Updated techniques and evidence for endoscopic ultrasound-guided tissue acquisition from solid pancreatic lesions.

Endoscopic ultrasound-guided tissue acquisition (EUS-TA), including fine-needle aspiration (EUS-FNA) and fine-needle biopsy (EUS-FNB), has revolutionized specimen collection from intra-abdominal organs, especially the pancreas. Advances in personalized medicine and more precise treatment have increased demands to collect specimens with higher cell counts, while preserving tissue structure, leading to the development of EUS-FNB needles. EUS-FNB has generally replaced EUS-FNA as the procedure of choice for EUS-TA of pancreatic cancer. Various techniques have been tested for their ability to enhance the diagnostic performance of EUS-TA, including multiple methods of sampling at the time of puncture, on-site specimen evaluation, and specimen processing. In addition, advances in next-generation sequencing have made comprehensive genomic profiling of EUS-TA samples feasible in routine clinical practice. The present review describes updates in EUS-TA sampling techniques of pancreatic lesions, as well as methods for their evaluation.

The Efficiency of In Vitro Differentiation of Primate iPSCs into Cardiomyocytes Depending on Their Cell Seeding Density and Cell Line Specificity.

A thorough characterization of induced pluripotent stem cells (iPSCs) used with in vitro models or therapeutics is essential. Even iPSCs derived from a single donor can exhibit variability within and between cell lines, which can lead to heterogeneity in results and hinder the promising future of cell replacement therapies. In this study, the cell seeding density of human and rhesus monkey iPSCs was tested to maximize the cell line-specific yield of the generated cardiomyocytes. We found that, despite using the same iPSC generation and differentiation protocols, the cell seeding density for the cell line-specific best differentiation efficiency could differ by a factor of four for the four cell lines used here. In addition, the cell lines showed differences in the range of cell seeding densities that they could tolerate without the severe loss of differentiation efficiency. Overall, our data show that the cell seeding density is a critical parameter for the differentiation inefficiency of primate iPSCs to cardiomyocytes and that iPSCs generated with the same episomal approach still exhibit considerable heterogeneity. Therefore, individual characterization of iPSC lines is required, and functional comparability with in vivo processes must be ensured to warrant the translatability of in vitro research with iPSCs.

Seeding improves the strength of bio-tiles grown with microbially induced calcium carbonate precipitation.

Bio-tiles are a biobased alternative to conventional tiles that utilise a promising technology called microbially induced calcium carbonate (CaCO3) precipitation (MICP). This technology has low energy requirements and also sequesters carbon. Bio-tiles have been made in previous work using a submersion method, however, the process required additives such as 0.3 M magnesium chloride to achieve bio-tiles that meet international standards. The current study aimed to improve the bio-tile strength properties with CaCO3 crystal seeding and a pumping method instead of the use of magnesium that also increases ionic strength. With this technique, cementation solution containing the required calcium and urea for the MICP reaction was pumped through a sealed mould in a series of programmed treatments. The highest concentration of ureolytic Sporosarcina pasteurii with an effective urease activity of 40 mmol NH4-N/L·min was found to be most beneficial to the breaking strength of the bio-tiles, as were the shortest retention times of 1 h between treatments. Seeding with CaCO3 crystals offered significant benefit to the MICP process. Pre-seeding of the geotextiles was explored and the mass of seeds initially present on the geotextiles was found to have a direct improvement on the breaking strength of 21-82 %, increasing with seed loading. The highest CaCO3 seed loading tested of 0.072 g seeds/cm2 geotextile resulted in bio-tiles with a breaking strength of 940 ± 92 N and a modulus of rupture of 16.4 ± 1.7 N/mm2, meeting international targets for extruded tiles with 6-10 % water absorption. When a seed loading of 0.021 g/cm2 was used instead, bio-tiles meeting targets for tiles with a water absorption of >10 % were produced at 628 ± 18 N and 10.5 ± 1.1 N/mm2.

First case report of benign subcutaneous thyroid tissue implantation following transoral endoscopic thyroidectomy vestibular approach (TOETVA).

Background: Following the era of remote access thyroid surgery in the 1990s, several techniques were developed including transoral endoscopic thyroidectomy vestibular approach (TOETVA), which was invented in 2016. TOETVA has gained acceptance and proven comparable results to the conventional open thyroidectomy. Despite the potential complications that may occur as a result of remote access thyroid surgery, such as nerve, vascular, and tracheal injury, seroma, and hypoparathyroidism, there was an extremely rare late complication of a benign subcutaneous thyroid implantation, which have not been reported following TOETVA. Case Description: A 28-year-old female was developed multiple subcutaneous nodules after undergoing right lobe TOETVA for 2 years due to a 3.1 cm benign nodular goiter. The nodules were excised via submandibular incision and the pathological results were shown as benign. Conclusions: Thyroid tissue implantation may result from intracorporeal thyroid tissue rupture, as reported in this research. Extending the vestibular incision to 2-2.5 cm and partially cutting the specimen within the retrieval bag were options to prevent further tissue damage or spillage during specimen extraction. Meanwhile, a separate incision, such as the axillary or submandibular incision, may be required to retrieve the larger nodules. Even though there were no absolute guidelines or contraindications for patient selection in TOETVA, an awareness of tissue breakage should always be considered. The optimal size of the nodule for vestibular removal, which would minimize the risk of tissue breakage, still required additional research.

"One blade, two cuts?" A multidisciplinary survey investigating practice variability of scalpel blade change for simultaneous excision of multiple skin lesions in the same patient.

BACKGROUND: Skin cancer incidence increases globally, requiring effective preventive measures and evidence-based treatment strategies. Current guidelines advocate for surgical excision as a first-line treatment for most early skin cancers. The study investigated practices regarding changing scalpel blades when excising multiple skin lesions in the same patient during the same visit (CSB) and explored how beliefs about iatrogenic seeding influence individual norms of practice. METHODS: A multidisciplinary survey was conducted among 173 medical specialists involved in skin cancer care. Participants provided demographic information, years of experience, and practices regarding CSB in four clinical scenarios (first excised tumor: basal cell carcinoma, squamous cell carcinoma, melanoma suspect, and evident melanoma). Practice variations based on specialty, experience, and beliefs about seeding risk were statistically assessed. RESULTS: Surgeons exhibited a significantly higher tendency to change blades compared to non-surgeons across all diagnoses. Iatrogenic seeding (56.52%) and clinical training (18.84%) were the main reasons provided for CSB. Beliefs about seeding risk did not differ significantly between specialties. CONCLUSIONS: Although the practice of CSB lacks strong scientific rationale, the approach to this practice significantly varies among different medical specialties. Healthcare professionals should critically evaluate and standardize evidence-based practices to ensure optimal patient care and mitigate potential harm.

Intracerebral inoculation of healthy non-transgenic rats with a single aliquot of oligomeric amyloid-ß (1-42) profoundly and progressively alters brain function throughout life.

One of the puzzling aspects of sporadic Alzheimer's disease (AD) is how it commences. Changes in one key brain peptide, amyloid-beta (Aß), accompany disease progression, but whether this comprises a trigger or a consequence of AD is still a topic of debate. It is clear however that the cerebral presence of oligomeric Aß (1-42) is a key factor in early AD-pathogenesis. Furthermore, treatment of rodent brains with oligomeric Aß (1-42) either in vitro or in vivo, acutely impairs hippocampal synaptic plasticity, creating a link between Aß-pathology and learning impairments. Here, we show that a once-off inoculation of the brains of healthy adult rats with oligomeric Aß (1-42) exerts debilitating effects on the long-term viability of the hippocampus, one of the primary targets of AD. Changes are progressive: months after treatment, synaptic plasticity, neuronal firing and spatial learning are impaired and expression of plasticity-related proteins are changed, in the absence of amyloid plaques. Early changes relate to activation of microglia, whereas later changes are associated with a reconstruction of astroglial morphology. These data suggest that a disruption of Aß homeostasis may suffice to trigger an irreversible cascade, underlying progressive loss of hippocampal function, that parallels the early stages of AD.

Different neurotoxicity and seeding activity between α-synuclein oligomers formed in plasma of patients with Parkinson's disease and multiple system atrophy.

Previous studies have shown that α-synuclein (α-Syn) aggregates derived from the brains of patients with Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit different phosphorylation, cytotoxicity, and seeding activity. However, the mechanism underlying the differences remains poorly understood. Here, recombinant human α-Syn was incubated in the plasma of patients with PD and MSA, and the oligomers formed in the plasma (PD-O-α-Syn and MSA-O-α-Syn) were purified and analyzed for their phosphorylation, cytotoxicity and seeding activity. In vitro assays revealed that both PD-O-α-Syn and MSA-O-α-Syn were phosphorylated at serine 129. However, the phosphorylation degree of MSA-O-α-Syn was significantly higher than that of PD-O-α-Syn. In addition, MSA-O-α-Syn exhibited stronger cytotoxicity and seeding activity compared with PD-O-α-Syn. In vivo experiments showed that mice receiving intrastriatal inoculation of MSA-O-α-Syn developed more severe motor dysfunction and dopaminergic degeneration than mice receiving intrastriatal inoculation of PD-O-α-Syn. Compared with the mice inoculated with PD-O-α-Syn, the mice inoculated with MSA-O-α-Syn accumulated more phosphorylated and oligomerized α-Syn in the striatum and brain regions (substantia nigra, hippocampus and prefrontal cortex) away from the inoculated site. The results obtained suggest that α-Syn oligomers formed in PD and MSA plasma are different in phosphorylation, cytotoxicity, and seeding activity.

Islet amyloid polypeptide fibril catalyzes amyloid-ß aggregation by promoting fibril nucleation rather than direct axial growth.

Aberrant aggregation of amyloid-ß (Aß) and islet amyloid polypeptide (IAPP) into amyloid fibrils underlies the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes (T2D), respectively. T2D significantly increases AD risk, with evidence suggesting that IAPP and Aß co-aggregation and cross-seeding might contribute to the cross-talk between two diseases. Experimentally, preformed IAPP fibril seeds can accelerate Aß aggregation, though the cross-seeding mechanism remains elusive. Here, we computationally demonstrated that Aß monomer preferred to bind to the elongation ends of preformed IAPP fibrils. However, due to sequence mismatch, the Aß monomer could not directly grow onto IAPP fibrils by forming multiple stable ß-sheets with the exposed IAPP peptides. Conversely, in our control simulations of self-seeding, the Aß monomer could axially grow on the Aß fibril, forming parallel in-register ß-sheets. Additionally, we showed that the IAPP fibril could catalyze Aß fibril nucleation by promoting the formation of parallel in-register ß-sheets in the C-terminus between bound Aß peptides. This study enhances our understanding of the molecular interplay between Aß and IAPP, shedding light on the cross-seeding mechanisms potentially linking T2D and AD. Our findings also underscore the importance of clearing IAPP deposits in T2D patients to mitigate AD risk.

MAPT mutations associated with familial tauopathies lead to formation of conformationally distinct oligomers that have cross-seeding ability.

The microtubule associated protein, tau, is implicated in a multitude of neurodegenerative disorders that are collectively termed as tauopathies. These disorders are characterized by the presence of tau aggregates within the brain of afflicted individuals. Mutations within the MAPT gene that encodes the tau protein form the genetic backdrop for familial forms of tauopathies, such as frontotemporal dementia (FTD), but the molecular consequences of such alterations and their pathological effects are unclear. We sought to investigate the conformational properties of the aggregates of three tau mutants: A152T, P301L, and R406W, all implicated within FTD, and compare them to those of the native form (WT-Tau 2N4R). Our immunochemical analysis reveals that mutants and WT tau oligomers exhibit similar affinity for conformation-specific antibodies but have distinct morphology and secondary structure. Additionally, these oligomers possess different dye-binding properties and varying sensitivity to proteolytic processing. These results point to conformational variety among them. We then tested the ability of the mutant oligomers to cross-seed the aggregation of WT tau monomer. Using similar array of experiments, we found that cross-seeding with mutant aggregates leads to the formation of conformationally unique WT oligomers. The results discussed in this paper provide a novel perspective on the structural properties of oligomeric forms of WT tau 2N4R and its mutant, along with shedding some light on their cross-seeding behavior.

"Prion-like" seeding and propagation of oligomeric protein assemblies in neurodegenerative disorders.

Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation of such proteins in diseased brains is believed to be the end-stage of a stepwise aggregation of misfolded monomers to insoluble cross-ß fibrils via a series of differently sized soluble oligomers/protofibrils. Several studies have shown how α-synuclein, amyloid-ß, tau and other amyloidogenic proteins can act as nucleating particles and thereby share properties with misfolded forms, or strains, of the prion protein. Although the roles of different protein assemblies in the respective aggregation cascades remain unclear, oligomers/protofibrils are considered key pathogenic species. Numerous observations have demonstrated their neurotoxic effects and a growing number of studies have indicated that they also possess seeding properties, enabling their propagation within cellular networks in the nervous system. The seeding behavior of oligomers differs between the proteins and is also affected by various factors, such as size, shape and epitope presentation. Here, we are providing an overview of the current state of knowledge with respect to the "prion-like" behavior of soluble oligomers for several of the amyloidogenic proteins involved in neurodegenerative diseases. In addition to providing new insight into pathogenic mechanisms, research in this field is leading to novel diagnostic and therapeutic opportunities for neurodegenerative diseases.

Mast seeding is stronger in taller plants.

Introduction: Two economies of scale, predator satiation and pollination efficiency, have been proposed to explain the evolutionary mechanisms of mast seeding adopted by some long-lived plants. Plant height is strongly selected by pollination vectors and may also provide economies of scale; however, it remains unknown whether there is a close relationship between adult plant height and mast seeding intensity. Methods: Here, we analyzed mast seeding intensity of 158 plant species to test if adult plant height can select for mast seeding. Results: We show that mast seeding intensities are higher in taller plant species irrespective of phylogeny, life form, pollination vector, and type of Spermatophytes. We also show that anemophily rather than entomophily selects for taller plant species and higher mast seeding intensities. Discussion: The linear correlations and evolutionary links between adult plant height and mast seeding intensity provide evidence that mast seeding could have evolved as an adaptation to taller strategy of perennial plant species.

Optimizing forage harvest and the nutritive value of Italian ryegrass-based mixed forage cropping under northwestern Himalayan conditions.

The scarcity of high-quality forage has a significant influence on the productivity and profitability of livestock. Addressing this concern, an investigation was undertaken to assess the effects of distinct Italian ryegrass genotypes, namely, Punjab ryegrass-1, Kashmir collection, and Makhan grass, in conjunction with varying seeding ratios of Italian ryegrass to Egyptian clover. The seeding ratios considered were 100:0 (Italian ryegrass to Egyptian clover), 75:25, 50:50, and 25:75. All possible combinations of Italian ryegrass and Egyptian clover with seeding ratios were set up in a randomized complete block design and replicated thrice. Co-cultivating Italian ryegrass and Egyptian clover at a 75:25 seeding ratio yields the best yield benefit, as determined by the land equivalent ratio. It is noteworthy that in this configuration, real yield loss is higher for Egyptian clover and for Italian ryegrass when the seeding ratio is 25:75. The higher competitiveness of Italian ryegrass in comparison to Egyptian clover is highlighted by the competitive ratio. Notably, the nutritive parameter, crude protein yield, was significantly higher in the Makhan grass-based 50:50 and 75:25 seeding ratio. Results of the study ascertained the compatibility of grass-legume co-cultivation with significantly higher quantity and quality forage harvested under mixed cropping systems whereas Makhan grass as the superior and dominant genotype in comparison to Kashmir collection. The outcomes of this study revealed that the 100:0 seeding ratio, coupled with the Makhan grass genotype, exhibited superior performance in terms of cumulative forage harvest, dry matter accumulation, net returns, and benefit-cost ratio.

Intracellular tau fragment droplets serve as seeds for tau fibrils.

Intracellular tau aggregation requires a local protein concentration increase, referred to as "droplets". However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer's disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. These intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.

Human peritoneal fluid exerts ovulation- and nonovulation-sourced oncogenic activities on transforming fallopian tube epithelial cells.

Secretory cells in the fallopian tube fimbria epithelium (FTE) are regarded as the main cells of origin of ovarian high-grade serous carcinoma (HGSC). Ovulation is the main cause of FTE oncogenesis, which proceeds through a sequence of TP53 mutations, chromosomal instability due to Rb/cyclin E aberration, in situ carcinoma (STIC), and metastasis to the ovary and peritoneum (metastatic HGSC). Previously, we have identified multiple oncogenic activities of the ovulatory follicular fluid (FF), which exerts the full spectrum of transforming activity on FTE cells at different stages of transformation. After ovulation, the FF is transfused into the peritoneal fluid (PF), in which the FTE constantly bathes. We wondered whether PF exerts the same spectrum of oncogenic activities as done by FF and whether these activities are derived from FF. By using a panel of FTE cell lines with p53 mutation (FT282-V), p53/CCNE1 aberrations (FT282-CCNE1), and p53/Rb aberrations plus spontaneous transformation, and peritoneal metastasis (FEXT2), we analyzed the changes of different transformation phenotypes after treating with FF and PF collected before or after ovulation. Similar to effects exhibited by FF, we found that, to a lesser extent, PF promoted anchorage-independent growth (AIG), migration, anoikis resistance, and peritoneal attachment in transforming FTE cells. The more transformed cells were typically more affected. Among the transforming activities exhibited by PF treatment, AIG, Matrigel invasion, and peritoneal attachment growth were higher with luteal-phase PF treatment than with the proliferative-phase PF treatment, suggesting an ovulation source. In contrast, changes in anoikis resistance and migration activities were similar in response to treatment with PF collected before and after ovulation, suggesting an ovulation-independent source. The overall transforming activity of luteal-phase PF was verified in an i.p. co-injection xenograft mouse model. Co-injection of Luc-FEXT2 cells with either FF or luteal-phase PF supported early peritoneal implantation, whereas co-injection with follicular-phase PF did not. This study, for the first time, demonstrates that PF from ovulating women can promote different oncogenic phenotypes in FTE cells at different stages of malignant transformation. Most of these activities, other than anoikis resistance and cell migration, are sourced from ovulation.

Intracranial seeding of pituitary neuroendocrine tumor: a case report.

Background: Pituitary neuroendocrine tumors (PitNETs) are predominantly benign, though a minority may exhibit invasive tendencies. A diagnosis of metastatic PitNETs, in the absence of malignant histology, hinges on the identification of craniospinal and/or systemic metastases. Only a minority of PitNETs exhibit intracranial seeding. Notably, craniotomy for PitNETs excision is a prominent catalyst for iatrogenic seeding. Case Description: This article presented a compelling case that 15 years following craniotomy for the resection of a somatotroph PitNET, a lesion emerged at the left frontal base within the ethmoid sinus. Subsequent post-operative pathology unveiled a mature plurihormonal pituitary specific transcription factor 1 (PIT-1)-lineage PitNET. Growth hormone (GH) levels decreased significantly from 22.8 ng/mL pre-operation to 2 ng/mL post-operative, and concurrently, prolactin (PRL) levels decreased from 26.7 ng/mL pre-operation to 4.5 ng/mL post-operation. Furthermore, in the follow-up examination conducted 5 months after the operation, both GH and PRL levels were found to be within the normal range for the patient. This robustly suggested that the initial surgical procedure played a key role in the development of the lesion. Conclusions: This underscores the paramount significance of strictly adhering to the non-tumor removal during craniotomy for PitNETs excision. Regardless of apparent complete resection on imaging, it remains imperative to conduct routine follow-up evaluations, encompassing both imaging studies and hormone level assessments.

Ultrasensitive detection of aggregated α-synuclein using quiescent seed amplification assay for the diagnosis of Parkinson's disease.

BACKGROUND: Seed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson's disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation. METHODS: We introduced a modified form of SAA, known as Quiescent SAA (QSAA), and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies (control group). Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies. Additionally, skin samples were collected from 214 PD patients and 208 control subjects. Data were analyzed from April 2019 to May 2023. RESULTS: QSAA successfully amplified αSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils. In the skin samples from 214 PD cases and 208 non-PD cases, QSAA demonstrated high sensitivity (90.2%) and specificity (91.4%) in differentiating between PD and non-PD cases. Notably, more αSyn aggregates were detected by QSAA compared to immunofluorescence with the pS129-αSyn antibody in consecutive slices of both brain and skin samples. CONCLUSION: We introduced the new QSAA method tailored for in situ amplification of αSyn aggregates in brain and skin samples while maintaining tissue integrity, providing a streamlined approach to diagnosing PD with individual variability. The integration of seeding activities with the location of deposition of αSyn seeds advances our understanding of the mechanism underlying αSyn misfolding in PD.

On the friendship paradox and inversity: A network property with applications to privacy-sensitive network interventions.

We provide the mathematical and empirical foundations of the friendship paradox in networks, often stated as "Your friends have more friends than you." We prove a set of network properties on friends of friends and characterize the concepts of ego-based and alter-based means. We propose a network property called inversity that quantifies the imbalance in degrees across edges and prove that the sign of inversity determines the ordering between ego-based or alter-based means for any network, with implications for interventions. Network intervention problems like immunization benefit from using highly connected nodes. We characterize two intervention strategies based on the friendship paradox to obtain such nodes, with the alter-based and ego-based strategy. Both strategies provide provably guaranteed improvements for any network structure with variation in node degrees. We demonstrate that the proposed strategies obtain several-fold improvement (100-fold in some networks) in node degree relative to a random benchmark, for both generated and real networks. We evaluate how inversity informs which strategy works better based on network topology and show how network aggregation can alter inversity. We illustrate how the strategies can be used to control contagion of an epidemic spreading across a set of village networks, finding that these strategies require far fewer nodes to be immunized (less than 50%, relative to random). The interventions do not require knowledge of network structure, are privacy-sensitive, are flexible for time-sensitive action, and only require selected nodes to nominate network neighbors.

Skin α-Synuclein Seeding Activity in Patients with Type 1 Gaucher Disease.

BACKGROUND: Patients with type 1 Gaucher disease (GD1) have a significantly increased risk of developing Parkinson's disease (PD). OBJECTIVE: The objective of this study was to evaluate skin α-synuclein (αSyn) seeding activity as a biomarker for GD1-related PD (GD1-PD). METHODS: This single-center study administered motor and cognitive examinations and questionnaires of nonmotor symptoms to adult patients with GD1. Optional skin biopsy was performed for skin αSyn seed amplification assay (αSyn SAA) using real-time quaking-induced conversion assay. RESULTS: Forty-nine patients were enrolled, and 36 underwent skin biopsy. Two study participants had PD. Ten participants were αSyn SAA positive (27.8%), 7 (19.4%) were intermediate, and 19 (52.8%) were negative. Positive αSyn seeding activity was observed in the single GD1-PD case who consented to biopsy. αSyn SAA positivity was associated with older age (p = 0.043), although αSyn SAA positivity was more prevalent in patients with GD1 than historic controls. CONCLUSIONS: Longitudinal follow-up is required to determine whether skin αSyn seeding activity can be an early biomarker for GD1-PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A North American climate-masting-irruption teleconnection and its change under future climate.

Atmospheric variability can impact biological populations by triggering facultative migrations, but the stability of these atmosphere-biosphere connections may be vulnerable to climate change. As an example, we consider the leading mode of continental-scale facultative migration of Pine Siskins, where the associated ecological mechanism is changes in resource availability, with a mechanistic pathway of climate conditions affecting mast seeding patterns in trees which in turn drive bird migration. The three summers prior to pine siskin irruption feature an alternating west-east mast-seeding dipole in conifer trees with opposite anomalies over western and eastern North America. The climate driver of this west-east mast-seeding dipole, referred to as the North American Dipole, occurs during summer in the historical record, but shifts to spring in response to future climate warming during this century in a majority of global climate models. Identification of future changes in the timing of the climate driver of boreal forest mast seeding have broadly important implications for the dynamics of forest ecosystems.