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POISON DART FROGS, members of the Dendrobatidae family, wear some of the most brilliant and beautiful colors on Earth. Depending on their habitats, which extend from the tropical forests of [...]

AbstractThe recent rediscovering of the Millefiori Piemontese breed, previously considered as extinct, has led to its genetic characterisation: establishing the basis for its recovery and preservation. This study describes the morpho-biometric traits and compares the genetic variability of the Millefiori Piemontese breed with that of other local chicken breeds using 26 microsatellite markers. A subset of 14 markers was used to compare the genetic variation of the Millefiori Piemontese breed with that of two other Piedmontese chicken breeds (Bionda Piemontese and Bianca di Saluzzo) as well as 17 Italian and 2 commercial hybrids, whose genetic variability has already been investigated. The present study confirmed the sexual dimorphism and assessed the genetic variability of the Millefiori Piemontese in terms of number of alleles/locus (Na = 4), the effective number of alleles (Nea = 3), observed (Ho = 0.56) and expected heterozygosity (He = 0.53), self-coancestry (IB = 0.65), potential extinction risk (ERI = 2), and its contribution to the Italian poultry biodiversity (GDT = −0.60). The results indicate that, despite its small population size (Ne = 56), the Millefiori Piemontese population exhibits significant genetic diversity, making it a valuable resource for breeding programs focused on preserving the breed and safeguarding its biodiversity. This study is the first to investigate the genetic variability of the Millefiori Piemontese breed and compare it with other local poultry breeds. The findings highlight the genetic uniqueness of the Millefiori breed and its significant contribution to the biodiversity of chickens in Piedmont and Italy, emphasising the importance of its conservation.

ABSTRACTObjectiveThe aim of this study was to identify whether the coping strategy of active self-care, and the coping resource of employment flexibility were moderators of the relationships between parental distress and parenting practices, and parental experience and parenting practices, in parents of adolescents.MethodThis research was part of a larger study conducted by the Parenting Research Centre who surveyed a representative sample of 2600 Victorian parents on their parental concerns, approaches, and experiences using computer-assisted telephone interviews.ResultsResults demonstrated that employment flexibility and active self-care significantly moderated the relationship between a demanding parental experience and autonomy-supportive parent-child communication, and that active self-care moderated the relationship between the belief parenting comes naturally and negative parenting. It was concluded that both coping indicators had protective effects on parenting practices, through interacting with parental experience.ConclusionsPractical implications of this research include enhancement of parental interventions by lending evidence that both self-care and employment flexibility promote parent-child communication and protect against more aversive parenting behaviours.

HER2 expression and overexpression is characterized by spatial and temporal heterogeneity.HER2 heterogeneity can be a determinant of response and resistance to HER2-targeting agents in HER2-positive solid tumors.Since its predictive role varies across solid tumors and HER2-targeting agents, HER2 heterogeneity is not an agnostic predictor of treatment benefit.

SEVERAL YEARS AGO, on assignment for National Geographic, I ventured inside a cave in Uganda to photograph a roost of roughly 100,000 Egyptian fruit bats. The bats are common throughout [...]

There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer.

In 1991, National Geographic magazine assigned me to my first major story: 'America's Gulf Coast.' Over 27 weeks. I ranged from South Texas to Key West, covering everything from Mardi [...]

Despite the paramount importance in metal(loid) detoxification by phytochelatin synthase(PCS) genes, no comprehensive analysis of their evolutionary patterns has been carried out in land plants in general and in crops in particular. A phylogenetic large-scale analysis of gene duplication in angiosperms was carried out followed by in vitrorecombinant protein assays as well as complementation analysis (growth, thiol-peptides, elements) of Arabidopsis cad1–3mutant with four representative PCSgenes from two model crop species, Malus domesticaand Medicago truncatula. We uncovered a so far undetected ancient tandem duplication (D duplication) spanning the whole core eudicotyledon radiation. Complementation with PCSgenes from both D-subclades from M. domesticaand M. truncatuladisplayed clear in vivoconservation of the differences between D1 and D2 paralogous proteins in plant growth, phytochelatin, and glutathione pools, as well as element contents under metal(loid) stress. In vitrorecombinant PCS analysis identified analogous patterns of differentiation, showing a higher activity of D2 PCSgenes, so far largely overlooked, compared to their paralogs from the D1 clade. This suggests that in many other crop species where the duplication is present, the D2 copy might play a significant role in metal(loid) detoxification. The retention of both PCSparalogs and of their functional features for such long divergence time suggests that PCScopy number could be constrained by functional specialization and/or gene dosage sensitivity. These results uncover the patterns of PCSevolution in plant genomes and of functional specialization of their paralogs in the genomes of two important model crops.

When clustering molecular dynamics (MD) trajectories into a few metastable conformational states, the assumption of time scale separation between fast intrastate fluctuations and rarely occurring interstate transitions is often not valid. Hence, when we construct a Markov state model (MSM) from these states, the naive estimation of the macrostate transition matrix via simply counting transitions between the states may lead to significantly too-short implied time scales and thus to too-fast population decays. In this work, we discuss advanced approaches to estimate the transition matrix. Assuming that Markovianity is at least given at the microstate level, we consider the Laplace-transform-based method by Hummer and Szabo, as well as a direct microstate-to-macrostate projection, which by design yields correct macrostate population dynamics. Alternatively, we study the recently proposed quasi-MSM ansatz of Huang and co-workers to solve a generalized master equation, as well as a hybrid method that employs MD at short times and MSM at long times. Adopting a one-dimensional toy model and an all-atom folding trajectory of HP35, we discuss the virtues and shortcomings of the various approaches.

This work describes a new platform for sensing mass or rheological properties of gases with unprecedented responsivity and limits of detection. The system consists of a microcantilever working in a phase-locked loop (PLL) with an imposed phase between its excitation and deflection signals. The optically detected cantilever deflection is demodulated against digitally synthetized reference signals, and the quadrature component ( ${Q}$ -signal) is used as the error parameter in a PI controller, which continuously tracks the oscillation frequency. The direct digital synthesis of the reference and actuation signals allows low-noise and fast-transient responses of the sensor for real-time detection of minute changes of any environmental parameter. A general analytical model is derived, used to understand the dynamical response of the platform, and validated against experiments using different gases and pressures. In particular, the responsivity of the sensor to density variations of the fluids and the stability of its frequency response are studied and measured. It is shown that the responsivity and the achieved limits of detection depend on the chosen phase imposed in the loop. A limit of detection for density variations of $3.5\times 10^{-{4}}$ kg/ $\text{m}^{{3}}$ in air is measured, in agreement with the theoretical predictions, and one to two orders of magnitude lower than any reported value achieved with the same type of physical uncoated resonant sensors.

ObjectivesEarly-onset colorectal cancer (EO-CRC) incidence is increasing, raising a clinical challenge. Clinicians tend to treat EO-CRC patients with more intensive regimens despite the lack of survival benefits, based on an age-related bias. Limited evidence is available regarding treatment-related toxicities in this peculiar subset of patients.MethodsWe performed a literature search in MEDLINE/PubMed, EMBASE and Scopus, looking for reporting of nausea, vomiting and diarrhoea occurring in patients with EO-CRC, defined by age lower than 50 years old at initial diagnosis, while receiving anticancer treatment.Results2318 records were screened and 9 full-text articles were considered eligible for inclusion for a total of 59 783 patients (of whom 8681 EO-CRC patients). We found nausea and vomiting occurring at higher incidence among EO-CRC compared with older patients, while no difference was reported as for diarrhoea. Peritoneal involvement, age younger than 40, female gender, suboptimal adherence to guidelines and oxaliplatin might represent potential risk factors for increased nausea and vomiting in patients with EO-CRC.ConclusionEO-CRC patients experience more nausea and vomiting but equal or less diarrhoea compared with older patients. Adherence to clinical guidelines is recommended, and more data are warranted to assess if an enhanced antiemetic approach might be required, particularly in case of specific risk factors.

The monoclonal antibodies panitumumab and cetuximab that target the epidermal growth factor receptor (EGFR) have expanded the range of treatment options for metastatic colorectal cancer. Initial evaluation of these agents as monotherapy in patients with EGFR-expressing chemotherapy-refractory tumors yielded response rates of approximately 10%. The realization that detection of positive EGFR expression by immunostaining does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Oncogenic activation of signaling pathways downstream of the EGFR, such as mutation of KRAS, BRAF, or PIK3CA oncogenes, or inactivation of the PTEN tumor suppressor gene is central to the progression of colorectal cancer. Tumor KRAS mutations, which may be present in 35%-45% of patients with colorectal cancer, have emerged as an important predictive marker of resistance to panitumumab or cetuximab treatment. In addition, among colorectal tumors carrying wild-type KRAS, mutation of BRAFor PIK3CA or loss of PTEN expression may be associated with resistance to EGFR-targeted monoclonal antibody treatment, although these additional biomarkers require further validation before incorporation into clinical practice. Additional knowledge of the molecular basis for sensitivity or resistance to EGFRtargeted monoclonal antibodies will allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and could also provide rationale for combining therapies to overcome primary resistance. The use of KRAS mutations as a selection biomarker for anti-EGFR monoclonal antibody (eg, panitumumab or cetuximab) treatment is the first major step toward individualized treatment for patients with metastatic colorectal cancer.

INTRODUCTION Though strides have been made, women continue to face various forms of workplace discrimination. Earnings represent one such area. According to US Census Bureau estimates from 2004, the median [...], The purpose of this study was to examine the influence of teacher sex and student sex on perceptions of fit and teacher effectiveness. Students (43 women, 55 men) enrolled at a large public university in the Southwest United States participated in an experimental study in which they viewed a women's health lecture online and then responded to a questionnaire. Results from the observed path analysis indicate that while the teacher's sex did not directly influence perceptions of fit, there was a significant student sex x teacher sex interaction. Among women who viewed the lecture, fit perceptions were higher for the female teacher over the male teacher. Men who viewed the lecture did not vary in their ratings. Finally, the perceived fit of the teacher was reliably related to overall evaluation of instruction. Contributions to theory and practice are discussed.

AbstractThis study investigated activated crystalline silicon dioxide (SIL) supplementation in late pregnancy and lactating sows on reproductive parameters as well as the performance of suckling piglets. Eighty sows were assigned to two groups: control (CON, n = 40), and activated crystalline SIL (n = 40). Both treatments received identical basal diets, without (CON), or with 0.3 kg of activated SIL/ton at day 111 of pregnancy up to day 21 of lactation. The sows were evaluated at day110 of gestation and at day 21 of lactation for individual body weight (BW), backfat (BF), average daily feed intake (ADFI), percentage of BW and BF loss, and milk production. The litter was evaluated for size and BW at birth, and at 21 d old, likewise the preweaning survival percentage. At day 21 lactation, the SIL sows were 2.39% heavier than the CON group. The sows also had an increase of 5.05% in milk yield compared to the CON sows. In addition, SIL sows showed lower weight loss compared to CON sows. The weaned piglets from SIL sows had an increase of 4.43% in BW compared to CON sows. In conclusion, supplementation of 0.03% of activated crystalline SIL applied to late pregnancy, and to lactating sows reduced weight loss and marginally improved the milk yield and BW of piglets at weaning.HighlightsThe activated crystalline silicon dioxide (SIL) in diets from late pregnancy to lactation reduced body weight loss of sows.Sows that received activated crystalline SIL in late pregnancy and lactating period trended to improve the milk yield in 5.05%.The piglets from sows fed activated crystalline SIL tended to enhance 4.43% in body weight at 21-d old.

National Geographic Kids features an article on the Photo Ark project by photographer Joel Sartore, who aims to photograph over 25,000 animal species in zoos, aquariums, and sanctuaries. The article highlights a photo shoot with Lucy, a Florida panther at ZooTampa in Florida, showcasing Sartore's use of plain backgrounds to focus on the animals. Lucy, raised by zoo staff, is comfortable around people but cannot be released into the wild. The project aims to raise awareness about animal conservation and offers tips on how to save animals. [Extracted from the article]

The emerging sectors of agriculture, such as organics, urban, and local food, tend to be dominated by farms that are smaller, more transient, more diverse, and more dispersed than the traditional farms in the rural areas of the United States. As a consequence, a list frame of all farms within one of these sectors is difficult to construct and, even with the best of efforts, is incomplete. The United States Department of Agriculture’s (USDA’s) National Agricultural Statistics Service (NASS) maintains a list frame of all known and potential U.S. farms and uses this list frame as the sampling frame for most of its surveys. Traditionally, NASS has used its area frame to assess undercoverage. However, getting a good measure of the incompleteness of the NASS list frame using an area frame is cost prohibitive for farms in these emerging sectors that tend to be located within and near urban areas. In 2016, NASS conducted the Local Food Marketing Practices (LFMP) survey. Independent samples were drawn from (1) the NASS list frame and (2) a web-scraped list of local food farms. Using these two samples and capture–recapture methods, the total number and sales of local food operations at the United States, regional, and state levels were estimated. To our knowledge, the LFMP survey is the first survey in which a web-scraped list frame has been used to assess undercoverage in a capture–recapture setting to produce official statistics. In this article, the methods are presented, and the challenges encountered are reviewed. Best practices and open research questions for conducting surveys using web-scraped list frames and capture–recapture methods are discussed.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RASwild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAFand EGFRmutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFRmutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RASWT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.

Vaginal suppositories containing boric acid are as effective as antifungal drugs in treating vaginal yeast infections, but the infection may recur when the woman stops using them. Researchers are studying boric acid for this use because many antifungal drugs have severe side effects.

A proposed hydroelectric dam would inundate much of the new Madidi national park in Bolivia. The 4.7-milion-acre park is a remote, biologically diverse rainforest that has not yet been completely explored.

The National Wildlife Refuge System covers about 4% of the US and protects a wide variety of wildlife. However, reduced government spending, coupled with growing pressures from commercial sectors, are threatening the viability of the system.

How gene expression is controlled to preserve human T cell quiescence is poorly understood. Here we show that non-canonical splicing variants containing long interspersed nuclear element 1 (LINE1) enforce naive CD4+T cell quiescence. LINE1-containing transcripts are derived from CD4+T cell-specific genes upregulated during T cell activation. In naive CD4+T cells, LINE1-containing transcripts are regulated by the transcription factor IRF4 and kept at chromatin by nucleolin; these transcripts act in cis, hampering levels of histone 3 (H3) lysine 36 trimethyl (H3K36me3) and stalling gene expression. T cell activation induces LINE1-containing transcript downregulation by the splicing suppressor PTBP1 and promotes expression of the corresponding protein-coding genes by the elongating factor GTF2F1 through mTORC1. Dysfunctional T cells, exhausted in vitro or tumor-infiltrating lymphocytes (TILs), accumulate LINE1-containing transcripts at chromatin. Remarkably, depletion of LINE1-containing transcripts restores TIL effector function. Our study identifies a role for LINE1 elements in maintaining T cell quiescence and suggests that an abundance of LINE1-containing transcripts is critical for T cell effector function and exhaustion.

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1–6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes—SUV420H1(also known as KMT5B), ARID1Band CHD8—in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages—γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons—but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

As the PCI bus becomes the interface of choice for most desktop systems, it's clear the benefits of high-bandwidth and plug-and-play operation do not come easy. Unlike its ISA and [...]

Insights on the social, economic and environmental aspects of the states around the Gulf of Mexico are presented. Environmental impacts of the industries and human activity in the Gulf Coast are tackled. The experiences of local people in these areas are also related.

The article reports that Angelfish glow as if neon under water, and Chameleons can change their poison frogs dare to clothe in the most unnatural of blues and yellows effective in discouraging predators, experts presume. Topics include National Geographic Society, committed to illuminating and protecting the wonder of the the Photo Ark project founded by National Geographic Explorer Joel Sartore; and the National Geographic Photo Ark to use images to help save threatened species and habitat.

Since the nineties, the incidence of sporadic early-onset (EO) cancers has been rising worldwide. The underlying reasons are still unknown. However, identifying them is vital for advancing both prevention and intervention. Here, we exploit available knowledge derived from clinical observations to formulate testable hypotheses aimed at defining the causal factors of this epidemic and discuss how to experimentally test them. We explore the potential impact of exposome changes from the millennials to contemporary young generations, considering both environmental exposures and enhanced susceptibilities to EO-cancer development. We emphasize how establishing the time required for an EO cancer to develop is relevant to defining future screening strategies. Finally, we discuss the importance of integrating multi-dimensional data from international collaborations to generate comprehensive knowledge and translate these findings back into clinical practice.

Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+Tregand eomesodermin homolog (EOMES)+type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+Tr1-like cells, but not Tregcells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Tregcells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

AbstractIn a scenario of climate change and risk of losing biodiversity, the safeguard of locally adapted breeds and their genetic reservoirs assumes a key role. Furthermore, these breeds are linked to their rearing territory maintenance also through the nutritional, economic or social value of their products. This study focussed on the analysis of milk protein genetic variability of the Piedmontese, the most abundant beef Italian breed, and the Barà-Pustertaler breed, through the testing of individual milk samples by isoelectrofocusing. Allelic and haplotypes frequencies were analysed and the presence of rare variants (CSN1S1*G, 0.7%, and CSN2*C, 0.7%, in Barà and Piedmontese breeds, respectively) was detected. The analysed breeds showed allelic frequencies close to the one found in breeds with good cheesemaking aptitude, like the Italian Brown and Reggiana breeds (e.g. CSN2*B, 20.7% and 16.4%, and CSN3*B, 41,1% and 35%, in Piedmontese and Barà breeds, respectively), and are a good reservoir of alleles that are decreasing (e.g. CSN2*B) in Italian Holstein. Moreover, they have higher frequencies of interesting haplotypes (e.g. BA1B, 8% and 11.2%, and BA2B, 20.8 and 13.1% in Piedmontese and Barà breeds, respectively) that could positively influence composition, nutritional, and technological properties of milk. These breeds could be used to further investigate the effects of variants and haplotypes that could help support the evolution and the changing demands of the dairy sector.HighlightsIn order to address the problem of climate change effects on animal biodiversity, local breeds should be safeguarded and valorised.The analysed breeds have discrete frequencies of milk protein variants and casein haplotypes associated with good technological properties.Knowing the genetic background of non-dairy commercial breeds is the first step to preserve potentially useful genetic variability.

The Pennsylvania RR may have been known as the Standard Railroad of the World, but its station in Clifton, Pa., was far from standard for the Pennsy. The station was […]

In theory, it's supposed to be fun--a series of photo trips to the Brazilian Pantanal for NATIONAL GEOGRAPHIC. But you have to figure that if you go repeatedly to one [...]

In mammals, mechanics at multiple stages—nucleus to cell to ECM—underlie multiple physiological and pathological functions from its development to reproduction to death. Under this inspiration, substantial research has established the role of multiple aspects of mechanics in regulating fundamental cellular processes, including spreading, migration, growth, proliferation, and differentiation. However, our understanding of how these mechanical mechanisms are orchestrated or tuned at different stages to maintain or restore the healthy environment at the tissue or organ level remains largely a mystery. Over the past few decades, research in the mechanical manipulation of the surrounding environment—known as substrate or matrix or scaffold on which, or within which, cells are seeded—has been exceptionally enriched in the field of tissue engineering and regenerative medicine. To do so, traditional tissue engineering aims at recapitulating key mechanical milestones of native ECM into a substrate for guiding the cell fate and functions towards specific tissue regeneration. Despite tremendous progress, a big puzzle that remains is how the cells compute a host of mechanical cues, such as stiffness (elasticity), viscoelasticity, plasticity, non-linear elasticity, anisotropy, mechanical forces, and mechanical memory, into many biological functions in a cooperative, controlled, and safe manner. High throughput understanding of key cellular decisions as well as associated mechanosensitive downstream signaling pathway(s) for executing these decisions in response to mechanical cues, solo or combined, is essential to address this issue. While many reports have been made towards the progress and understanding of mechanical cues—particularly, substrate bulk stiffness and viscoelasticity—in regulating the cellular responses, a complete picture of mechanical cues is lacking. This review highlights a comprehensive view on the mechanical cues that are linked to modulate many cellular functions and consequent tissue functionality. For a very basic understanding, a brief discussion of the key mechanical players of ECM and the principle of mechanotransduction process is outlined. In addition, this review gathers together the most important data on the stiffness of various cells and ECM components as well as various tissues/organs and proposes an associated link from the mechanical perspective that is not yet reported. Finally, beyond addressing the challenges involved in tuning the interplaying mechanical cues in an independent manner, emerging advances in designing biomaterials for tissue engineering are also explored.

IMPORTANCE: Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti–epidermal growth factor receptors, and the optimal regimen for an anti–epidermal growth factor receptors–based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined. OBJECTIVE: To determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen. DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018. INTERVENTIONS: Patients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A. RESULTS: Overall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07; P = .01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B. CONCLUSIONS AND RELEVANCE: In patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02476045

Physical activity behavior change theorists are actively shifting the field to better align with the science of motivation and decision making. With this shift has come increasing interest in the role of affective judgments, habit, and identity in long-term physical activity maintenance, as well as the importance of framing physical activity in ways that protect autonomy and support personal values. This special communication makes the case for dog walking as a physical activity modality that fits well with the field's new focus. The authors provide an overview of dog walking research performed to date and discuss unanswered research questions. Given the large percentage of U.S. households that own a dog and the mainstream animal welfare movement to rehome adoptable shelter pets, there are innumerable opportunities to leverage the human-dog bond to increase physical activity levels.Dog walking interventions may be a highly practical approach to population-level physical activity promotion.

The bacterial genotoxin colibactin promotes colorectal cancer (CRC) tumorigenesis, but systematic assessment of its impact on DNA repair is lacking, and its effect on response to DNA-damaging chemotherapeutics is unknown. We find that CRC cell lines display differential response to colibactin on the basis of homologous recombination (HR) proficiency. Sensitivity to colibactin is induced by inhibition of ATM, which regulates DNA double-strand break repair, and blunted by HR reconstitution. Conversely, CRC cells chronically infected with colibactin develop a tolerant phenotype characterized by restored HR activity. Notably, sensitivity to colibactin correlates with response to irinotecan active metabolite SN38, in both cell lines and patient-derived organoids. Moreover, CRC cells that acquire colibactin tolerance develop cross-resistance to SN38, and a trend toward poorer response to irinotecan is observed in a retrospective cohort of CRCs harboring colibactin genomic island. Our results shed insight into colibactin activity and provide translational evidence on its chemoresistance-promoting role in CRC.

INTO MADIDI'S TEEMING JUNGLE: A PHOTOGRAPHER'S JOURNAL He's photographed many wild places, so Joel Sartore knew his visit to Madidi would be no walk in the park. But he didn't [...]

AbstractThe feed utilisation of young chicks is characterised by a suboptimal fat digestibility, which can be improved by means of dietary emulsifiers. The objective of this study was to evaluate the effect of dietary Globin on the energy efficiency and digestibility of starter feeds and on the production performance of broilers throughout the whole rearing cycle.A total of 224-day-old ROSS 708 chickens (14 birds/pen, 8 replicates/treatment) were fed ad libitumwith either a basal diet (C) or a basal diet with the addition of 0.05% Globin during the starter (d1–10), growing (d10–25) and finisher (d25–35) periods. Nutrient digestibility (aD), protein metabolisability (aMCP), energy efficiency (EE) and net energy for production (NEp) were assessed during the starter period. The average daily feed intake (ADFI), average daily gain (ADG), feed conversion ratio (FCR) and protein efficiency ratio (PER) were measured of each growth period.Globin significantly decreased FCR (p= .020) and increased aDfat(p= .021), EE (p= .028) and NEp (p= .011) during the starter period. aMCP(p= .049) and PER (p= .039) were higher in the Globin group than in the Control group. The increased availability of energy from dietary fat, as a result of Globin supplementation, possibly shifted the use of the absorbed amino acids towards an anabolic metabolism, and this could explain the increased aMCPand PER but similar aDCP. The overall performance was similar between groups, although Globin tended to increase PER (p= .064) overall.HighlightsGlobin dietary supplementation was studied in broiler chickens.Globin improved digestibility and nutrient efficiency utilization in the first period.The overall performance was similar between groups.

Tissue engineers have explored a set of materials cues that can allow control of cell viability and guide cell fate and functions. Although the effect of substrate stiffness on cell fate has been extensively studied and established, the role of substrate stress relaxation, the ability of a substrate to dissipate cell-induced forces, is only emerging. Recently, several studies have demonstrated that substrate stress relaxation is an important mechanical cue for cell spreading, proliferation and differentiation in vitro. In this mini-review, we highlight the influence of substrate stress relaxation on cell behavior and function as well as provide future perspectives. Firstly, we describe the methods used for characterizing the stress relaxation/creep responses of hydrogels along with the molecular origin of viscoelastic properties. Then, we highlight the most recent studies elucidating the stress relaxation effect on cellular behavior using physically cross-linked hydrogels. Finally, we report on an emerging alternative design of tunable viscoelastic hydrogels: chemically cross-linked (reversible linkages) adaptable hydrogels that have been used as stable 3D cell culture platforms for a few years in the era of hydrogel systems.

Introduction:The mesenchymal stromal cells (MSCs) have gained considerable popularity owing to the vast possibilities and lack of ethical constraints. MSCs serve as multipotent progenitors for several niche components in the bone marrow (BM) and play an essential role in the quiescence, proliferation, and differentiation of hematopoietic stem cells. Recently, MSCs from BM (BM-MSCs) represent an attractive cell source for tissue engineering, thanks to their immunomodulatory property, self-renewing and high proliferative capability. BM-MSCs have multi-lineages (adipogenesis, chondrogenesis, osteogenesis) potential and in combination with biomaterials, well support cell-attachments and stimulate extracellular matrix synthesis. For these reasons, BM-MSCs have a great potential for regenerative medicine applications. The present research aims to evaluate the ability of BM-MSCs to proliferate and differentiate toward the osteogenic lineage into innovative three-dimensional bioresorbable scaffold based on gelatin-chitosan hydrogel with a poly(lactic acid) lattice structure (PLA-CH) for regenerative medicine applications in the presence of fetal bovine serum (FBS) or human platelet lysate (HPL) with or without the osteogenic medium (OM).

ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

The article presents questions and answers asked to the photographers related to experiences in the field including an item carried at all times in the field, the first memorable incident, and a memorable save in the field.