Positive Signals Research Articles

Trehalose signaling regulates metabolites associated with the quality of rose flowers under drought stress

Drought is an environmental factor affecting the yield and quality of rose flowers, but the potential molecular regulatory mechanism remains unclear. Here, the physiological indexes and related compound contents of rose flowers were determined under drought stress, of which flower size, fresh/dry weight, and carbohydrate accumulation were significantly reduced, whereas the contents of total phenols, total flavonoids, total anthocyanins, and volatile compounds increased compared with normal growth conditions. Transcriptome profiling identified that trehalose signaling may be involved in this process, and that the expression level of various trehalose anabolic pathway genes such as trehalose-6-phosphate synthases and trehalose phosphatases were repressed, whereas the contents of trehalose (Tre) and its precursor trehalose-6-phosphate (T6P) decreased under drought stress. Furthermore, exogenous spraying of Tre and T6P could alleviate the wilting phenomenon caused by drought stress and promote the accumulation of starch, soluble sugar, and lignin in the petals. Results indicated that T6P or Tre, as a positive regulatory signal, improves the drought tolerance of rose plants and maintains the quality of rose flowers under drought conditions, which provides new insights into the effects of drought stress on flower quality.

ИЗУЧЕНИЕ ВАЛИДАЦИОННЫХ ХАРАКТЕРИСТИК МЕТОДИК ИСПЫТАНИЯ НА ПОДЛИННОСТЬ И КОЛИЧЕСТВЕННОГО ОПРЕДЕЛЕНИЯ АЦИЗОЛА В СТОМАТОЛОГИЧЕСКОМ ГЕЛЕ

In the quality assurance system for medicinal products, an important role is played by the procedure for validation of analytical methods at the stages of development, testing, technology and serial production. The need for validation at the stage of drug development is due to the fact that it is possible to promptly identify the shortcomings of the method and significantly improve it. The purpose of this study is to validate methods for testing «The authenticity» and «Quantitative determination» of acyzole in dental gel. Materials and methods. To achieve this goal, an active pharmaceutical substance of pharmacopoeial quality was used. When developing methods for testing for “Authenticity,” a reaction with oxalic acid to the zinc cation determined in the composition of acyzole was used. For the quantitative determination of acyzole, the complexometric method was used. The objects of the study were three series of gel samples. Results and discussion. As a result of the research, a method for testing «Authenticity» was developed; it was found that the proposed method is characterized by a negative analytical signal on model mixtures free of the analyte component and placebo, and a positive analytical signal on model mixtures of various compositions containing the analyte component. The validation characteristics of methods for the quantitative determination of acyzole in the gel were studied. positive results were obtained. The proposed methods can be used for inclusion in the regulatory documentation for the developed gel. Conclusion. When assessing the validation characteristics of the proposed methods, it was established that the methods for testing the «Authenticity» and «Quantitative determination» of acyzole in the gel are specific, the methods of quantitative determination are characterized by accuracy and repeatability, a linear dependence in the analytical range of ±20% of the declared amount of acyzole, which allows them to be used for a reliable assessment quality of the developed dental gel.

Initial development of perceptions of ability and intent factors of (un)trustworthiness in short‐term teams

SummaryIndividual perceptions of team trustworthiness are critical antecedents to the development of relationships within teams. Yet, clarity is needed regarding the focus of these individual perceptions and how they change, particularly at the outset of team interactions. Two distinct research streams have emerged regarding trustworthiness. One proposes a difference between perceived ability and intent, whereas the other proposes a difference between confident positive and negative expectations of others. Regardless of their structure, theory suggests that perceptions of team trustworthiness ought to develop across performance episodes as individuals identify more with their team and have more information about how they are performing. We explore these relationships across three distinct performance episodes in newly formed short‐term teams. Our results support a four‐factor model of trustworthiness within the context of short‐term, lab‐based teams. Further, perceptions regarding teammates' abilities tended to change quickly and curvilinearly while those regarding teammates' intents changed linearly. Positive team performance signals bolstered individual perceptions of team trustworthiness in ability and intent but not perceived team untrustworthiness. Negative team performance signals bolstered individual perceptions of team untrustworthiness in ability and intent while harming both types of individual perceptions of team trustworthiness. This study supports propositions from the model of trust over time and lays the groundwork for a comprehensive approach toward trust research within teams.

A Dual-Cascade Activatable Near-Infrared Fluorescent Probe for Precise Intraoperative Imaging of Tumor.

Accurate intraoperative tumor delineation is critical to achieving successful surgical outcomes. However, conventional techniques typically suffer from poor specificity and low sensitivity and are time-consuming, which greatly affects intraoperative decision-making. Here, we report a cascade activatable near-infrared fluorescent (NIRF) probe IR780SS@CaP that can sequentially respond to tumor acidity and elevated glutathione levels for accurate intraoperative tumor localization. Compared with nonactivatable and single-factor activatable probes, IR780SS@CaP with a cascade strategy can minimize nonspecific activation and false positive signals in a complicated biological environment, affording a superior tumor-to-normal tissue ratio to facilitate the delineation of abdominal metastases. Small metastatic lesions that were less than 1 mm in diameter can be precisely identified by IR780SS@CaP and completely excised under NIRF imaging guidance. This study could benefit tumor diagnosis and image-guided tumor surgery by providing real-time information and reliable decision support, thus reducing the risk of both recurrence and complications to improve patient outcomes.

Regulated public accessibility to municipalities’ financial reports and bond interest cost

PurposeIn this study, we examine regulated public accessibility to municipalities’ financial reports and bond interest cost. In particular, we examine whether there is information content in a component of a constrained filing period that is useful to municipal bond market participants. The component of a filing period that we focus on is the period of time between an audit report date and a regulated public accessibility date.Design/methodology/approachTo explore our research question, we collect a sample of observations from municipalities that: (1) are required to post annual/audit financial reports on a centralized state-level repository that includes a “transparent” date stamp on when reports are made publicly available and (2) have issued general obligation bonds. Our sample is limited to one observation per municipality. The sample period is 2006–2019. In terms of approach, we use an ordinary least square (OLS) regression model to empirically test whether the time period between municipalities’ audit report date and state-required repository filing date is associated with general obligation bond interest cost.FindingsWe find support for the idea that there is information content in a component of a constrained filing period. In particular, we hypothesize and find a positive association between the time period between an audit report date and a state filing date and general obligation bond interest cost. Seemingly, this component of time may provide something unique or not available in other components of a constrained filing period (e.g. the fiscal year-end date to the audit report date). In post hoc analyses, we also find that both components of the constrained filing period in our setting (i.e. the audit report date to state filing date and the fiscal year-end date to audit report date) need to be considered for either of the components to be significant. Moreover, although both components are necessary, the audit report date to state filing date component appears to have a slightly stronger association (in terms of statistical significance) with general obligation bond interest costs.Research limitations/implicationsTo our knowledge, Illinois is the only state that provides a date stamp on when municipalities’ financial information is made publicly available on a centralized repository. As such we focus on municipalities in Illinois. While this increases the internal validity of our research, it potentially limits generalizability across other states. Also, as a reflection of the sample constraint, the number of observations in our study is relatively small. As part of post hoc analyses, we take a closer look at our sample, model and variables used to test our hypothesis.Practical implicationsFor stakeholders, each component of a constrained filing period may provide unique information. For example, the time period between an audit report date and a regulated filing date may send a positive signal about the quality of financial management to investors. For regulators, requiring some sort of centralized public access to municipal financial reports that have transparent time constraints may help states provide stronger governance and help lower municipalities’ borrowing costs.Originality/valueWe use a novel approach (with the Illinois date stamp filing information) to examine our research question. Most prior research has often relied on an assumption that the time between fiscal year-end and the audit report date is the component of time that provides useful information to investors (e.g. Henke and Maher, 2016). In our setting, we explore and find that a component of a constrained filing time period (i.e. the date from an audit filing to a required public accessibility filing) may also provide impactful information to investors.

Characterizing genetic variation on the Z chromosome in Schistosoma japonicum reveals host-parasite co-evolution

BackgroundSchistosomiasis is a neglected tropical disease that afflicts millions of people worldwide; it is caused by Schistosoma, the only dioecious flukes with ZW systems. Schistosoma japonicum is endemic to Asia; the Z chromosome of S. japonicum comprises one-quarter of the entire genome. Detection of positive selection using resequencing data to understand adaptive evolution has been applied to a variety of pathogens, including S. japonicum. However, the contribution of the Z chromosome to evolution and adaptation is often neglected.MethodsWe obtained 1,077,526 high-quality SNPs on the Z chromosome in 72 S. japonicum using re-sequencing data publicly. To examine the faster Z effect, we compared the sequence divergence of S. japonicum with two closely related species, Schistosoma haematobium and S. mansoni. Genetic diversity was compared between the Z chromosome and autosomes in S. japonicum by calculating the nucleotide diversity (π) and Dxy values. Population structure was also assessed based on PCA and structure analysis. Besides, we employed multiple methods including Tajima’s D, FST, iHS, XP-EHH, and CMS to detect positive selection signals on the Z chromosome. Further RNAi knockdown experiments were performed to investigate the potential biological functions of the candidate genes.ResultsOur study found that the Z chromosome of S. japonicum showed faster evolution and more pronounced genetic divergence than autosomes, although the effect may be smaller than the variation among genes. Compared with autosomes, the Z chromosome in S. japonicum had a more pronounced genetic divergence of sub-populations. Notably, we identified a set of candidate genes associated with host-parasite co-evolution. In particular, LCAT exhibited significant selection signals within the Taiwan population. Further RNA interference experiments suggested that LCAT is necessary for S. japonicum survival and propagation in the definitive host. In addition, we identified several genes related to the specificity of the intermediate host in the C-M population, including Rab6 and VCP, which are involved in adaptive immune evasion to the host.ConclusionsOur study provides valuable insights into the adaptive evolution of the Z chromosome in S. japonicum and further advances our understanding of the co-evolution of this medically important parasite and its hosts.Graphical

A dopamine mechanism for reward maximization

Individual survival and evolutionary selection require biological organisms to maximize reward. Economic choice theories define the necessary and sufficient conditions, and neuronal signals of decision variables provide mechanistic explanations. Reinforcement learning (RL) formalisms use predictions, actions, and policies to maximize reward. Midbrain dopamine neurons code reward prediction errors (RPE) of subjective reward value suitable for RL. Electrical and optogenetic self-stimulation experiments demonstrate that monkeys and rodents repeat behaviors that result in dopamine excitation. Dopamine excitations reflect positive RPEs that increase reward predictions via RL; against increasing predictions, obtaining similar dopamine RPE signals again requires better rewards than before. The positive RPEs drive predictions higher again and thus advance a recursive reward-RPE-prediction iteration toward better and better rewards. Agents also avoid dopamine inhibitions that lower reward prediction via RL, which allows smaller rewards than before to elicit positive dopamine RPE signals and resume the iteration toward better rewards. In this way, dopamine RPE signals serve a causal mechanism that attracts agents via RL to the best rewards. The mechanism improves daily life and benefits evolutionary selection but may also induce restlessness and greed.

Detection of EWSR1 gene rearrangement by fluorescence in situ hybridization in bone and soft tissue tumors: clinical application evaluation and atypical signal analysis

Objective: To investigate the clinical application of EWSR1 gene rearrangement by fluorescence in situ hybridization (FISH) in bone and soft tissue tumors and to analyze the cases with atypical signal pattern. Methods: The cases detected for EWSR1 gene rearrangement by FISH in Beijing Jishuitan Hospital, Capital Medical University from 2014 to 2021 were collected, and the value of detecting EWSR1 gene rearrangement for diagnosing bone and soft tissue tumors was analyzed. The cases with atypical positive signals were further analyzed by next generation sequencing (NGS). Results: FISH using EWSR1 break-apart probe kit was successfully performed in 97% (205/211) of cases, 6 cases failed. Four of the 6 failures were due to improper decalcification, 1 case due to signal overlap caused by thick slices, and 1 case due to signal amplification and disorder. EWSR1 gene rearrangements were positive in 122 cases (122/205, 59%), atypical positive signal in 8 cases (8/205, 4%), and negative in 75 cases (75/205, 37%). In cases testing positive, the percentage of positive cells ranged from 34% to 98%, with 120 cases (120/122, 98%) showing a positive cell percentage greater than 50%. Among the 205 successfully tested cases, 156 cases were histologically diagnosed as Ewing's sarcoma, of which 110 were positive (110/156, 71%), 7 were atypical positive (7/156, 4%), and 39 were negative (39/156, 25%). Nine cases were histologically diagnosed as clear cell sarcoma of soft tissue, of which 6 were positive (6/9), 1 was atypical positive (1/9), and 2 were negative (2/9). Five cases were histologically diagnosed as extraskeletal myxoid chondrosarcoma, of which 2 were positive (2/5) and 3 were negative (3/5). Three cases were histologically diagnosed as angiomatoid fibrous histiocytoma, of which 2 were positive (2/3) and 1 was negative (1/3). Two cases were histologically diagnosed as myoepithelioma of soft tissue, of which 1 was positive (1/2) and 1 was negative (1/2). One case was histologically diagnosed as olfactory neuroblastoma with a positive result. The 29 other tumor cases including osteosarcoma, synovial sarcoma, and malignant melanoma and others were all negative. Basing on histology as the standard for diagnosis and considering atypical positive cases as negative, comparing with the 29 cases of other tumors as control group, the sensitivity for diagnosing Ewing's sarcoma through the detection of EWSR1 gene rearrangement was 71%, and the specificity was 100%; the sensitivity for diagnosing clear cell sarcoma of soft tissue was 67%, and the specificity was 100%; the sensitivity for diagnosing extraskeletal myxoid chondrosarcoma was 40%, and the specificity was 100%; the sensitivity for diagnosing angiomatoid fibrous histiocytoma was 67%, and the specificity was 100%; the sensitivity for diagnosing myoepithelioma of soft tissue was 50%, and the specificity was 100%; the sensitivity for diagnosing olfactory neuroblastoma was 100%, and the specificity was 100%. Four of 8 cases with atypical positive signals analyzed by NGS showed EWSR1 rearrangement, including EWSR1::FLI1 in one case of Ewing sarcoma, EWSR1::NFATC2 in one case of EWSR1::NFATC2-rearranged sarcoma, EWSR1::ATF1 in one case of clear cell sarcoma of soft tissue and EWSR1::NR4A3 in one case of extraskeletal myxoid chondrosarcoma. Conclusions: Detection of EWSR1 rearrangement by FISH is of utmost significance in the diagnosis of bone and soft tissue tumors. Cases with atypical positive signals should be further scrutinized, correlating with their histomorphology and verifying by NGS if necessary.

A Stable and Sensitive Engineering Bacterial Sensor via Physical Biocontainment and Two-Stage Signal Amplification.

Although engineering bacterial sensors have outstanding advantages in reflecting the actual bioavailability and continuous monitoring of pollutants, the potential escape risk of engineering microorganisms and lower detection sensitivity have always been one of the biggest challenges limiting their wider application. In this study, a core-shell hydrogel bead with functionalized silica as the core and alginate-polyacrylamide as the shell have been developed not only to realize zero escape of engineered bacteria but also to maintain cell activity in harsh environments, such as extremely acidic/alkaline pH, high salt concentration, and strong pressure. Particularly, after combining the selective preconcentration toward pollutants by functionalized core and the positive feedback signal amplification of engineering bacteria, biosensors have realized two-stage signal amplification, significantly improving the detection sensitivity and reducing the detection limit. In addition, this strategy was actually applied to the detection of As(III) and As(V) coexisting in environmental samples, and the detection sensitivity was increased by 3.23 and 4.39 times compared to sensors without signal amplification strategy, respectively, and the detection limits were as low as 0.39 and 0.86 ppb, respectively.

Fluorescent and Colorimetric Dual-Readout Immunochromatographic Assay for the Detection of Phenamacril Residues in Agricultural Products.

The fungicide phenamacril has been employed to manage Fusarium and mycotoxins in crops, leading to persistent residues in the environment and plants. Detecting phenamacril is pivotal for ensuring environmental and food safety. In this study, haptens and artificial antigens were synthesized to produce antiphenamacril monoclonal antibodies (mAbs). Additionally, gold nanoparticles coated with a polydopamine shell were synthesized and conjugated with mAbs, inducing fluorescence quenching in quantum dots. Moreover, a dual-readout immunochromatographic assay that combines the positive signal from fluorescence with the negative signal from colorimetry was developed to enable sensitive and precise detection of phenamacril within 10 min, achieving detection limits of 5 ng/mL. The method's reliability was affirmed by using spiked wheat flour samples, achieving a limit of quantitation of 0.05 mg/kg. This analytical platform demonstrates high sensitivity, outstanding accuracy, and robust tolerance to matrix effects, making it suitable for the rapid, onsite, quantitative screening of phenamacril residues.

Isolation and Characterization of the Vascular Endothelial Growth Factor Receptor Targeting ScFv Antibody Fragments Derived from Phage Display Technology.

Angiogenesis, as a tumor hallmark, plays an important role in the growth and development of the tumor vasculature system. There is a huge amount of evidence suggesting that the vascular endothelial growth factor receptor (VEGFR-2)/VEGF-A axis is one of the main contributors to tumor angiogenesis and metastasis. Thus, inhibition of the VEGFR-2 signaling pathway by anti-VEGFR-2 mAb can retard tumor growth. In this study, we employ phage display technology and solution-phase biopanning (SPB) to isolate specific single-chain variable fragments (scFvs) against VEGFR-2 and report on the receptor binding characteristics of the candidate scFvs A semisynthetic phage antibody library to isolate anti-VEGFR-2 scFvs through an SPB performed with decreasing concentrations of the VEGFR-2-His tag and VEGFR-2-biotin. After successful expression and purification, the specificity of the selected scFv clones was further analyzed by enzyme-linked immunosorbent assay (ELISA), flow cytometry, and immunoblotting. The competition assay was undertaken to identify the VEGFR-2 receptor-blocking properties of the scFvs. Furthermore, the molecular binding characteristics of candidate scFvs were extensively studied by peptide-protein docking. Polyclonal ELISA analysis subsequent to four rounds of biopanning showed a significant enrichment of VEGFR-2-specific phage clones by increasing positive signals from the first round toward the fourth round of selection. The individual VEGFR-2-reactive scFv phage clones were identified by monoclonal phage ELISA. The sequence analysis and complementarity-determining region alignment identified the four unique anti-VEGFR-2-scFv clones. The soluble and purified scFvs displayed binding activity against soluble and cell-associated forms of VEGFR-2 protein in the ELISA and flow cytometry assays. Based on the inference from the molecular docking results, scFvs D3, E1, H1, and E9 recognized domains 2 and 3 on the VEGFR-2 protein and displayed competition with VEGF-A for binding to VEGFR-2. The competition assay confirmed that scFvs H1 and D3 can block the VEGFR-2/VEGF-A interaction. In conclusion, we identified novel VEGFR-2-blocking scFvs that perhaps exhibit the potential for angiogenesis inhibition in VEGFR-2-overexpressed tumor cells.

CgSHIP2 negatively regulates the mRNA expressions of CgIL-17s in response to Vibrio splendidus stimulation in Crassostrea gigas

SH2 domain containing inositol polyphosphate5-phosphatase-2 (SHIP2) is a member of the 5-phosphatase family, acting as a vital negative regulator of immune response in vertebrates. In the present study, a SHIP2 homologue (designed as CgSHIP2) was identified from Pacific oyster, Crassostrea gigas. There was a SH2 domain, an IPPc domain and a SAM domain in CgSHIP2. The mRNA transcripts of CgSHIP2 were widely expressed in all the tested tissues with the highest expression in haemolymph. The mRNA expressions of CgSHIP2 in haemocytes increased significantly at 6, 12, 48 and 72 h after Vibrio splendidus stimulation. The positive green signals of CgSHIP2 protein were mainly located in cytoplasm of haemocytes. After the expression of CgSHIP2 was inhibited by RNA interference, the mRNA transcripts of interleukin 17s (CgIL-17-1, CgIL-17-2, CgIL-17-3 and CgIL-17-6) in the haemocytes increased significantly at 24 h after V. splendidus stimulation, which were 8.15-fold (p < 0.001), 3.44-fold (p < 0.05), 2.15-fold (p < 0.01) and 4.63-fold (p < 0.05) compared with that in NC-RNAi group, respectively. Obvious branchial swelling and cilium shedding in gills were observed in CgSHIP2-RNAi group at 24 h after V. splendidus stimulation. The results suggested that CgSHIP2 played an important role in controlling inflammatory response induced by bacteria in oysters.

Sales Order Backlog and Credit Ratings

This study examines the association between sales order backlog and credit ratings. We posit that credit rating agencies consider order backlog as a positive signal about strong future demand and incorporate that into their rating decisions and provide higher ratings to firms with substantial order backlogs. However, being a non-GAAP, unaudited metric, order backlog could also reduce financial reporting quality and hence, credit ratings of firms. Using a sample of US firms from 1980 to 2017, we find a positive and significant association between order backlog and credit ratings, suggesting that order backlog serves as a valuable measure in credit rating assessment by providing positive signals about future earnings to rating agencies.

Abstract PO5-22-09: Positive pegulicianine fluorescence rate in the lumpectomy cavity correlates with tumor distance to margins in excised tissue

Abstract Title: Positive pegulicianine fluorescence rate in the lumpectomy cavity correlates with tumor distance to margins in excised tissue Background: A randomized, two-arm pivotal study of pegulicianine fluorescence guided surgery (pFGS) at 14 US sites was conducted using the Lumicell Direct Visualization System (DVS) to identify residual cancer in the lumpectomy cavity after the standard of care (SoC) tumor excision. We reported that the Lumicell DVS detects residual cancer in the lumpectomy cavity, including in orientations pathologically negative on the SoC specimen. In addition, 15% (9 of 62) of patients with positive SoC margins were converted to final negative margins by taking Lumicell DVS directed cavity margins, avoiding a second unnecessary surgery. Interestingly, 8 of these 9 patients had no tumor found in the Lumicell DVS guided specimens. We hypothesize that fluorescence decreases as the distance from the tumor boundary increases. We analyzed data from the pivotal study (NCT03686215) to assess correlation of pegulicianine signal with tumor-to-margin distance, and its potential clinical value. Methods: The pivotal study enrolled 406 patients undergoing breast conserving surgery (BCS) for stage 0-III breast cancers. Patients received an IV injection of pegulicianine 2-6 hours prior to surgery. After the standard of care lumpectomy was completed, additional Lumicell DVS-guided cavity margins were excised at sites of positive pegulicianine fluorescence signal in the lumpectomy cavity walls using a hand-held imaging device and patient-calibrated cancer detection software. The positive fluorescence rate, that is, the rate at which the Lumicell DVS indicates areas suspected to contain cancer, was calculated as the ratio of orientations with positive pegulicianine signal to the total number of orientations with (1) negative margins, (2) positive margins and (3) positive margins with ink on tumor, on the initial SoC lumpectomy specimen. Calculations were made on a per-margin basis. Positive margins were defined as ink on tumor for invasive cancer and tumor less than 2 mm from the margin for ductal carcinoma in situ (DCIS) alone. Results: Results are presented in Table 1. We found a statistically significant higher positive fluorescence rate in orientations with positive margins (p=0.044). The positive fluorescence rate was even higher (21.1%) when only considering cases with ink on tumor (a subset of the positive margin group). Discussion: By design, pegulicianine is activated by enzymes within the tumor and in stromal cells at the invasive front surrounding the tumor. Thus, when tumor is closer to the edge of the lumpectomy specimen, the rate of positive pegulicianine fluorescence in the cavity increases, being highest when there is tumor present at the inked margin. This feature of pegulicianine fluorescence guides the surgeon to resect more tissue in these areas in order to achieve a negative margin of the required width. The conversion of positive margins after the SoC lumpectomy to appropriately wide final negative margins prevents a second surgery, even when there is no tumor in the DVS guided margins. These findings have strengthened our understanding of the utility of this technology. Table 1 Positive cavity wall fluorescence rate for SoC lumpectomy positive margins, SoC lumpectomy negative margins and SoC lumpectomy ink on tumor margins Citation Format: Irene Wapnir, E Shelley Hwang, Kelly Hunt, David Carr, Peter Blumencranz, Manna Chang, Kate Smith, Jorge Ferrer, Barbara Smith. Positive pegulicianine fluorescence rate in the lumpectomy cavity correlates with tumor distance to margins in excised tissue [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-22-09.

Abstract PO2-13-10: Predicting outcomes in locally advanced breast cancer through profiling post-neoadjuvant tissue-based minimal residual disease

Abstract Background: Neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can down-stage disease prior to surgery, monitor chemo-sensitivity, and provide key prognostic information via pathologic response that guides adjuvant treatment. Greater residual disease as assessed by the residual cancer burden (RCB) index is associated with inferior outcomes but imperfectly predicts recurrence, particularly in triple negative breast cancer (TNBC) where there is heterogeneity of outcomes across RCB scores. As an alternative to RCB and PCR, blood-based minimal residual disease (MRD) from circulating tumor DNA (ctDNA) has been explored. However, poor sensitivity limits ctDNA, which is typically negative post-NAC when treatment decisions are made in patients who later recur. Methods: To address this lack of sensitivity, we developed tissue-based MRD (t-MRD) to assess molecular disease burden in post-NAC breast and lymph node resection tissue. We performed whole exome sequencing on diagnostic tumor and matched germline tissues from five pilot patients with early-stage TNBC with a range of responses to NAC. For each patient, we designed a personalized assay to track tumor-specific SNVs, combined with limited panel of genes recurrently mutated in breast cancer, to enable MRD detection. We then applied this assay to DNA from individual pathology blocks from the tumor resection via ultra-deep targeted hybrid capture. We assessed each sample for the presence of MRD using a Monte Carlo statistical framework to integrate all tumor mutations as previously described (Newman et al, Nature Biotechnology 2016). We aggregated results across all pathology blocks from each case to define each patient’s t-MRD profile and assessed the performance of t-MRD versus gold standard pathologic assessment. Results: We tracked a mean of 136 MRD reporters per case across 119 post-NAC blocks derived from five patients. Twenty-five samples had pathologic residual disease and 28 had detectable t-MRD. There was strong concordance between t-MRD mean allele frequency (AF) and tumor cellularity as assessed by pathology, defined as percent cellularity within the region containing viable tumor (Spearman r = 0.9052, p&amp;lt; 0.0001), and excellent classification of true positive pathology samples by genomic sequencing (AUC = 0.9675, p &amp;lt; 0.0001). Samples (n = 6) where t-MRD but not pathologic residual disease was detected had a lower mean AF than those where there was also histologic residual disease (p=0.0001). Among the five studied cases, we confirmed a molecular complete response with no t-MRD detected in the RCB-0 case (0/44 t-MRD positive blocks). In the two RCB-III cases, we observed more diffuse t-MRD than that assessed by pathology (n = 4 additional blocks with t-MRD but not pathologic disease detected), and in the RCB-II case, we detected minimal t-MRD in only a single block where pathology did not detect residual disease. Significance: By applying blood-based MRD assessment tools to tumor tissue, we developed t-MRD to profile molecular residual disease at the landmark post-NAC timepoint when disease burden is low and adjuvant treatment decisions are made. We demonstrated high concordance with gold standard pathologic assessment, with increased sensitivity and minimal false positive signal. Further studies assessing the additional prognostic value of t-MRD beyond stage-based prognostication and post-NAC RCB scores are ongoing. Citation Format: Julia Ransohoff, Mia Carleton, Alisha Birk, Gregory Bean, Melinda Telli, Ash Alizadeh, James Ford, George Duran, Michael Khodadoust, David Kurtz. Predicting outcomes in locally advanced breast cancer through profiling post-neoadjuvant tissue-based minimal residual disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-10.

Going beyond the "self" in self-control: Interpersonal consequences of commitment strategies.

Commitment strategies are effective mechanisms individuals can use to overcome self-control problems. Across seven studies (and two supplemental studies), we explore the negative interpersonal consequences of commitment strategy choice and use. In Study 1, using an incentivized trust game, we demonstrate that individuals trust people who choose to use a commitment strategy less than those who choose to use willpower to achieve their goals. Study 2 shows this relationship holds across four domains and for integrity-based trust in particular. Study 3 provides evidence that it is the choice to use the strategy rather than strategy use itself that incurs this integrity penalty. In Studies 4-5b, we demonstrate that this effect is driven, at least in part, by the fact that people infer past performance from strategy choice. Finally, Study 6 provides evidence that people select commitment strategies more in private than in public, which is consistent with the notion that people anticipate the negative consequences of commitment strategy choice. Thus, we establish the role of willpower as a positive signal in impression formation as well as the negative interpersonal consequences of choosing to rely on external aides when faced with temptation. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Conserved expression of the zebrafish syt4 gene in GABAergic neurons in the cerebellum of adult fishes revealed by mammalian SYT4 immunoreactive-like signals

Synaptotagmin 4 (syt4) belongs to the synaptotagmin protein family, which has 17 and 28 family members in human and zebrafish, respectively. In zebrafish and rodents, syt4 is known to express abundantly in the entire central nervous system in the early developmental stages. In adult rodents, the gene expression shifts to be predominant in the cerebellum, mostly in Purkinje cells, a type of GABAergic neurons. However, there is no report of the expression pattern of syt4 in the adult zebrafish brain. Therefore, we hypothesize that the expression of syt4 is conserved in adult zebrafish and is specific to the GABAergic neurons, likely Purkinje cells, in the cerebellum. To examine the hypothesis, we first show that only one copy of syt4 gene remains in the zebrafish genome, and it is orthologous to the gene in other vertebrates. We further observe mammalian SYT4 antibody immunoreactive-like (mSYT4-ir) signals in several structures in the hindbrain including the medial divisions of the valvula cerebelli and the corpus cerebelli. In addition, our observations indicate the presence of mSYT4-ir signals in GABAergic neurons, most notably in the Purkinje cell layer of the molecular layer in the aforementioned structures. Conversely, mSYT4-ir signals are not observed in glutamatergic or cholinergic neurons. Therefore, we deduce that the syt4 gene in zebrafish exhibits a homologous expression pattern to those of previously studied vertebrate species, which is revealed by the positive immunoreactive-like signals of mammalian SYT4 antibodies.

Pip5k1γ regulates axon formation by limiting Rap1 activity.

During their differentiation, neurons establish a highly polarized morphology by forming axons and dendrites. Cortical and hippocampal neurons initially extend several short neurites that all have the potential to become an axon. One of these neurites is then selected as the axon by a combination of positive and negative feedback signals that promote axon formation and prevent the remaining neurites from developing into axons. Here, we show that Pip5k1γ is required for the formation of a single axon as a negative feedback signal that regulates C3G and Rap1 through the generation of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). Impairing the function of Pip5k1γ results in a hyper-activation of the Fyn/C3G/Rap1 pathway, which induces the formation of supernumerary axons. Application of a hyper-osmotic shock to modulate membrane tension has a similar effect, increasing Rap1 activity and inducing the formation of supernumerary axons. In both cases, the induction of supernumerary axons can be reverted by expressing constitutively active Pip5k. Our results show that PI(4,5)P2-dependent membrane properties limit the activity of C3G and Rap1 to ensure the extension of a single axon.

Dental Disorders Reported to the FDA Adverse Event Reporting System in Association with Buprenorphine: An Analysis by Ingredient Composition and Route of Administration.

Prior research has suggested buprenorphine-containing medications may be associated with an increased risk of dental disorders. However, published data describing adverse dental reactions in buprenorphine users by active ingredient composition and route of administration are limited. The purpose of this study was to evaluate the influence of formulation on spontaneous reporting of dental disorders among patients treated with buprenorphine. Adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) between 2015 and 2022 were analyzed. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated to measure disproportionality of dental disorder reporting as classified by 39 Medical Dictionary for Regulatory Activities preferred terms. Compared to pooled reports for all other drugs across FAERS, both buprenorphine monotherapy (ROR 3.09; 95% CI 2.61-3.66) and combination buprenorphine/naloxone (ROR 14.61; 95% CI 13.34-16.01) were associated with positive disproportionality signals. Signals of disproportionate dental disorder reporting were also detected for buprenorphine medicines administered by sublingual (ROR 20.03; 95% CI 18.04-22.24), buccal (ROR 4.46; 95% CI 3.00-6.61) and oral (ROR 7.17; 95% CI 5.03-10.22) routes, but not for other modalities. In considering active ingredient and route together, sublingual buprenorphine monotherapies (ROR 23.55; 95% CI 17.84-31.11) and sublingual buprenorphine/naloxone (ROR 19.47; 95% CI 17.39-21.80) were each associated with disproportionate reporting of dental disorders. Subject to the limitations of spontaneous adverse event data, this study identified significantly disproportionate reporting of dental disorders to FAERS among patients treated with buprenorphine- containing medications, including formulations administered by sublingual, buccal and oral routes. These findings are consistent with prior data and suggest that regular oral care and proper dental hygiene be emphasized for patients undergoing therapy with orally dissolving buprenorphine.

Asymmetric Impacts of ENSO on Boreal Winter Southern Subtropical Cell in the Indian Ocean

AbstractThe interannual relationships between the southern subtropical cell (SSTC) in the Indian Ocean (IO) and the El Niño‐Southern Oscillation (ENSO) are examined. The results demonstrate that the impacts of ENSO on the boreal winter IO SSTC display a notable negative skewness, with the amplification of the SSTC during La Niña being far stronger than its reduction during El Niño. This difference is mainly attributed to an asymmetry in anomalous meridional geostrophic transport, characterized by more robust southward (weaker northward) geostrophic transport anomalies during La Niña (El Niño) events. Further analyses reveal that the differing longitudinal positions of the ENSO‐related sea surface temperature anomaly (SSTA) are the primary drivers of the asymmetry in anomalous meridional geostrophic transport via the oceanic and atmospheric teleconnections. Compared to the warm SSTA in El Niño events, the La Niña‐related cool SSTA in the central‐eastern equatorial Pacific displays a greater westward extension, which induces stronger surface easterlies over the western equatorial Pacific, and then initiates a more substantial sea surface height anomaly (SSHA) in the southeast Indian Ocean (SEIO) through oceanic waveguides. This leads to a heightened zonal SSHA gradient over the southern IO, resulting in a larger anomalous meridional geostrophic transport. On the other hand, the westward extension of negative SSTA during La Niña winters triggers anomalous cyclonic northerlies along the western coast of Australia by shifting the Walker circulation westward. These coastal northerlies amplify the positive SSHA signals in the SEIO and enhance the anomalous meridional geostrophic transport, ultimately contributing to a more robust IO SSTC response.