Global Amplification Research Articles

IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptional networks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities, integrating functional genomics screening, spatial proteomics, and global chromatin mapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is required for IRF4 expression and functionally associates with IRF4 protein on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitors remain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinations of SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providing a promising strategy for relapsed/refractory disease.

Latitudinal distribution of biomarkers across the western Arctic Ocean and the Bering Sea: an approach to assess sympagic and pelagic algal production

Abstract. The drastic decline of Arctic sea ice due to global warming and polar amplification of environmental changes in the Arctic basin profoundly alter primary production with consequences for polar ecosystems and the carbon cycle. In this study, we use highly branched isoprenoids (HBIs), brassicasterol, dinosterol and terrestrial biomarkers (n-alkanes and campesterol) in surface sediments to assess sympagic and pelagic algal production with changing sea-ice conditions along a latitudinal transect from the Bering Sea to the high latitudes of the western Arctic Ocean. Suspended particulate matter (SPM) was also collected in surface waters at several stations of the Chukchi Sea to provide snapshots of phytoplankton communities under various sea-ice conditions for comparison with underlying surface sediments. Our results show that sympagic production (IP25 and HBI-II) increased northward between 62 and 73∘ N, with maximum values at the sea-ice edge in the Marginal Ice Zone (MIZ) between 70 and 73∘ N in the southeastern Chukchi Sea and along the coast of Alaska. It was consistently low at northern high latitudes (>73∘ N) under extensive summer sea-ice cover and in the Ice-Free Zone (IFZ) of the Bering Sea. Enhanced pelagic sterols and HBI-III occurred in the IFZ across the Bering Sea and in the southeastern Chukchi Sea up to 70–73∘ N in MIZ conditions, which marks a shift of sympagic over pelagic production. In surface water SPM, pelagic sterols display similar patterns as chlorophyll a, increasing southward with higher amounts found in the Chukchi shelf, pointing to the dominance of diatom production. Higher cholesterol values were found in the mid-Chukchi Sea shelf where phytosterols were also abundant. This compound prevailed over phytosterols in sediments, compared to SPM, reflecting efficient consumption of algal material in the water column by herbivorous zooplankton.

Paternity testing using 21 STR Loci in a biotechnology approach: case of Rwandan Population

INTRODUCTION: We focused on a sample size of 141 unrelated Rwandan persons to genotype21 STR loci that were relied up in establishing allele frequencies, heterozygosity and power ofexclusion. This study aims at exploring allele frequencies on a representative sample from Rwandanpopulation to determine probability of paternity for sampled families basing on polymorphic STRsloci, using 21 autosomal-STR loci by Genetic Analyzer 3500X.METHODS: This was an experimental study and global filer TM Express PCR Amplification kit wasused to amplify 21 autosomal STR loci.RESULTS: The total number of observed alleles was 270; the largest number of different alleleswas seen in SE33 and D18S51 loci. The locus with the highest heterozygosity was SE33, while locusTH01 had the lowest heterozygosity. The heterozygosity of the 21 STR loci ranged from 71.3%(TH01) to 91.6% (SE33) with an average of 81.1% a good indicator of high genetic variability. Forall microsatellites analyzed the power of exclusion ranged from 43.4% (TH01) to 78.1% (SE33)with an average of 58.2%. For seven of eight cases examined in paternity test alleged father wasnot excluded as biological father of child. The results found in examination of case 8 indicated thatthe alleged father was not the biological father of the child.CONCLUSION: Based on calculated statistical parameters, the population of Rwanda may usethese 21 STR loci as a vital tool for forensic identification and paternity testing.

Surveillance of Contagious Equine Metritis: Results of the First 5-Year Period of French Proficiency Tests for Taylorella equigenitalis Detection by Real-Time PCR

Contagious equine metritis (CEM) detection by PCR is recognized by the European Union according to Commission Implementing Regulation (EU) No 846/2014, and real-time PCR is now recommended by the World Organisation for Animal Health Terrestrial Manual at the same level as the culture method. The present study highlights the creation of an efficient network of approved laboratories in France in 2017 for CEM detection by real-time PCR. The network currently consists of 20 laboratories. A first proficiency test (PT) was organized by the national reference laboratory for CEM in 2017 to evaluate the performance of the early network, followed by annual proficiency tests organized for ongoing periodic assessment of network performance. Results of the 5 PTs organized from 2017 to 2021 are presented, during which 5 real-time PCRs and 3 DNA extraction methods were used. Overall, 99.20% of the qualitative data corresponded to expected results and the R-squared of global DNA amplification calculated for each PT varied from 0.728 to 0.899. DNA extraction is also an important step in the analytical process, and results were more favorable with direct lysis compared to column extraction. Focusing on the most commonly used PCR (PCR 1: 86.4% of results) showed lowest cycle threshold values with direct lysis compared to column and magnetic bead extractions, and with magnetic bead extraction compared to column extraction, but neither of these differences were statistically significant.

Alexandrium on the Alaskan Beaufort Sea shelf: Impact of upwelling in a warming Arctic

The harmful algal genus Alexandrium has characteristically been found in temperate and subtropical regions; however recent evidence suggests global warming may be expanding its range into high latitude waters. Alexandrium cysts have previously been documented in the Chukchi Sea and we hypothesize that Alexandrium may be expanding further into the Arctic due to distribution by the Beaufort shelfbreak jet. Here we document the presence of Alexandrium catenella along the Alaskan Beaufort Sea shelf, marking an expansion of its known range. The observations of A. catenella were made using three different methods: FlowCAM imaging, 18S eukaryotic sequencing, and real-time quantitative PCR. Four occupations of a shelf/slope transect spanned the evolution of a strong wind-driven upwelling event over a 5-day period. A nearby mooring provided the physical context for the event, revealing that enhanced easterly winds reversed the Beaufort shelfbreak jet to the west and induced upwelling of colder, denser water onto the outer shelf. A. catenella sequences dominated the surface phytoplankton community at the onset of the upwelling event. This signal vanished during and after the event, likely due to a combination of alongstream advection, cross-stream advection, and wind mixing. These results suggest contrasting physical processes that are both subject to global warming amplification, delivery of warm waters via the Beaufort shelfbreak jet and upwelling, may control the proliferation of this potential harmful alga into the Arctic.

Distinct mechanisms of planar polarization by the core and Fat-Dachsous planar polarity pathways in the Drosophila wing.

Planar polarity describes the coordinated polarization of cells within a tissue plane, and in animals can be determined by the "core" or Fat-Dachsous pathways. Current models for planar polarity establishment involve two components: tissue-level "global" cues that determine the overall axis of polarity and cell-level feedback-mediated cellular polarity amplification. Here, we investigate the contributions of global cues versus cellular feedback amplification in the core and Fat-Dachsous pathways during Drosophila pupal wing development. We present evidence that these pathways generate planar polarity via distinct mechanisms. Core pathway function is consistent with strong feedback capable of self-organizing cell polarity, which can then be aligned with the tissue axis via weak or transient global cues. Conversely, generation of cell polarity by the Ft-Ds pathway depends on strong global cues in the form of graded patterns of gene expression, which can then be amplified by weak feedback mechanisms.

Mechanical coupling of supracellular stress amplification and tissue fluidization during exit from quiescence

Cellular quiescence is a state of reversible cell cycle arrest that is associated with tissue dormancy. Timely regulated entry into and exit from quiescence is important for processes such as tissue homeostasis, tissue repair, stem cell maintenance, developmental processes, and immunity. However, little is known about processes that control the mechanical adaption to cell behavior changes during the transition from quiescence to proliferation. Here, we show that quiescent human keratinocyte monolayers sustain an actinomyosin-based system that facilitates global cell sheet displacements upon serum-stimulated exit from quiescence. Mechanistically, exposure of quiescent cells to serum-borne mitogens leads to rapid amplification of preexisting contractile sites, leading to a burst in monolayer tension that subsequently drives large-scale displacements of otherwise motility-restricted monolayers. The stress level after quiescence exit correlates with the level of quiescence depth at the time of activation, and a critical stress magnitude must be reached to overcome the cell sheet displacement barrier. The study shows that static quiescent cell monolayers are mechanically poised for motility, and it identifies global stress amplification as a mechanism for overcoming motility restrictions in confined confluent cell monolayers.

Hasty sensorimotor decisions rely on an overlap of broad and selective changes in motor activity.

Humans and other animals are able to adjust their speed-accuracy trade-off (SAT) at will depending on the urge to act, favoring either cautious or hasty decision policies in different contexts. An emerging view is that SAT regulation relies on influences exerting broad changes on the motor system, tuning its activity up globally when hastiness is at premium. The present study aimed to test this hypothesis. A total of 50 participants performed a task involving choices between left and right index fingers, in which incorrect choices led either to a high or to a low penalty in 2 contexts, inciting them to emphasize either cautious or hasty policies. We applied transcranial magnetic stimulation (TMS) on multiple motor representations, eliciting motor-evoked potentials (MEPs) in 9 finger and leg muscles. MEP amplitudes allowed us to probe activity changes in the corresponding finger and leg representations, while participants were deliberating about which index to choose. Our data indicate that hastiness entails a broad amplification of motor activity, although this amplification was limited to the chosen side. On top of this effect, we identified a local suppression of motor activity, surrounding the chosen index representation. Hence, a decision policy favoring speed over accuracy appears to rely on overlapping processes producing a broad (but not global) amplification and a surround suppression of motor activity. The latter effect may help to increase the signal-to-noise ratio of the chosen representation, as supported by single-trial correlation analyses indicating a stronger differentiation of activity changes in finger representations in the hasty context.

Three-dimensional feature matching improves coverage for single-cell proteomics based on ion mobility filtering.

SUMMARYSingle-cell proteomics (scProteomics) promises to advance our understanding of cell functions within complex biological systems. However, a major challenge of current methods is their inability to identify and provide accurate quantitative information for low-abundance proteins. Herein, we describe an ion-mobility-enhanced mass spectrometry acquisition and peptide identification method, transferring identification based on FAIMS filtering (TIFF), to improve the sensitivity and accuracy of label-free scProteomics. TIFF extends the ion accumulation times for peptide ions by filtering out singly charged ions. The peptide identities are assigned by a three-dimensional MS1 feature matching approach (retention time, accurate mass, and FAIMS compensation voltage). The TIFF method enabled unbiased proteome analysis to a depth of >1,700 proteins in single HeLa cells, with >1,100 proteins consistently identified. As a demonstration, we applied the TIFF method to obtain temporal proteome profiles of >150 single murine macrophage cells during lipopolysaccharide stimulation and identified time-dependent proteome changes. A record of this paper’s transparent peer review process is included in the supplemental information.

MYC overexpression leads to increased chromatin interactions at super-enhancers and MYC binding sites.

The MYC oncogene encodes for the MYC protein and is frequently dysregulated across multiple cancer cell types, making it an attractive target for cancer therapy. MYC overexpression leads to MYC binding at active enhancers, resulting in a global transcriptional amplification of active genes. Because super-enhancers are frequently dysregulated in cancer, we hypothesized that MYC preferentially invades into super-enhancers and alters the cancer genome organization. To that end, we performed ChIP-seq, RNA-seq, circular chromosome conformation capture (4C-seq), and Spike-in Quantitative Hi-C (SIQHiC) on the U2OS osteosarcoma cell line with tetracycline-inducible MYC. MYC overexpression in U2OS cells modulated histone acetylation and increased MYC binding at super-enhancers. SIQHiC analysis revealed increased global chromatin contact frequency, particularly at chromatin interactions connecting MYC binding sites at promoters and enhancers. Immunofluorescence staining showed that MYC molecules formed punctate foci at these transcriptionally active domains after MYC overexpression. These results demonstrate the accumulation of overexpressed MYC at promoter–enhancer hubs and suggest that MYC invades into enhancers through spatial proximity. At the same time, the increased protein–protein interactions may strengthen these chromatin interactions to increase chromatin contact frequency. CTCF siRNA knockdown in MYC-overexpressed U2OS cells demonstrated that removal of architectural proteins can disperse MYC and abrogate the increase in chromatin contacts. By elucidating the chromatin landscape of MYC-driven cancers, we can potentially target MYC-associated chromatin interactions for cancer therapy.

Suppression of Unattended Features Is Independent of Task Relevance.

Feature-based attention serves the separation of relevant from irrelevant features. While global amplification of attended features is coherently described as a key mechanism for feature-based attention, nature and constituting factors of neural suppressive interactions are far less clear. One aspect of global amplification is its flexible modulation by the task relevance of the to-be-attended stimulus. We examined whether suppression is similarly modulated by their respective task relevance or is mandatory for all unattended features. For this purpose, participants saw a display of randomly moving dots with 3 distinct colors and were asked to report brief events of coherent motion for a cued color. Of the 2 unattended colored clouds, one contained distracting motion events while the other was irrelevant and without such motion events throughout the experiment. We used electroencephalography-derived steady-state visual-evoked potentials to investigate early visual processing of the attended, unattended, and irrelevant color under sustained feature-based attention. The analysis revealed a biphasic process with an early amplification of the to-be-attended color followed by suppression of the to-be-ignored color relative to a pre-cue baseline. Importantly, the neural dynamics for the unattended and always irrelevant color were comparable. Suppression is thus a mandatory mechanism affecting all unattended stimuli irrespective of their task relevance.

‘FAKE NEWS’ AND OTHER PROBLEMATIC INFORMATION: STUDYING DISSEMINATION AND DISCOURSE PATTERNS

Encompassed by the disputed term ‘fake news’, a variety of overtly or covertly biased, skewed, or falsified reports claiming to present factual information are now seen to constitute a critical challenge to the effective dissemination of news and information across established and emerging democratic societies. Such content – variously also classifiable as propaganda, selective reporting, conspiracy theory, inadvertent misinformation, and deliberate disinformation – in itself is not new; however, contemporary digital and social media networks enable its global dissemination and amplification, by human and algorithmic actors (Woolley & Howard 2017), ordinary users and professional agents, outside of, in opposition to, or sometimes also in collusion with, the mainstream media (Shao et al. 2017; Vargo et al. 2017). Various political, commercial, and state actors are suspected to have exploited this ‘fake news’ ecosystem to influence public opinion, in major votes ranging from the Brexit referendum to national elections, and/or to utilise discourse around ‘fake news’ to generally undermine trust in media, political, and state institutions. This panel brings together a number of perspectives that combine systematic, large-scale, mixed-methods analysis of the empirical evidence for the global dissemination of, engagement with, and visibility of problematic information in public debate with the study of the public discourse about ‘fake news’, and the operationalisation of this concept by politicians and other societal actors to downplay inconvenient facts or reject critical questions. In combination, its five papers present a substantive collection of innovative approaches to the ‘fake news’ concept, exploring the dissemination of problematic information itself at larger and smaller scales as well as examining the operationalisation of the idea of ‘fake news’ in pursuit of specific ideological aims. This produces a new and more comprehensive picture of the overall impact of ‘fake news’, in all its forms, on contemporary societies.

Internal Validation of Global Filer PCR Amplification Kit in DNA Section of Punjab Forensic Science Agency, Lahore

Background: Global Filer PCR Amplification Kit is a 6-dye amplification assay, which amplifies 24 genetic loci simultaneously in a single reaction. The amplification system encompasses both Combined DNA Index System loci and European standard set loci along with a highly polymorphic short tandem repeat (STR) locus SE33. The addition of a Y-STR marker and an insertion deletion marker of Y chromosome has provided additional aid in the gender identification of Amelogenin-Y null males. Global Filer PCR Amplification Kit has provided understandably more discrimination power compared with Identifiler Plus PCR Amplification Kit currently being used in Punjab Forensic Science Agency (PFSA). Methodology: In this study, Global Filer PCR Amplification Kit was internally validated in PFSA following the Scientific Working Group on DNA Analysis Methods laid principles to establish quality assurance parameters and interpretation guidelines. Known nonprobative DNA samples were utilized in this study to determine the sensitivity, establishment of proper thresholds for analysis, mixture analysis to determine detectable mixture ratios, contamination assessment, and reproducibility for the new method. Conclusion: The results of this internal validation strongly suggest the use of Applied Biosystems Global Filer PCR Amplification Kit in forensic casework analysis.

An Improved Caulobacter crescentus Operon Annotation Based on Transcriptome Data.

Caulobacter crescentus is a model alphaproteobacterium with a well-studied genetic network controlling its cell cycle. Essential for such studies is an accurate map of the expressed features of its genome. Here, we provide an updated map of the expressed RNAs by integrative analysis of 5' global rapid amplification of cDNA ends, transcriptome sequencing, rifampicin treatment RNA sequencing, and RNA end-enriched sequencing data sets.

Possible Influence of Tropical Indian Ocean Sea Surface Temperature on the Proportion of Rapidly Intensifying Western North Pacific Tropical Cyclones during the Extended Boreal Summer

AbstractThis study examines the possible impact of tropical Indian Ocean (TIO) sea surface temperature anomalies (SSTAs) on the proportion of rapidly intensifying tropical cyclones (PRITC) over the western North Pacific (WNP) during the extended boreal summer (July–November). There is a robust interannual association (r= 0.46) between TIO SSTAs and WNP PRITC during 1979–2018. Composite analyses between years with warm and cold TIO SSTAs confirm a significant impact of TIO SSTA on WNP PRITC, with PRITC over the WNP basin being 50% during years with warm TIO SSTAs and 37% during years with cold TIO SSTAs. Tropical cyclone heat potential appears to be one of the most important factors in modulating the interannual change of PRITC over the WNP with a secondary role from midlevel moisture changes. Interannual changes in these large-scale factors respond to SSTA differences characterized by a tropics-wide warming, implying a possible global warming amplification on WNP PRITC. The possible footprint of global warming amplification of the TIO is deduced from 1) a significant correlation between TIO SSTAs and global mean SST (GMSST) and a significant linear increasing trend of GMSST and TIO SSTAs, and 2) an accompanying small difference of PRITC (~8%) between years with detrended warm and cold TIO SSTAs compared to the difference of PRITC (~13%) between years with nondetrended warm and cold TIO SSTAs. Global warming may contribute to increased TCHP, which is favorable for rapid intensification, but increased vertical wind shear is unfavorable for TC genesis, thus amplifying WNP PRITC.

Conscious perception and the modulatory role of dopamine: no effect of the dopamine D2 agonist cabergoline on visual masking, the attentional blink, and probabilistic discrimination

RationaleConscious perception is thought to depend on global amplification of sensory input. In recent years, striatal dopamine has been proposed to be involved in gating information and conscious access, due to its modulatory influence on thalamocortical connectivity.ObjectivesSince much of the evidence that implicates striatal dopamine is correlational, we conducted a double-blind crossover pharmacological study in which we administered cabergoline—a dopamine D2 agonist—and placebo to 30 healthy participants. Under both conditions, we subjected participants to several well-established experimental conscious-perception paradigms, such as backward masking and the attentional blink task.ResultsWe found no evidence in support of an effect of cabergoline on conscious perception: key behavioral and event-related potential (ERP) findings associated with each of these tasks were unaffected by cabergoline.ConclusionsOur results cast doubt on a causal role for dopamine in visual perception. It remains an open possibility that dopamine has causal effects in other tasks, perhaps where perceptual uncertainty is more prominent.

Circulating Cell-Free Plasma DNA in Noninvasive Prenatal Paternity Testing with Short Tandem Repeats (STRs).

Paternity relationship can be established using STR markers in a minimally invasive manner during the prenatal period in the early weeks of pregnancy or in advanced pregnancy using circulating cell-free DNA (ccf DNA) drawn from the mother. The aim of our presentation is to demonstrate the advantages of ccf plasma DNA in establishing the paternity of an unborn child. Between mother and the alleged father (AF) of the fetus, an avuncular relationship as uncle-niece exists. As biological samples, saliva was collected with buccal swabs from the mother and AF. For the fetus, we separated plasma from drawn blood from the mother, and further, we isolated ccf DNA from the mother's plasma sample. The DNA samples were quantified on a 7500 ABI Real-Time PCR using Investigator Quantiplex Pro Kit (Qiagen, Germany). Genotyping of the DNA samples was performed on a ProFlex PCR System (Thermo Scientific, USA) using the multiplex STR markers from Global Filer PCR Amplification Kit (Thermo Scientific, USA). Further, PCR products were run on capillary electrophoresis on an ABI 3500 Genetic Analyzer (Applied Biosystems, USA). The AF was confirmed as the biological father of the child, with a probability of paternity (PP) = 99.99999% and a cumulative paternity index (CPI) = 8.300 x 103. In the case of advanced pregnancies from sexual assaults or incestuous relationships, the use of ccf DNA to establish the genetic profile of the fetus represents an advantage for establishing the paternity relationship between the fetus and AF. The method proves its efficiency as it has the advantage of speed of probation through forensic genetic expertise.

A High Offset Distribution Tolerance High Resolution ISFET Array With Auto-Compensation for Long-Term Bacterial Metabolism Monitoring.

This paper presents a CMOS ion-sensitive-field-effect-transistor (ISFET) array with superior offset distribution tolerance, resolution and linearity for long-term bacterial metabolism monitoring. A floating gate ISFET is adopted as the sensing front end to maximize ion sensitivity and support ultra-long-term measurement. To solve the DC offset issue induced by trapped chargers and drifts in each ISFET sensor, a complementary readout scheme with column offset compensation is proposed. P-type and N-type source followers are combined to cover a wide range of input DC offsets while maintaining small area and high linearity. The DC offset is digitally compensated during signal readout to facilitate global amplification and quantization. Fabricated in 0.18μm standard CMOS process, the ISFET array can tolerate an offset distribution beyond power supply with a linear pH-to-output response. Due to high ion sensitivity and low circuit noise, the whole system achieves a high resolution of 0.017pH. The proposed ISFET system has successfully demonstrated an accurate pH monitoring of normal Escherichis coli growth for 11 hours and its response to antibiotics, showing long-term bacterial metabolism monitoring capability.

A Living, Single Cell View of Myc's Effects on Transcription

How does c-MYC act on transcription events in single living cells to cause a global amplification of gene expression? To answer this question, we employ two recently-developed imaging techniques: 1) single-molecule FISH to quantify RNA in fixed cells, and 2) live cell imaging with the MS2-PP7 stem loop system to observe real-time RNA production at a given gene locus. Our results from both the exogenous reporter and endogenous gene show that MYC increases the duration of transcription events— this results in greater gene expression, but also an increase in its heterogeneity. These findings provide living, single cell evidence of MYC as a global amplifier of gene expression, and suggests the mechanism is by stabilizing the active period of a gene. We speculate that the added consequence of MYC's propensity to increase gene expression heterogeneity could drive cells to transiently populate pathological states and phenotypes that may ultimately make them susceptible to cancer. In addition, we seek to assess the direct effects of MYC on gene transcription. We engineered a photo-inducible version of MYC (Pi-MYC) to achieve spatial and temporal control of MYC within living cells. We demonstrate that Pi-MYC has oncogenic capability similar to wildtype MYC by coordinating with mutant RAS to transform mouse fibroblasts and inducing them to exhibit anchorage-independent growth. This tool shall allow us to follow the direct activity of genes in response to MYC perturbation.

Amplification and Suppression of Traveling Waves along the Mouse Organ of Corti: Evidence for Spatial Variation in the Longitudinal Coupling of Outer Hair Cell-Generated Forces.

Mammalian hearing sensitivity and frequency selectivity depend on a mechanical amplification process mediated by outer hair cells (OHCs). OHCs are situated within the organ of Corti atop the basilar membrane (BM), which supports sound-evoked traveling waves. It is well established that OHCs generate force to selectively amplify BM traveling waves where they peak, and that amplification accumulates from one location to the next over this narrow cochlear region. However, recent measurements demonstrate that traveling waves along the apical surface of the organ of Corti, the reticular lamina (RL), are amplified over a much broader region. Whether OHC forces accumulate along the length of the RL traveling wave to provide a form of "global" cochlear amplification is unclear. Here we examined the spatial accumulation of RL amplification. In mice of either sex, we used tones to suppress amplification from different cochlear regions and examined the effect on RL vibrations near and far from the traveling-wave peak. We found that although OHC forces amplify the entire RL traveling wave, amplification only accumulates near the peak, over the same region where BM motion is amplified. This contradicts the notion that RL motion is involved in a global amplification mechanism and reveals that the mechanical properties of the BM and organ of Corti tune how OHC forces accumulate spatially. Restricting the spatial buildup of amplification enhances frequency selectivity by sharpening the peaks of cochlear traveling waves and constrains the number of OHCs responsible for mechanical sensitivity at each location.SIGNIFICANCE STATEMENT Outer hair cells generate force to amplify traveling waves within the mammalian cochlea. This force generation is critical to the ability to detect and discriminate sounds. Nevertheless, how these forces couple to the motions of the surrounding structures and integrate along the cochlear length remains poorly understood. Here we demonstrate that outer hair cell-generated forces amplify traveling-wave motion on the organ of Corti throughout the wave's extent, but that these forces only accumulate longitudinally over a region near the wave's peak. The longitudinal coupling of outer hair cell-generated forces is therefore spatially tuned, likely by the mechanical properties of the basilar membrane and organ of Corti. Our findings provide new insight into the mechanical processes that underlie sensitive hearing.