Tools for live-cell imaging of cytoskeletal and nuclear behavior in the unconventional yeast, Aureobasidium pullulans.

Aureobasidium pullulans is a ubiquitous fungus with a wide variety of morphologies and growth modes including "typical" single-budding yeast, and interestingly, larger multinucleate yeast than can make multiple buds in a single cell cycle. The study of A. pullulans promises to uncover novel cell biology, but currently tools are lacking to achieve this goal. Here, we describe initial components of a cell biology toolkit for A. pullulans, which is used to express and image fluorescent probes for nuclei as well as components of the cytoskeleton. These tools allowed live-cell imaging of the multinucleate and multibudding cycles, revealing highly synchronous mitoses in multinucleate yeast that occur in a semiopen manner with an intact but permeable nuclear envelope. These findings open the door to using this ubiquitous polyextremotolerant fungus as a model for evolutionary cell biology.

EUS-guided coil injection therapy in the management of gastric varices: the first U.S. multicenter experience (with video).

BACKGROUND AND AIMS: Despite the significant morbidity associated with gastric variceal bleeding, there is a paucity of high-quality data regarding optimal management. EUS-guided coil injection therapy (EUS-COIL) has recently emerged as a promising endoscopic modality for the treatment of gastric varices (GV), particularly compared with traditional direct endoscopic glue injection. Although there are data on the feasibility and safety of EUS-COIL in the management of GV, these have been limited to select centers with particular expertise. The aim of this study was to report the first U.S. multicenter experience of EUS-COIL for the management of GV. METHODS: This retrospective analysis included patients with bleeding GV or GV at risk of bleeding who underwent EUS-COIL at 10 U.S. tertiary care centers between 2018 and 2022. Baseline patient and procedure-related information was obtained. EUS-COIL entailed the injection of .018 inch or .035 inch hemostatic coils using a 22-gauge or 19-gauge FNA needle. Primary outcomes were technical success (defined as successful deployment of coil into varix under EUS guidance with diminution of Doppler flow), clinical success (defined as cessation of bleeding if present and/or absence of bleeding at 30 days' postintervention), and intraprocedural and postprocedural adverse events. RESULTS: A total of 106 patients were included (mean age 60.4 ± 12.8 years; 41.5% female). The most common etiology of GV was cirrhosis (71.7%), with alcohol being the most common cause (43.4%). Overall, 71.7% presented with acute GV bleeding requiring intensive care unit stay and/or blood transfusion. The most common GV encountered were isolated GV type 1 (60.4%). A mean of 3.8 ± 3 coils were injected with a total mean length of 44.7 ± 46.1 cm. Adjunctive glue or absorbable gelatin sponge was injected in 82% of patients. Technical success and clinical success were 100% and 88.7%, respectively. Intraprocedural adverse events (pulmonary embolism and GV bleeding from FNA needle access) occurred in 2 patients (1.8%), and postprocedural adverse events occurred in 5 (4.7%), of which 3 were mild. Recurrent bleeding was observed in 15 patients (14.1%) at a mean of 32 days. Eighty percent of patients with recurrent bleeding were successfully re-treated with repeat EUS-COIL. No significant differences were observed in outcomes between high-volume (>15 cases) and low-volume (<7 cases) centers. CONCLUSIONS: This U.S. multicenter experience on EUS-COIL for GV confirms high technical and clinical success with low adverse events. No significant differences were seen between high- and low-volume centers. Repeat EUS-COIL seems to be an effective rescue option for patients with recurrent bleeding GV. Further prospective studies should compare this modality versus other interventions commonly used for GV.

Particle-based simulations reveal two positive feedback loops allow relocation and stabilization of the polarity site during yeast mating.

Many cells adjust the direction of polarized growth or migration in response to external directional cues. The yeast Saccharomyces cerevisiae orient their cell fronts (also called polarity sites) up pheromone gradients in the course of mating. However, the initial polarity site is often not oriented towards the eventual mating partner, and cells relocate the polarity site in an indecisive manner before developing a stable orientation. During this reorientation phase, the polarity site displays erratic assembly-disassembly behavior and moves around the cell cortex. The mechanisms underlying this dynamic behavior remain poorly understood. Particle-based simulations of the core polarity circuit revealed that molecular-level fluctuations are unlikely to overcome the strong positive feedback required for polarization and generate relocating polarity sites. Surprisingly, inclusion of a second pathway that promotes polarity site orientation generated relocating polarity sites with properties similar to those observed experimentally. This pathway forms a second positive feedback loop involving the recruitment of receptors to the cell membrane and couples polarity establishment to gradient sensing. This second positive feedback loop also allows cells to stabilize their polarity site once the site is aligned with the pheromone gradient.

Endoscopic Ultrasound Guided Shear Wave Elastography Is Safe With High Feasibility and Reproducibility When Used in the Pancreas: Findings From a Prospective Cohort.

OBJECTIVES: The aim of this study was to assess the safety, feasibility, and reproducibility of endoscopic ultrasound shear wave elastography (EUS-SWE) in the pancreas. METHODS: This is a prospective registry of consecutive patients undergoing clinically indicated EUS. Ten readings of SWE velocities (Vs [distance/time, m/s]) were obtained in the head (HOP), body, and tail of pancreas to quantify tissue stiffness. Each Vs score was accompanied by a reliability measurement VsN (%) with VsN >50% considered reliable. Safety was evaluated by perioperative complications rate. Feasibility was determined by technical success of obtaining measurements. Reproducibility was evaluated using intraclass correlation coefficient analysis. RESULTS: Total of 3320 EUS-SWE measurements were performed on 117 patients without perioperative complications. Measurement success rate was 100% across all locations. Reliable measurements were more common in the HOP (953/1120 [85.1%]) followed by body (853/1130 [75.5%]) and tail of pancreas (687/1070 [64.2%]) (P < 0.001). The analysis showed good reproducibility in all locations (intraclass correlation coefficient range, 0.80-0.89). CONCLUSIONS: Endoscopic ultrasound-SWE is safe, has 100% technical success rate, and is highly reproducible when used in the pancreas. Our study suggests that SWE measurements in the HOP offer the highest reliability, likely because of large study area and less respiratory artifact.

Increasing Pancreatic Cancer Incidence in Young Women in the United States: A Population-Based Time-Trend Analysis, 2001-2018.

BACKGROUND & AIMS: Previous studies have shown an increasing incidence of pancreatic cancer (PC), especially in younger women; however, this has not been externally validated. In addition, there are limited data about contributing factors to this trend. We report age and sex-specific time-trend analysis of PC age-adjusted incidence rates (aIRs) using the National Program of Cancer Registries database without Surveillance Epidemiology and End Results data. METHODS: PC aIR, mortality rates, annual percentage change, and average annual percentage change (AAPC) were calculated and assessed for parallelism and identicalness. Age-specific analyses were conducted in older (≥55 years) and younger (<55 years) adults. PC incidence based on demographics, tumor characteristics, and mortality were evaluated in younger adults. RESULTS: A total of 454,611 patients were diagnosed with PC between 2001 and 2018 with significantly increasing aIR in women (AAPC = 1.27%) and men (AAPC = 1.14%) without a difference (P = .37). Similar results were seen in older adults. However, in younger adults (53,051 cases; 42.9% women), women experienced a greater increase in aIR than men (AAPCs = 2.36%, P < .001 vs 0.62%, P = 0.62) with nonparallel trends (P < .001) and AAPC difference of 1.74% (P < .001). This AAPC difference appears to be due to rising aIR in Blacks (2.23%; P < .001), adenocarcinoma histopathologic subtype (0.89%; P = .003), and location in the head-of-pancreas (1.64%; P < .001). PC mortality was found to be unchanged in women but decreasing in counterpart men (AAPC difference = 0.54%; P = .001). CONCLUSION: Using nationwide data, covering ≈64.5% of the U.S. population, we externally validate a rapidly increasing aIR of PC in younger women. There was a big separation of the incidence trend between women and men aged 15-34 years between 2001 and 2018 (>200% difference), and it did not show slowing down.

Epidemiologic risk factors for patients admitted with chronic pancreatitis and pancreatic ductal adenocarcinoma in the United States.

BACKGROUND: Epidemiological studies of chronic pancreatitis (CP) and its association with pancreatic ductal adenocarcinoma (PDAC) are limited. Understanding demographic and ethno-racial factors may help identify patients at the highest risk for CP and PDAC. AIM: To evaluate the ethno-racial risk factors for CP and its association with PDAC. The secondary aim was to evaluate hospitalization outcomes in patients admitted with CP and PDAC. METHODS: This retrospective cohort study used the 2016 and 2017 National Inpatient Sample databases. Patients included in the study had ICD-10 codes for CP and PDAC. The ethnic, socioeconomic, and racial backgrounds of patients with CP and PDAC were analyzed. RESULTS: Hospital admissions for CP was 29 per 100000, and 2890 (0.78%) had PDAC. Blacks [adjusted odds ratio (aOR) 1.13], men (aOR 1.35), age 40 to 59 (aOR 2.60), and being overweight (aOR 1.34) were significantly associated with CP (all with P < 0.01). In patients with CP, Whites (aOR 1.23), higher income, older age (aOR 1.05), and being overweight (aOR 2.40) were all significantly associated with PDAC (all with P < 0.01). Men (aOR 1.81) and Asians (aOR 15.19) had significantly increased mortality (P < 0.05). Hispanics had significantly increased hospital length of stay (aOR 5.24) (P < 0.05). CONCLUSION: Based on this large, nationwide analysis, black men between 40-59 years old and overweight are at significantly increased risk for admission with CP. White men older than 40 years old and overweight with higher income were found to have significant associations with CP and PDAC. This discrepancy may reflect underlying differences in healthcare access and utilization among different socioeconomic and ethno-racial groups.

Targeted secretion: Myosin V delivers vesicles through formin condensates.

Secretory vesicles are often delivered to very specific targets, like pre-synaptic terminals or cell tips, to focus exocytosis. New work suggests that a biomolecular condensate focuses actin filaments that deliver incoming vesicles through the condensate to the plasma membrane.

Quality improvement project on the development of a management algorithm for iatrogenic perforations and the long-term impact on physician knowledge.

Background and study aims Acute iatrogenic endoscopic perforations (AIEPs) can have high morbidity and mortality, especially colonic perforations. Knowledge of diagnosis and AIEP management can improve patient care. The aims of this study were to: develop an evidence-based AIEP management algorithm; study its short-term and long-term impact on physician knowledge; and evaluate physician knowledge using hypothetical clinical scenarios. Methods An institutional AIEP management algorithm was created using the most current recommendations from the American Society for Gastrointestinal Endoscopy and the European Society of Gastrointestinal Endoscopy. Input from advanced endoscopists, nurses, and anesthesiologists was also obtained. We assessed change in physician knowledge using a 10-item questionnaire before (pretest), a standardized one-page AIEP educational material and algorithm immediately after (post-test) to test short-term retention, and 6 months later (6-month reassessment) to test long-term retention. With the 6-month reassessment, two clinical scenarios based on real AIEP were presented to evaluate application of knowledge. Results Twenty-eight subjects (8 gastroenterology fellows and 20 practicing gastroenterologists) participated in the assessments. Pretest and immediate post-test accuracies were 75 % and 95 % ( P  < 0.01), respectively. Six-month reassessment accuracies were 83.6 %, significantly worse compared to post-test accuracies ( P  < 0.05), but significantly improved compared to pretest accuracies ( P  < 0.05). Accuracies for clinical scenarios #1 and #2 were 67.5 % and 60.3 %, respectively. Fellows had similar accuracies when compared to practicing gastroenterologists. Conclusions Using standardized methodology and a multidisciplinary approach, an AIEP management algorithm was created to improve patient care and alleviate physician and staff stress. In addition, we showed that a one-page educational document on perforations can significantly improve short-term and long-term physician knowledge, although periodic reeducation is needed.

Mechanism of commitment to a mating partner in Saccharomyces cerevisiae.

Many cells detect and follow gradients of chemical signals to perform their functions. Yeast cells use gradients of extracellular pheromones to locate mating partners, providing a tractable model for understanding how cells decode the spatial information in gradients. To mate, yeast cells must orient polarity toward the mating partner. Polarity sites are mobile, exploring the cell cortex until they reach the proper position, where they stop moving and "commit" to the partner. A simple model to explain commitment posits that a high concentration of pheromone is detected only upon alignment of partner cells' polarity sites and causes polarity site movement to stop. Here we explore how yeast cells respond to partners that make different amounts of pheromone. Commitment was surprisingly robust to various pheromone levels, ruling out the simple model. We also tested whether adaptive pathways were responsible for the robustness of commitment, but our results show that cells lacking those pathways were still able to accommodate changes in pheromone. To explain this robustness, we suggest that the steep pheromone gradients near each mating partner's polarity site trap the polarity site in place.

Comparison of no stent fixation, endoscopic suturing, and a novel over-the-scope clip for stent fixation in preventing migration of fully covered self-expanding metal stents: a retrospective comparative study (with video).

BACKGROUND AND AIMS: Endoscopic suturing and over-the-scope clips (OTSCs) are used to prevent migration of fully covered self-expandable metal stents (FCSEMSs). Recently, a dedicated OTSC was developed for securing FCSEMSs. Our primary aim was to compare the frequency of stent migration without stent fixation versus fixation with suturing or OTSCs, and out secondary aims were to compare clinical success, procedure duration, and adverse events. METHODS: A retrospective cohort study evaluated the outcome of stent placement throughout the entire GI tract from 2013 to 2021. Stent migration was determined as stent displacement ≥2 cm endoscopically or radiographically. Clinical success was defined as resolution of indication at follow-up. RESULTS: Four hundred thirty-three procedures were performed, 239 (55%) without fixation, 140 (32%) with suturing, and 54 (12%) with OTSCs. Stent migration rates were 62% without fixation, 57% with suturing, and 35% with OTSCs (P = .013). The median time to stent migration was 3 weeks without fixation, 5 weeks with suturing, and 6 weeks with OTSCs (P = .023). The clinical success rate was 43%. The median procedure time for OTSCs was shorter compared with suturing (42 vs 68 minutes, P = .002). Adverse event rates trended toward being lowest with OTSCs at 9% compared with 21% without fixation and 18% with suturing (P > .05). CONCLUSIONS: OTSCs for stent fixation were found to have significantly lower migration rates compared with no fixation and suturing. Moreover, OTSCs were associated with decreased overall procedure time and total costs per procedure while trending to be associated with fewer adverse events.

Novel Endoscopic Polypectomy Surveillance Technique for Fundic Gland Polyps in Familial Adenomatous Polyposis Can Improve Early Detection of Dysplasia and Gastric Cancer.

INTRODUCTION: Fundic gland polyps (FGPs) are commonly found in patients with familial adenomatous polyposis (FAP) and are considered benign. Biopsies are not routinely performed, and conventional forceps may be time-consuming and/or yield nonrepresentative histology. The purpose of this study was to evaluate the role of a novel endoscopic polypectomy surveillance (EPS), a large volume cold-snare polypectomy technique of random FGPs, in the incidence of dysplasia and gastric cancer (GC) in FAP. METHODS: This is a retrospective longitudinal cohort of patients with FAP referred to a tertiary care center for duodenal adenoma surveillance and who underwent EPS of FGPs between 2001 and 2019. Demographic, endoscopic, and clinicopathologic information was reviewed. RESULTS: Thirty-five patients with FAP were identified at initial endoscopy by the mean age of 43.4 years (±12.8). One hundred thirteen surveillance endoscopies were performed in total using EPS. Dysplasia of FGPs was present on initial esophagogastroduodenoscopy in 7 patients (20%), and 13 additional patients (46.4%) progressed to low-grade dysplasia. Three patients (15%) who subsequently had progression to GC were found to have signet ring cell cancer within the foci of FGPs through EPS. One patient presented as metastatic GC. Progression from nondysplastic FGP to low-grade dysplasia occurred over 63 months (±46.3) with further progression to GC over 34 months (±8.5). Endoscopic risk factors for cancer were polyps >10 mm in size ( P < 0.001) and carpeting of polyps ( P < 0.001). The 5-year cumulative incidence of developing dysplasia was 35.7%. DISCUSSION: We identified that the incidence of dysplasia and GC is higher than previously reported in patients with FAP. Our study used a novel EPS technique and was able to identify GC within the foci of FGPs. Upper endoscopic guidelines should include a more rigorous sampling method for FGPs, such as EPS, to optimize early detection of dysplasia and GC.

Polypectomy for Large Polyps with Endoscopic Mucosal Resection.

Beginning in 1955, when the saline injection was first described to prevent transmural injury during polyp fulguration, endoscopic mucosal resection (EMR) has grown exponentially, both in scope and in practice. Because EMR is an organ-preserving technique even for large polyps, this allows for comparable outcomes to surgery, but substantially improved cost savings and significantly reduced morbidity and mortality. To achieve this, however, one must master the 4 fundamental components that are critical to the success of EMR- time, team, tools, and technique. This article aims to provide a compendium of state of the art updates within the field of endoluminal resection.

Pheromone Guidance of Polarity Site Movement in Yeast.

Cells' ability to track chemical gradients is integral to many biological phenomena, including fertilization, development, accessing nutrients, and combating infection. Mating of the yeast Saccharomyces cerevisiae provides a tractable model to understand how cells interpret the spatial information in chemical gradients. Mating yeast of the two different mating types secrete distinct peptide pheromones, called a-factor and α-factor, to communicate with potential partners. Spatial gradients of pheromones are decoded to guide mobile polarity sites so that polarity sites in mating partners align towards each other, as a prerequisite for cell-cell fusion and zygote formation. In ascomycetes including S. cerevisiae, one pheromone is prenylated (a-factor) while the other is not (α-factor). The difference in physical properties between the pheromones, combined with associated differences in mechanisms of secretion and extracellular pheromone metabolism, suggested that the pheromones might differ in the spatial information that they convey to potential mating partners. However, as mating appears to be isogamous in this species, it is not clear why any such signaling difference would be advantageous. Here we report assays that directly track movement of the polarity site in each partner as a way to understand the spatial information conveyed by each pheromone. Our findings suggest that both pheromones convey very similar information. We speculate that the different pheromones were advantageous in ancestral species with asymmetric mating systems and may represent an evolutionary vestige in yeasts that mate isogamously.

Cultivating PhD Aspirations during College.

Science, technology, engineering, and mathematics (STEM) career barriers persist for individuals from marginalized communities due to financial and educational inequality, unconscious bias, and other disadvantaging factors. To evaluate differences in plans and interests between historically underrepresented (UR) and well-represented (WR) groups, we surveyed more than 3000 undergraduates enrolled in chemistry courses. Survey responses showed all groups arrived on campus with similar interests in learning more about science research. Over the 4 years of college, WR students maintained their interest levels, but UR students did not, creating a widening gap between the groups. Without intervention, UR students participated in lab research at lower rates than their WR peers. A case study pilot program, Biosciences Collaborative for Research Engagement (BioCoRE), encouraged STEM research exploration by undergraduates from marginalized communities. BioCoRE provided mentoring and programming that increased community cohesion and cultivated students' intrinsic scientific mindsets. Our data showed that there was no statistical significant difference between BioCoRE WR and UR students when surveyed about plans for a medical profession, graduate school, and laboratory scientific research. In addition, BioCoRE participants reported higher levels of confidence in conducting research than non-BioCoRE Scholars. We now have the highest annual number of UR students moving into PhD programs in our institution's history.

Chemotropism and Cell-Cell Fusion in Fungi.

Fungi exhibit an enormous variety of morphologies, including yeast colonies, hyphal mycelia, and elaborate fruiting bodies. This diversity arises through a combination of polar growth, cell division, and cell fusion. Because fungal cells are nonmotile and surrounded by a protective cell wall that is essential for cell integrity, potential fusion partners must grow toward each other until they touch and then degrade the intervening cell walls without impacting cell integrity. Here, we review recent progress on understanding how fungi overcome these challenges. Extracellular chemoattractants, including small peptide pheromones, mediate communication between potential fusion partners, promoting the local activation of core cell polarity regulators to orient polar growth and cell wall degradation. However, in crowded environments, pheromone gradients can be complex and potentially confusing, raising the question of how cells can effectively find their partners. Recent findings suggest that the cell polarity circuit exhibits searching behavior that can respond to pheromone cues through a remarkably flexible and effective strategy called exploratory polarization.

Orientation of Cell Polarity by Chemical Gradients.

Accurate decoding of spatial chemical landscapes is critical for many cell functions. Eukaryotic cells decode local chemical gradients to orient growth or movement in productive directions. Recent work on yeast model systems, whose gradient sensing pathways display much less complexity than those in animal cells, has suggested new paradigms for how these very small cells successfully exploit information in noisy and dynamic pheromone gradients to identify their mates. Pheromone receptors regulate a polarity circuit centered on the conserved Rho-family GTPase, Cdc42. The polarity circuit contains both positive and negative feedback pathways, allowing spontaneous symmetry breaking and also polarity site disassembly and relocation. Cdc42 orients the actin cytoskeleton, leading to focused vesicle traffic that promotes movement of the polarity site and also reshapes the cortical distribution of receptors at the cell surface. In this article, we review the advances from work on yeasts and compare them with the excitable signaling pathways that have been revealed in chemotactic animal cells.

Endoscopic full-thickness resection of polyps involving the appendiceal orifice: a multicenter international experience.

BACKGROUND: Endoscopic resection of lesions involving the appendiceal orifice remains a challenge. We aimed to report outcomes with the full-thickness resection device (FTRD) for the resection of appendiceal lesions and identify factors associated with the occurrence of appendicitis. METHODS: This was a retrospective study at 18 tertiary-care centers (USA 12, Canada 1, Europe 5) between November 2016 and August 2020. Consecutive patients who underwent resection of an appendiceal orifice lesion using the FTRD were included. The primary outcome was the rate of R0 resection in neoplastic lesions, defined as negative lateral and deep margins on post-resection histologic evaluation. Secondary outcomes included the rates of: technical success (en bloc resection), clinical success (technical success without need for further surgical intervention), post-resection appendicitis, and polyp recurrence. RESULTS: 66 patients (32 women; mean age 64) underwent resection of colonic lesions involving the appendiceal orifice (mean [standard deviation] size, 14.5 (6.2) mm), with 40 (61 %) being deep, extending into the appendiceal lumen. Technical success was achieved in 59/66 patients (89 %), of which, 56 were found to be neoplastic lesions on post-resection pathology. Clinical success was achieved in 53/66 (80 %). R0 resection was achieved in 52/56 (93 %). Of the 58 patients in whom EFTR was completed who had no prior history of appendectomy, appendicitis was reported in 10 (17 %), with six (60 %) requiring surgical appendectomy. Follow-up colonoscopy was completed in 41 patients, with evidence of recurrence in five (12 %). CONCLUSIONS: The FTRD is a promising non-surgical alternative for resecting appendiceal lesions, but appendicitis occurs in 1/6 cases.

A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement.

Cells polarize their movement or growth toward external directional cues in many different contexts. For example, budding yeast cells grow toward potential mating partners in response to pheromone gradients. Directed growth is controlled by polarity factors that assemble into clusters at the cell membrane. The clusters assemble, disassemble, and move between different regions of the membrane before eventually forming a stable polarity site directed toward the pheromone source. Pathways that regulate clustering have been identified but the molecular mechanisms that regulate cluster mobility are not well understood. To gain insight into the contribution of chemical noise to cluster behavior we simulated clustering using the reaction-diffusion master equation (RDME) framework to account for molecular-level fluctuations. RDME simulations are a computationally efficient approximation, but their results can diverge from the underlying microscopic dynamics. We implemented novel concentration-dependent rate constants that improved the accuracy of RDME-based simulations, allowing us to efficiently investigate how cluster dynamics might be regulated. Molecular noise was effective in relocating clusters when the clusters contained low numbers of limiting polarity factors, and when Cdc42, the central polarity regulator, exhibited short dwell times at the polarity site. Cluster stabilization occurred when abundances or binding rates were altered to either lengthen dwell times or increase the number of polarity molecules in the cluster. We validated key results using full 3D particle-based simulations. Understanding the mechanisms cells use to regulate the dynamics of polarity clusters should provide insights into how cells dynamically track external directional cues.

Chemotactic movement of a polarity site enables yeast cells to find their mates.

How small eukaryotic cells can interpret dynamic, noisy, and spatially complex chemical gradients to orient growth or movement is poorly understood. We address this question using Saccharomyces cerevisiae, where cells orient polarity up pheromone gradients during mating. Initial orientation is often incorrect, but polarity sites then move around the cortex in a search for partners. We find that this movement is biased by local pheromone gradients across the polarity site: that is, movement of the polarity site is chemotactic. A bottom-up computational model recapitulates this biased movement. The model reveals how even though pheromone-bound receptors do not mimic the shape of external pheromone gradients, nonlinear and stochastic effects combine to generate effective gradient tracking. This mechanism for gradient tracking may be applicable to any cell that searches for a target in a complex chemical landscape.