Engineering Native Biological Complexity from the Inside-out and Outside-in.

Focusing on engineering control over cell function and fate, this article examines the critical balance of 'outside-in' and 'inside-out signaling in tissue development and regeneration. It highlights emerging strategies to manipulate these interactions, including biomaterial design and synthetic biology to influence this delicate equilibrium and fine tune cellular responses.

Re-evaluating Methods for Assessing Differences in Response in Ileal vs. Colonic Crohn's Disease: A Post-hoc Analysis of the FITZROY Trial.

BACKGROUND AND AIMS: The ileum is the most commonly affected segment of the gastrointestinal tract in Crohn's disease (CD). We aimed to determine whether disease location affects response to filgotinib, a Janus kinase (JAK) inhibitor, in patients with moderate-to-severely active Crohn's disease (CD) and applying appropriate methods to account for differences in measuring disease activity in the ileum compared to the colon. METHODS: This post-hoc analysis of data from the FITZROY phase 2 trial (NCT02048618) compared changes in the Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) amongst patients with ileal-dominant and isolated colonic CD treated with 10 weeks of filgotinib 200 mg daily or placebo. A mixed effects model for repeated measures was used to test whether ileal disease responded differently than colonic disease, by evaluating for effect modification using the interaction term of treatment assignment-by-disease location. RESULTS: Numerically greater proportions of patients with isolated colonic disease compared to ileal-dominant CD achieved clinical remission (CDAI <150, 75.9% vs. 41.6%) and endoscopic response (SES-CD reduction by 50%, 52.5% vs. 15.5%) at Week 10. However, after adjusting for baseline disease activity by disease location and within-patient clustering effects, there was no significant difference in treatment response by disease location (mean difference in ΔCDAI between ileal-dominant vs. isolated colonic disease +9.24 [95% CI: -87.19, +105.67], p=0.85; mean difference in ΔSES-CD -1.93 [95% CI: -7.03, +3.44], p=0.48). CONCLUSIONS: Filgotinib demonstrated similar efficacy in ileal-dominant and isolated colonic CD when controlling for baseline disease activity and clustering effects.

IBD Matchmaking - Rational Combination Therapy.

A growing number of patients with Crohn's disease and ulcerative colitis have disease that is refractory to multiple advanced therapies, have undergone multiple surgeries and require further treatment options. For this reason, there has been increasing use of multiple simultaneous advanced targeted therapies. While knowledge on combined advanced targeted therapy (CATT) in inflammatory bowel disease has been largely limited to observational data and early phase randomized controlled trials, combination of therapies is commonplace in many other diseases. This review discusses conceptual frameworks of CATT in inflammatory bowel disease (IBD), provides context of combined therapies in other diseases, provides current evidence for CATT in IBD, and projects future applications and positioning of CATT using existing, novel, and orthogonal mechanisms of action. CATT aims to address the need to overcome low efficacy rates and frequent loss of response of current individual therapies. Both treatment exposure and disease duration are major determinants of response to therapy. Identification of safe and effective CATT may impact positioning of this strategy to apply to a broader IBD population.

Habitat occupancy of the threatened Diademed Plover (Phegornis mitchellii) is not affected by llama grazing or peatland size, but declines with peatland humidity.

Many habitat-specialist organisms occur in distinct, patchy habitat, yet do not occupy all patches, and an important question is why apparently suitable habitat remains unoccupied. We examined factors influencing patch occupancy in near-threatened, little-known Diademed Plovers (Phegornis mitchellii), arguably the bird most specialized to life in High Andean peatlands. Andean peatlands are well-suited to occupancy modelling because they are discrete patches of humid habitat within a matrix of high-altitude steppe. We hypothesized that Diademed Plovers occupy preferably larger and more humid peatlands, and avoid peatlands used for grazing by llamas and vicuñas, which may trample vegetation and nests. From December 2021 to February 2022 (breeding season), we conducted plover occupancy surveys (2-4) on 40 peatlands at Lagunas de Vilama, a landscape of arid steppe and wetlands above 4,500 m in NW Argentina. We measured peatland size, grazing pressure, topographic and remotely-sensed variables that correlate with humidity, and incorporated these as covariates in occupancy models. Occupancy models showed that more than 50% of the studied peatlands were used by Diademed Plovers and most showed signs of reproduction, highlighting the importance of the Vilama Wetlands for Diademed Plover conservation. Within peatlands, Diademed Plovers were most often associated with headwaters. The top ranked occupancy model included constant detection, random spatial effects, and a single occupancy covariate: mean NDWI (Normalized Difference Water Index, an index correlated with water content and humidity) over the previous three years. Contrary to our prediction, Diademed Plovers preferred less water-saturated peatlands (lower NDWI), possibly to avoid nest flooding. This may be especially important in wet years, like the year when we conducted our surveys. Neither peatland size nor grazing by llamas and vicuñas affected peatland use by Diademed Plovers, suggesting that llama grazing at current levels may be compatible with plover conservation. For organisms that specialize on humid habitats, such as peatlands, factors affecting occupancy may vary temporally with variation in climate, and we recommend follow-up surveys across multi-year timescales to untangle the impact of climate on animals' use of humid habitats.

Molecular profiling of 888 pediatric tumors informs future precision trials and data-sharing initiatives in pediatric cancer.

To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children's Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.

Retrotransposon-mediated disruption of a chitin synthase gene confers insect resistance to Bacillus thuringiensis Vip3Aa toxin.

The vegetative insecticidal protein Vip3Aa from Bacillus thuringiensis (Bt) has been produced by transgenic crops to counter pest resistance to the widely used crystalline (Cry) insecticidal proteins from Bt. To proactively manage pest resistance, there is an urgent need to better understand the genetic basis of resistance to Vip3Aa, which has been largely unknown. We discovered that retrotransposon-mediated alternative splicing of a midgut-specific chitin synthase gene was associated with 5,560-fold resistance to Vip3Aa in a laboratory-selected strain of the fall armyworm, a globally important crop pest. The same mutation in this gene was also detected in a field population. Knockout of this gene via CRISPR/Cas9 caused high levels of resistance to Vip3Aa in fall armyworm and 2 other lepidopteran pests. The insights provided by these results could help to advance monitoring and management of pest resistance to Vip3Aa.

Fully synthetic hydrogels promote robust crypt formation in intestinal organoids.

Initial landmark studies in the design of synthetic hydrogels for intestinal organoid culture identified precise matrix requirements for differentiation, namely decompression of matrix-imposed forces and supplementation of laminin. But beyond stating the necessity of laminin, organoid-laminin interactions have gone largely unstudied, as this ubiquitous requirement of exogenous laminin hinders investigation. In this work, we exploit a fast stress relaxing, boronate ester based synthetic hydrogel for the culture of intestinal organoids, and fortuitously discover that unlike all other synthetic hydrogels to date, laminin does not need to be supplemented for crypt formation. This highly defined material provides a unique opportunity to investigate laminin-organoid interactions and how it influences crypt evolution and organoid function. Via fluorescent labeling of non-canonical amino acids, we further show that adaptable boronate ester bonds increase deposition of nascent proteins, including laminin. Collectively, these results advance the understanding of how mechanical and matricellular signaling influence intestinal organoid development.

New developments in AMPK and mTORC1 cross-talk.

Metabolic homeostasis and the ability to link energy supply to demand are essential requirements for all living cells to grow and proliferate. Key to metabolic homeostasis in all eukaryotes are AMPK and mTORC1, two kinases that sense nutrient levels and function as counteracting regulators of catabolism (AMPK) and anabolism (mTORC1) to control cell survival, growth and proliferation. Discoveries beginning in the early 2000s revealed that AMPK and mTORC1 communicate, or cross-talk, through direct and indirect phosphorylation events to regulate the activities of each other and their shared protein substrate ULK1, the master initiator of autophagy, thereby allowing cellular metabolism to rapidly adapt to energy and nutritional state. More recent reports describe divergent mechanisms of AMPK/mTORC1 cross-talk and the elaborate means by which AMPK and mTORC1 are activated at the lysosome. Here, we provide a comprehensive overview of current understanding in this exciting area and comment on new evidence showing mTORC1 feedback extends to the level of the AMPK isoform, which is particularly pertinent for some cancers where specific AMPK isoforms are implicated in disease pathogenesis.

Stereotactic Radiosurgery for Intermediate (III) or High (IV-V) Spetzler-Martin Grade Arteriovenous Malformations: International Stereotactic Radiosurgery Society Practice Guideline.

BACKGROUND AND OBJECTIVES: Consensus guidelines do not exist to guide the role of stereotactic radiosurgery (SRS) in the management of patients with Spetzler-Martin Grade III-V arteriovenous malformations (AVMs). We sought to establish SRS practice guidelines for Grade III-V AVMs based on a critical systematic review of the published literature. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant search of Medline, Embase, and Scopus, 1986 to 2023, for publications reporting post-SRS outcomes in ≥10 Grade III-V AVMs with the median follow-up ≥24 months was performed. Primary end points were AVM obliteration and post-SRS hemorrhage. Secondary end points included dosimetric variables, Spetzler-Martin parameters, and neurological outcome. RESULTS: : In total, 2463 abstracts were screened, 196 manuscripts were reviewed, and 9 met the strict inclusion criteria. The overall sample of 1634 AVMs consisted of 1431 Grade III (88%), 186 Grade IV (11%), and 11 Grade V lesions (1%). Total median post-SRS follow-up was 53 months for Grade III and 43 months for Grade IV-V AVMs (ranges, 2-290; 12-262). For Grade III AVMs, the crude obliteration rate was 72%, and among Grade IV-V lesions, the crude obliteration rate was 46%. Post-SRS hemorrhage was observed in 7% of Grade III compared with 17% of Grade IV-V lesions. Major permanent deficits or death from hemorrhage or radiation-induced complications occurred in 86 Grade III (6%) and 22 Grade IV-V AVMs (12%). CONCLUSION: Most patients with Spetzler-Martin Grade III AVMs have favorable SRS treatment outcomes; however, the obliteration rate for Grade IV-V AVMs is less than 50%. The available studies are heterogenous and lack nuanced, long-term, grade-specific outcomes.

PTEN Regulates Myofibroblast Activation in Valvular Interstitials Cells based on Subcellular Localization.

Aortic valve stenosis (AVS) is characterized by altered mechanics of the valve leaflets, which disrupts blood flow through the aorta and can cause left ventricle hypotrophy. These changes in the valve tissue result in activation of resident valvular interstitial cells (VICs) into myofibroblasts, which have increased levels of αSMA in their stress fibers. The persistence of VIC myofibroblast activation is a hallmark of AVS. In recent years, the tumor suppressor gene phosphatase and tensin homolog (PTEN) has emerged as an important player in the regulation of fibrosis in various tissues (e.g., lung, skin), which motivated us to investigate PTEN as a potential protective factor against matrix-induced myofibroblast activation in VICs. In aortic valve samples from humans, we found high levels of PTEN in healthy tissue and low levels of PTEN in diseased tissue. Then, using pharmacological inducers to treat VIC cultures, we observed PTEN overexpression prevented stiffness-induced myofibroblast activation, whereas genetic and pharmacological inhibition of PTEN further activated myofibroblasts. We also observed increased nuclear PTEN localization in VICs cultured on stiff matrices, and nuclear PTEN also correlated with smaller nuclei, altered expression of histones and a quiescent fibroblast phenotype. Together, these results suggest that PTEN not only suppresses VIC activation, but functions to promote quiescence, and could serve as a potential pharmacological target for the treatment of AVS.

Calls to action on lung cancer management and research.

Lung cancer, the leading cause of cancer-related deaths globally, remains a pressing health issue despite significant medical advances. The New York Lung Cancer Foundation brought together experts from academia, the pharmaceutical and biotech industries as well as organizational leaders and patient advocates, to thoroughly examine the current state of lung cancer diagnosis, treatment, and research. The goal was to identify areas where our understanding is incomplete and to develop collaborative public health and scientific strategies to generate better patient outcomes, as highlighted in our "Calls to Action." The consortium prioritized 8 different calls to action. These include (1) develop strategies to cure more patients with early-stage lung cancer, (2) investigate carcinogenesis leading to lung cancers in patients without a history of smoking, (3) harness precision medicine for disease interception and prevention, (4) implement solutions to deliver prevention measures and effective therapies to individuals in under-resourced countries, (5) facilitate collaborations with industry to collect and share data and samples, (6) create and maintain open access to big data repositories, (7) develop new immunotherapeutic agents for lung cancer treatment and prevention, and (8) invest in research in both the academic and community settings. These calls to action provide guidance to representatives from academia, the pharmaceutical and biotech industries, organizational and regulatory leaders, and patient advocates to guide ongoing and planned initiatives.

Disentangling negative and positive symptoms in schizophrenia and autism spectrum disorder.

Autism spectrum disorder (ASD) and schizophrenia (SZ) share traits, especially in social skills and negative symptoms, and to a lesser degree positive symptoms. Differential diagnosis can be challenging and discerning expressive and experiential negative symptoms may provide knowledge with potential diagnostic and functional relevance that can guide treatment. Two exploratory factor analyses (EFA) were conducted to reveal the underlying dimensions of negative and positive symptoms using the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms & Negative Symptoms (SAPS/SANS) and the Autism Diagnostic Observation Schedule-Generic (ADOS-G). Three factors emerged from the negative symptom EFA (70.5 % variance): NF1) Expressive Negative; NF2) Experiential Negative; and NF3) Preoccupation, Absorption & Expressive Affective Flattening. Three positive factors emerged (68.6 % variance): PF1) Hallucinations-Delusions; PF2) Grandiosity; and PF3) Thought Disorder-ADOS positive Symptoms. SZ showed higher PF1 scores, and ASD had higher PF3 scores. No differences between groups were observed in the negative factors. Across groups, all negative factors were inversely associated with quality of life. Only NF1 and NF2 and PF1 were detrimentally related to social functioning. A discriminant function analysis using all factors classified correctly 84.4 % of participants, with PF1, NF1 followed by NF2 being the best predictors of diagnosis. Expressive negative followed by Experiential negative symptoms are of diagnostic value independent of and beyond SZ-related positive symptoms and are related with detrimental functioning. Findings confirm the need to distinctively target negative symptoms, and specific SZ-related and ASD-related positive symptoms, and especially the use of several assessment tools for diagnostic classification.

A universal artificial diet for corn rootworm (Diabrotica spp.) larval biopesticide assays.

We identified a single diet formulation that can be used for three Diabrotica species including southern (SCR), western (WCR), and northern corn rootworm (NCR) by evaluating the performance of these pests on specialized diets (F9800B diet for SCR, WCRMO-2 diet for WCR, and NCRMO-1 diet for NCR) and a larval diet (F9772 diet) widely used for lepidopteran species. After 10 days of rearing, the WCRMO-2 diet yielded better or equal larval growth and development of all three rootworm species compared to other diets. For SCR larvae, the WCRMO-2 diet outperformed other diets. Larval fresh weight, percent molt to 2nd instar, and percent molt to 3rd instar on the WCRMO-2 diet were 12-fold, 2.7-fold, and 14-fold increases, respectively compared to that of the F9800B diet. Significantly more SCR larvae survived on the WCRMO-2 diet (98.9%) than on the F9800B diet (90.6%). The WCRMO-2 diet supported WCR and NCR larvae equal to the NCRMO-1 diet and better than other diets. The F9772 diet was the worst diet of all examined species. The availability of a universal diet (the WCRMO-2 diet) for the three Diabrotica species would facilitate research programs to monitor resistance development and develop new control tactics targeting these important pests.

Differences Between the 2016 and 2022 Food and Drug Administration Guidance-Implications for Design and Interpretation of Clinical Trials in Ulcerative Colitis.

Background: In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes from the 2016 version merit further discussion as they impact clinical trial design and the interpretation of trial results. Methods: We compared both documents and critically appraised the changes and implications for future clinical trials. Results: The 2022 guidance recommends full colonoscopy, rather than flexible sigmoidoscopy, to document disease activity in all involved segments of the colon. The concordance between the findings of the 2 procedures is very high and there is little evidence to support colonoscopy over sigmoidoscopy. The use of colonoscopy, rather than sigmoidoscopy, is also associated with a higher burden to trial participants who must undergo full bowel preparation, cost, and a potential for more adverse events. The definition of the Mayo endoscopic score of 0 was changed from the original publication to "normal appearance of mucosa," which suggests that endoscopic signs of prior disease, such as pseudopolyps and scarring, are incompatible with a score 0, even though they are not associated with active disease. The term "mucosal healing" has been abolished and histologic outcomes defined as exploratory. A welcome change is that shorter washout periods than 5 half-lives will be considered to reduce patient exposure to corticosteroids as bridging therapy. Conclusions: The 2022 FDA draft guidance includes changes which for the most part are not informed by empirical evidence, which may ultimately complicate interpretation of future trials and preclude comparisons with past trials.

Emergency Department Visits And Hospital Capacity In The US: Trends In The Medicare Population During The COVID-19 Pandemic.

Although emergency department (ED) and hospital overcrowding were reported during the later parts of the COVID-19 pandemic, the true extent and potential causes of this overcrowding remain unclear. Using data on the traditional fee-for-service Medicare population, we examined patterns in ED and hospital use during the period 2019-22. We evaluated trends in ED visits, rates of admission from the ED, and thirty-day mortality, as well as measures suggestive of hospital capacity, including hospital Medicare census, length-of-stay, and discharge destination. We found that ED visits remained below baseline throughout the study period, with the standardized number of visits at the end of the study period being approximately 25 percent lower than baseline. Longer length-of-stay persisted through 2022, whereas hospital census was considerably above baseline until stabilizing just above baseline in 2022. Rates of discharge to postacute facilities initially declined and then leveled off at 2 percent below baseline in 2022. These results suggest that widespread reports of overcrowding were not driven by a resurgence in ED visits. Nonetheless, length-of-stay remains higher, presumably related to increased acuity and reduced available bed capacity in the postacute care system.

Additional impact of genetic ancestry over race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer.

The KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, a detailed understanding of how self-reported race and/or ethnicity (SIRE), genetically inferred ancestry (GIA), and their interaction affect KRAS mutation is largely unknown. Here, we investigated the associations between SIRE, quantitative GIA, and KRAS mutation and its allele-specific subtypes in a multi-ethnic cohort of 3,918 patients from the Boston Lung Cancer Survival cohort and the Chinese OrigiMed cohort with an independent validation cohort of 1,450 patients with NSCLC. This comprehensive analysis included detailed covariates such as age at diagnosis, sex, clinical stage, cancer histology, and smoking status. We report that SIRE is significantly associated with KRAS mutations, modified by sex, with SIRE-Asian patients showing lower rates of KRAS mutation, transversion substitution, and the allele-specific subtype KRASG12C compared to SIRE-White patients after adjusting for potential confounders. Moreover, GIA was found to correlate with KRAS mutations, where patients with a higher proportion of European ancestry had an increased risk of KRAS mutations, especially more transition substitutions and KRASG12D. Notably, among SIRE-White patients, an increase in European ancestry was linked to a higher likelihood of KRAS mutations, whereas an increase in admixed American ancestry was associated with a reduced likelihood, suggesting that quantitative GIA offers additional information beyond SIRE. The association of SIRE, GIA, and their interplay with KRAS driver mutations in NSCLC highlights the importance of incorporating both into population-based cancer research, aiming to refine clinical decision-making processes and mitigate health disparities.

Detection of periodic peaks in Karenia brevis concentration consistent with the time-delay logistic equation.

The logistic equation models single-species population growth with a sigmoid curve that begins as exponential and ends with an asymptotic approach to a final population determined by natural system carrying capacity. But the population of a natural system often does not stabilize as it approaches carrying capacity. Instead, it exhibits periodic change, sometimes with very large amplitudes. The time-delay modification of the logistic equation accounts for this behavior by connecting the present rate of population growth to conditions at an earlier time. The periodic change in population with time can progress from a monotonic approach to the carrying capacity; to oscillation around the carrying capacity; to limit-cycle periodic change; and, finally, to chaotic change. The presence of multiple species and inadequate sampling frequency and spatial coverage hinder the application of the time-delay logistic equation to real-world populations. Blooms of Karenia brevis along the southwest Florida Gulf Coast, however, provide a unique opportunity in that blooms are nearly monospecific and are sampled frequently over a wide geographic region; they are good candidates for testing the time-delay logistic equation. We show that these blooms exhibit peaks in concentration with periods in the range of 40-100 days, consistent with that predicted by the time-delay logistic equation. Cell concentrations in the valleys between the peaks are at least 2-3 orders of magnitude lower than peak values, offering predictable windows of opportunity for potential mitigation efforts.

Characterizing applications, exposure risks, and hazard communication for engineered nanomaterials in construction.

BACKGROUND: Engineered nanomaterials (ENMs) may pose health risks to workers. Objectives were to characterize ENM applications in construction, identify exposure scenarios, and evaluate the quality of safety data sheets (SDSs) for nano-enabled construction products. METHODS: SDSs and product data were obtained from a public database of nano-enabled construction products. Descriptive statistics were calculated for affected trades, product categories, and types of ENMs. A sample of SDSs (n = 33) was evaluated using modified criteria developed by NIOSH researchers. Bulk analysis via transmission electron microscopy characterized nanoparticles in a subset of products. RESULTS: Companies report using >50 ENMs in construction products. ENM composition could not be determined via SDSs for 38.1% of the 907 products examined. Polymers and metal oxides tied for most frequently reported ENMs (n = 87, 9.6%). Nano silica, graphene, carbon nanotubes, and silver nanoparticles were also frequently reported. Most of the products were paints and coatings (n = 483, 53.3%), followed by pre-market additives, cementitious materials, insulation, and lubricants. Workers in twenty construction trades are likely to handle nano-enabled products, these particularly encompass cement and brick masons, painters, laborers, carpenters, glaziers, and insulators. A wide range of exposure scenarios were identified. SDSs were classified as satisfactory (18%), in need of improvement (12%), or in need of significant improvement (70%). Bulk analyses revealed discrepancies between actual ENM composition and those in SDSs. DISCUSSION AND CONCLUSION: There has been significant progress investigating risks to construction workers posed by ENMs, but SDSs need major improvements. This study provides new insights on the use of ENMs in construction, exposure risks, and hazard communication.

Acute severe ulcerative colitis trials: the past, the present and the future.

Acute severe ulcerative colitis (ASUC), characterised by bloody diarrhoea and systemic inflammation, is associated with a significant risk of colectomy and a small risk of mortality. The landmark trial of cortisone in 1955 was pivotal for two reasons: first, for establishing the efficacy of a drug that remains a first-line therapy today and, second, for producing the first set of disease severity criteria and clinical trial endpoints that shaped the subsequent ASUC trial landscape. Trials in the 1990s and at the turn of the millennium established the efficacy of infliximab and ciclosporin, but since then, there has been little progress in drug development for this high-risk population. This systematic review evaluates all interventional randomised controlled trials (RCTs) conducted in patients hospitalised with severe UC. It provides an overview of the efficacy of treatments from past to present and assesses the evolution of trial characteristics with respect to study populations, eligibility criteria and study designs over time. This review details ongoing RCTs in this field and provides a perspective on the challenges for future clinical trial programmes and how these can be overcome to help deliver novel ASUC therapies.

Winter GPS tagging reveals home ranges during the breeding season for a boreal-nesting migrant songbird, the Golden-crowned Sparrow.

Determining space use for species is fundamental to understanding their ecology, and tracking animals can reveal insights into their spatial ecology on home ranges and territories. Recent technological advances have led to GPS-tracking devices light enough for birds as small as ~30 g, creating novel opportunities to remotely monitor fine-scale movements and space use for these smaller species. We tested whether miniaturized GPS tags can allow us to understand space use of migratory birds away from their capture sites and sought to understand both pre-breeding space use as well as territory and habitat use on the breeding grounds. We used GPS tags to characterize home ranges on the breeding grounds for a migratory songbird with limited available breeding information, the Golden-crowned Sparrow (Zonotrichia atricapilla). Using GPS points from 23 individuals across 26 tags (three birds tagged twice), we found home ranges in Alaska and British Columbia were on average 44.1 ha (95% kernel density estimate). In addition, estimates of territory sizes based on field observations (mean 2.1 ha, 95% minimum convex polygon [MCP]) were three times smaller than 95% MCPs created using GPS tags (mean 6.5 ha). Home ranges included a variety of land cover classes, with shrubland particularly dominant (64-100% of home range cover for all but one bird). Three birds tracked twice returned to the same breeding area each year, supporting high breeding site fidelity for this species. We found reverse spring migration for five birds that flew up to 154 km past breeding destinations before returning. GPS-tracking technology allowed for critical ecological insights into this migratory species that breeds in very remote locations.