this study we demonstrate that the behaviour observed is consistent with long-lasting transient phenomenon initiated, and amplified by the finite-sample effects and demographic noise. We present a novel mathematical analysis of a multi-stage model of cell growth which accurately reproduces the synchronised oscillations. As part of the analysis, we elucidate the transient and asymptotic phases of the dynamics and derive an analytical formula to quantify the effect of demographic noise in the appearance of the oscillations. The implications of these findings are broad, such as providing insight into experimental protocols that are used to study the growth of asynchronous populations and, in particular, those investigations relating to anti-cancer drug discovery.

Statement of Significance

Recent experiments have reported strong evidence of periodic oscillations in the proportion of young and old melanoma cells. The biological mechanism generating this synchronisation and the potential impact that can have on commonly used experimental protocols is still unclear. Here we studied a population of melanoma cells for which we found oscillations in the proportions of cells in each phase of the cell cycle. We demonstrate that these observations may be triggered by intrinsic demographic noise alone, rather than any active synchronisation mechanism requiring cell-cell communication. Our findings may have implications for typical experimental protocols which aim to produce asynchronous cell populations.
Phosphorylation of the Anaphase Promoting Complex activator CDH1/FZR regulates the transition from Meiosis I to Meiosis II in mouse male germ cell
Authors: Tanno Nobuhiro , Kuninaka Shinji , Fujimura Sayoko , Okamura Kaho , Takemoto Kazumasa , Araki Kimi , Araki Masatake , Saya Hideyuki , Ishiguro Kei-ichiro
Published: March 2020

CDH1/FZR is an activator of Anaphase promoting complex/Cyclosome (APC/C), best known for its role as E3 ubiquitin ligase that drives the cell cycle. APC/C activity is regulated by CDK-mediated phosphorylation of CDH1 during mitotic cell cycle. Although the critical role of CDH1 phosphorylation has been shown mainly in yeast andin vitrocell culture studies, its biological significance in mammalian tissuesin vivoremained elusive. Here, we examined thein vivorole of CDH1 phosphorylation using a mouse model, in which non-phosphorylatable substitutions were introduced in the putative CDK-phosphorylation sites of CDH1. Although ablation of CDH1 phosphorylation did not show substantial consequences in mouse somatic tissues, it led to severe testicular defects resulting in male infertility. In the absence of CDH1 phosphorylation, male juvenile germ cells entered meiosis normally but skipped meiosis II producing diploid spermatid-like cells. In aged testis, male germ cells were overall abolished, showing Sertoli cell-only phenotype. The present study demonstrated that phosphorylation of CDH1 is required for temporal regulation of APC/C activity at the transition from meiosis I to meiosis II, and for spermatoginial stem cell maintenance, which raised an insight into the sexual dimorphism of CDH1-regulation in germ cells.
Biodiverse food plants in the semiarid region of Brazil have unknown potential: A systematic review
Authors: Jacob Michelle Cristine Medeiros , Medeiros Maria Fernanda Araujo , Albuquerque Ulysses Paulino
Published: March 2020

Food biodiversity presents one of the most significant opportunities to enhance food and nutrition security today. The lack of data on many plants, however, limits our understanding of their potential and the possibility of building a research agenda focused on them. Our objective with this systematic review was to identify biodiverse food plants occurring in the Caatinga biome, Brazil, strategic for the promotion of food and nutrition security. We selected studies from the following databases: Web of Science, Medline/PubMed (via the National Library of Medicine), Scopus and Embrapa Agricultural Research Databases (BDPA). Eligible were original articles, published since 2008, studying food plants occurring in the Caatinga. We assessed the methodological quality of the studies we selected. We reviewed a total of fifteen studies in which 65 plants that met our inclusion criteria were mentioned. Of this amount, 17 species, including varieties, subspecies, and different parts of plants, had data on chemical composition, in addition to being mentioned as food consumed by rural communities in observational ethnobotanical studies. From the energy and protein data associated with these plants, we produced a ranking of strategic species. The plants with values higher than the average of the set were:Dioclea grandifloraMart. ex Benth (mucunã),Hymenaea courbarilL. (jatobá),Syagrus cearensisNoblick (coco-catolé),Libidibia ferrea(Mart. ex Tul.) L.P.Queiroz (jucá),Sideroxylon obtusifolium(Roem. & Schult.) T.D.Penn. (quixabeira). We suggest that the scientific community concentrates research efforts on tree legumes, due to their resilience and physiological, nutritional, and culinary qualities.
Seasonal variability in copepod biomass in a cyclonic eddy in the Bay of La Paz, southern Gulf of California, Mexico
Authors: Rocha Díaz Franco Antonio , Monreal Gómez María Adela , Monter Erik Coria , de León David Alberto Salas , Durán Campos Elizabeth
Published: March 2020

As one of the main groups composing marine zooplankton, copepods play an important role due to the position they occupy in the trophic web. Study of their biomass and relationship with the physical conditions of the water column are essential in order to evaluate the trophic structure and functions of any aquatic ecosystem. As a contribution to this topic, we assessed the copepod biomass inside a cyclonic eddy system during two different seasons in the Bay of La Paz in the southern Gulf of California, a region characterized by high biological productivity. Two oceanographic expeditions took place in the winter of 2006 and summer of 2009 on which a conductivity-temperature-depth (CTD) probe was used to determine the physical structure of the water column and oblique zooplankton hauls collected zooplankton samples. Satellite data were used to visualize chlorophyll-a distribution patterns. The results showed the presence of a well-defined mesoscale cyclonic eddy in both seasons, with high chlorophyll-a (CHLA) values at the edges of the eddy. Maximum values for copepod biomass were observed in winter and their distribution corresponded well with the circulation pattern and the CHLA values, forming a belt shape following the periphery of the eddy. The results presented herein highlight the impact of the mesoscale eddy on the planktonic ecosystem through its influence on hydrographic conditions in the water column. Other factors, such as ecological interactions, population dynamics, and feeding habits may play a role as well. Feeding behavior in particular is affected by high CHLA concentrations observed around the eddy which represent a source of food for these organisms.
Potential geographic distribution of the Tiger MosquitoAedes albopictus(Skuse, 1894) (Diptera: Culicidae) in current and future conditions for Colombia
Authors: Echeverry-Cárdenas Emmanuel , López-Castañeda Carolina , Carvajal-Castro Juan D. , Aguirre-Obando Oscar Alexander
Published: March 2020

In Colombia, little is known on the distribution of the Asian mosquitoAedes albopictus, main vector of dengue, chikungunya, and Zika in Asia and Oceania. Therefore, this work set out to estimate its current and future potential geographic distribution under the Representative Concentration Paths (RCP) 2.6 and 8.5 emission scenarios by 2050 and 2070, using ecological niche models. For this, predictions were made in MaxEnt, employing occurrences ofA. albopictusfrom their native area and South America and bioclimatic variables of these places. It was found that, since its invasion to Colombia,A. albopictusis present in 47% of the country, in peri-urban (20%), rural (23%), and urban (57%) areas between 0 and 1800 m, with Antioquia and Valle del Cauca being the departments with the most registries. The current estimation suggests thatA. albopictusis distributed in 96% of the territory up to 3000 m (p < 0.001). Additionally, by 2050 and 2070, below RCP 2.6, its distribution could diminish to nearly 90% including altitudes of 3100 m, while below RCP 8.5 it would be < 60% increasing its distribution up to 3200 m. These results suggest that, currently in Colombia,A. albopictusis found throughout the country and climate change could diminish eventually its area of distribution, but increase its altitudinal range. In Colombia, surveillance and vector control programs must focus their attention on this vector to avoid complications in the national public health setting.
Malaria in Southern Venezuela: The Hottest Hotspot in Latin America
Authors: Grillet ME , Moreno JE , Hernández JV , Vincenti-González MF , Noya O , Tami A , Paniz-Mondolfi A , Llewellyn M , Lowe R , Escalante AA , Conn JE
Published: March 2020

Malaria cases in Latin America reached ~1 million in 2017 and 2018, with 53% and 51% reported from Venezuela, respectively. In this study, we characterized the spatiotemporal dynamics of malaria transmission between 2007-2017 in southern Venezuela, the main endemic area of the country. We found that disease transmission was focal and more prevalent in the southeast of southern Venezuela where two persistent hotspots of Plasmodium vivax (76%) and P. falciparum (18%) linked to deforestation for illegal gold mining accounted for ~60% of the country-wide number of cases. Incidence has increased nearly tenfold in the last decade, showing an explosive epidemic growth due to a significant lack of disease control. We suggest that a source-sink pattern of Plasmodium sp. dispersal account for the re-emergence and progression of malaria transmission in the last 4 years across the country due to the internal migration of infected people to and from the hotspots and other malaria-prone ecosystems. We observe a similar pattern explaining the spillover of cases across international borders affecting neighboring countries. This study provides baseline epidemiological data and guidance for malaria control to further assess the dynamics of cross-border malaria, the role of asymptomatic carriers, drug-resistant evolution, and innovative control efforts in the Latin America region.