Theory predicts that individuals living in fission–fusion societies, in which group members frequently change subgroups, should modify grouping patterns in response to varying social and ...environmental conditions. Spotted hyaenas,
Crocuta crocuta, are long-lived carnivores that reside in permanent social groups called clans. Clans are complex, fission–fusion societies in which individual members travel, rest and forage in subgroups that frequently change composition. We studied two clans in Kenya to provide the first detailed description of fission–fusion dynamics in this species. Because social and ecological circumstances can influence the cohesiveness of animal societies, we evaluated the extent to which specific circumstances promote the formation of subgroups of various sizes. We found that cooperative defence of shared resources during interclan competition and protection from lions were cohesive forces that promoted formation of large subgroups. We also tested hypotheses suggesting factors limiting subgroup size. Mothers with small cubs avoided conspecifics, thereby reducing infanticide risk. Victims of aggression either reconciled fights or separated from former opponents to reduce the immediate costs of escalated aggression in the absence of food. As predicted by the ecological constraints hypothesis, hyaenas adjusted their grouping patterns over both short and long time scales in response to feeding competition.
Crocuta were most gregarious during periods of abundant prey, joined clanmates at ephemeral kills in numbers that correlated with the energetic value of the prey and gained the most energy when foraging alone because cooperative hunting attracted numerous competitors. Overall, our findings indicate that resource limitation constrains grouping in this species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Introduction: PB-718 is a fixed dose combination of PB-119 (GLP-1 receptor agonist) and PB-722 (glucagon receptor agonist in clinical development. Compared with a single molecule approach, PB-718 may ...offer the balance between GLP-1 and GCGR through adjusting the molar ratio of PB-119 and PB-722 to achieve optimal efficacy and safety. Linear pharmacokinetics, good tolerability and promising effect of weight loss have been demonstrated in a phase 1 study conducted in US. Here we report a phase 1b/2a study in Obesity Methods: Thirty-six patients with obesity (BMI 30.5-40.0 kg/m2) without diabetes were randomized to this 3-sequential cohorts study (NCT06147544). In each cohort, 12 subjects were randomized (3:1) to receive PB-718 (PB-119/PB-722 600/1560 μg, 900/2340 μg or 1600/4160 μg) or placebo SC. injections once a week for 12-18 weeks. The primary endpoints were safety and PK profile. The secondary efficacy endpoints included changes in body weight (BW), BMI, lipids and HbA1c levels. Liver MRI-PDFF and body composition analysis were also assessed. Results: Both PB-119 and PB-722 demonstrated dose-proportional increases in AUC0-last and Cmax ,showing linear, and synergic pharmacokinetics. At 12 weeks, BW, FPG, HbA1c, Lipid, insulin level and HOMA-IR all decreased dose-dependently, and significant reduction in BW of over 4-6% were observed. Serum uric acid was also decreased. Liver fat content and visceral fat mass also showed significant and dose-related reduction with PB-718 treatment. Meanwhile, PB-718 groups lost more fat mass than lean mass. GI side effects were the most common AEs, and were all grade 1 in severity. Conclusions: PB-718 was safe, had predicted PK profile, and led to greater reductions in BW, HbA1c, blood lipids, uric acid, liver fat content and visceral fat mass. These data highlight the potential for PB-718 to provide additional benefit, and support the development of PB-718 as a promising treatment for obesity and NASH. Disclosure K. Ding: None.
Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density ...and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ₃ as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid ...metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, ...thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Patients with resectable lung cancer were assigned to neoadjuvant pembrolizumab or placebo plus chemotherapy and adjuvant pembrolizumab or placebo. Two-year event-free survival was 62.4% with ...pembrolizumab and 40.6% with placebo.
The efficacy of immunotherapy in advanced HER2‐mutated non‐small‐cell lung cancer (NSCLC) remains incomprehensively studied. A total of 107 NSCLC patients with de novo HER2 mutations were ...retrospectively studied at Guangdong Lung Cancer Institute GLCI cohort, exon 20 insertions (ex20ins): 71.0% to compare clinical/molecular features and immune checkpoint inhibitor (ICI)‐based therapy efficacy between patients with ex20ins and non‐ex20ins. Two external cohorts (TCGA, n = 21; META‐ICI, n = 30) were used for validation. In the GLCI cohort, 68.2% of patients displayed programmed death‐ligand 1 (PD‐L1) expression < 1%. Compared with ex20ins patients, non‐ex20ins patients had more concurrent mutations in the GLCI cohort (P < 0.01) and a higher tumour mutation burden in the TCGA cohort (P = 0.03). Under ICI‐based therapy, advanced NSCLC patients with non‐ex20ins had potentially superior progression‐free survival median: 13.0 vs. 3.6 months, adjusted hazard ratio (HR): 0.31, 95% confidence interval (CI): 0.11–0.83 and overall survival (median: 27.5 vs. 8.1 months, adjusted HR: 0.39, 95% CI: 0.13–1.18) to ex20ins patients, consistent with findings in the META‐ICI cohort. ICI‐based therapy may serve as an option for advanced HER2‐mutated NSCLC, with potentially better efficacy in non‐ex20ins patients. Further investigations are warranted in clinical practice.
HER2‐mutated non‐small‐cell lung cancer (NSCLC) patients with HER2 mutations other than exon 20 insertions (non‐ex20ins) had higher tumour mutation burden than patients with HER2 ex20ins, whereas similar programmed death‐ligand 1 expression was observed. Under immune checkpoint inhibitor‐based therapy, advanced NSCLC patients with HER2 non‐ex20ins had potentially superior progression‐free survival and overall survival compared with patients with HER2 ex20ins.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Most industrial alloys contain a matrix phase and dispersed second-phase particles. Several thermomechanical processing (TMP) steps are usually needed to produce a final product, during which ...recrystallization and its related phenomena may take place. Second-phase particles may retard or accelerate recrystallization, depending on their size and spatial distribution, the TMP conditions, among others. Besides their effect on recrystallization kinetics, the introduction of second-phase particles creates additional interfaces within the matrix, it also modifies the grain structure and crystallographic texture after recrystallization, which then either improves or deteriorates the associated mechanical properties of the investigated materials. The interactions between second-phase particles and recrystallization are further complicated when these particles are not stable. In addition to particle coarsening, they can also precipitate out or dissolve into the matrix before, simultaneously with or after recrystallization. This review article attempts to summarize the recent progresses on the complex interaction between second-phase particles and recrystallization and the science behind them. This double-edge effect of second-phase particles on recrystallization behaviour and mechanical properties of metallic materials is still far from being clear. A better understanding of this issue is of high academic and industrial interests, since it provides potential freedom for TMP design and microstructure control.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
CRISPR-Cas systems enable microbial adaptive immunity and provide eukaryotic genome editing tools. These tools employ a single effector enzyme of type II or V CRISPR to generate RNA-guided, precise ...genome breaks. Here we demonstrate the feasibility of using type I CRISPR-Cas to effectively introduce a spectrum of long-range chromosomal deletions with a single RNA guide in human embryonic stem cells and HAP1 cells. Type I CRISPR systems rely on the multi-subunit ribonucleoprotein (RNP) complex Cascade to identify DNA targets and on the helicase-nuclease enzyme Cas3 to degrade DNA processively. With RNP delivery of T. fusca Cascade and Cas3, we obtained 13%–60% editing efficiency. Long-range PCR-based and high-throughput-sequencing-based lesion analyses reveal that a variety of deletions, ranging from a few hundred base pairs to 100 kilobases, are created upstream of the target site. These results highlight the potential utility of type I CRISPR-Cas for long-range genome manipulations and deletion screens in eukaryotes.
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•T. fusca type I CRISPR-Cas enables long-range genome deletions in human cells•The target-binding complex Cascade and helicase-nuclease Cas3 are both required•Genome engineering by type I CRISPR is crRNA guided and programmable•Heterogeneous deletions up to 100 kb are induced upstream of a genomic target site
Dolan et al. demonstrate that T. fusca type I CRISPR-Cas can generate a spectrum of large genome deletions in human cells. Cascade and Cas3 together induce heterogeneous DNA lesions upstream of a single CRISPR-targeted site, highlighting their potential utilities for long-range genome manipulation and deletion screen.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Evidence documents associations between neighborhood design and active and sedentary forms of travel. Most studies compare travel patterns for people located in different types of neighborhoods at ...one point in time adjusting for demographics. Most fail to account for either underlying neighborhood selection factors (reasons for choosing a neighborhood) or preferences (neighborhoods that are preferred) that impact neighborhood selection and behavior. Known as self-selection, this issue makes it difficult to evaluate causation among built form, behavior, and associated outcomes and to know how much more walking and less driving could occur through creating environments conducive to active transport. The current study controls for neighborhood selection and preference and isolates the effect of the built environment on walking, car use, and obesity. Separate analyses were conducted among 2056 persons in the Atlanta, USA based Strategies for Metropolitan Atlanta's Regional Transportation and Air Quality (SMARTRAQ) travel survey on selection factors and 1466 persons in the SMARTRAQ community preference sub-survey. A significant proportion of the population are “mismatched” and do not live in their preferred neighborhood type. Factors influencing neighborhood selection and individual preferences, and current neighborhood walkability explained vehicle travel distance after controlling for demographic variables. Individuals who preferred and lived in a walkable neighborhood walked most (33.9% walked) and drove 25.8 miles per day on average. Individuals that preferred and lived in car dependent neighborhoods drove the most (43 miles per day) and walked the least (3.3%). Individuals that do not prefer a walkable environment walked little and show no change in obesity prevalence regardless of where they live. About half as many participants were obese (11.7%) who prefer and live in walkable environments than participants who prefer car dependent environments (21.6%). Findings suggest that creating walkable environments may result in higher levels of physical activity and less driving and in slightly lower obesity prevalence for those preferring walkability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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