Physiological Window Research Articles

Multicellular adaptation to electrophysiological perturbations analyzed by deterministic and stochastic bioelectrical models.

Cells can compensate a disruptive change in one ion channel by compensatory changes in other channels. We have simulated the adaptation of a multicellular aggregate of non-excitable cells to the electrophysiological perturbation produced by the external blocking of a cation channel. In the biophysical model employed, we consider that this blocking provokes a cell depolarization that opens a voltage-gated calcium channel, thus allowing toxic Ca2+ levels. The cell adaptation to this externally-induced perturbation is ascribed to the multiplicity of channels available to keep the cell membrane potential within a physiological window. We propose that the cell depolarization provokes the upregulated expression of a compensatory channel protein that resets the cell potential to the correct polarized value, which prevents the calcium entry. To this end, we use two different simulation algorithms based on deterministic and stochastic methods. The simulations suggest that because of the local correlations coupling the cell potential to transcription, short-term bioelectrical perturbations can trigger long-term biochemical adaptations to novel stressors in multicellular aggregates. Previous experimental data on planarian flatworms' adaptation to a barium-containing environment is also discussed.

Two-Dimensional Layered Nano-MoS2 Induces Earthworm Immune Cell Apoptosis by Regulating Lysosomal Maintenance and Function: Toward Unbiased Screening and Validation of Suspicious Pathways.

Molybdenum-based nanosheets (NSMoS2) are increasingly applied in various fields and undergoing relevant risk evaluations on subjectively hypothesized toxicity pathways. However, risk assessment should be unbiased and focus on appropriate end points to avoid biased prescreening. Here, we developed an adverse biological outcome screening strategy based on nontargeted functional protein profiles in earthworm (Eisenia fetida) immune cells exposed to NSMoS2 and their ionic counterpart (Na2MoO4). Through this framework, the apoptosis-related processes with distinct mechanisms were rapidly identified and thoroughly validated phenotypically. Specifically, upon exposure to 50 μg Mo/mL Na2MoO4, cellular signaling and energy homeostasis were disrupted within the transcription-translation biological chain. The autophagic pathway was activated, which, together with energy deprivation, phenotypically induced significant autophagy that ultimately led to apoptosis. In contrast, NSMoS2, tested at the same concentration, caused a reprogramming of apoptotic gene and protein expressions. Transcriptome plasticity facilitated the endocytic-adaptive transcriptional profile characterized by cytoskeleton remodeling and lysosome organization/movement under NSMoS2 exposure. Subcellular dynamics further revealed NSMoS2-induced lysosomal damage with a time-sensitive physiological window, ultimately mediating apoptosis. These findings provide a mechanistic and visual understanding of the distinct risk profile of NSMoS2 compared to molybdate, highlighting the importance of integrating nontargeted screening and phenotypic validation in early risk warning.

Mechanisms for cardiac calcium pump activation by its substrate and a synthetic allosteric modulator using fluorescence lifetime imaging.

The discovery of allosteric modulators is an emerging paradigm in drug discovery, and signal transduction is a subtle and dynamic process that is challenging to characterize. We developed a time-correlated single photon-counting imaging approach to investigate the structural mechanisms for small-molecule activation of the cardiac sarcoplasmic reticulum Ca2+-ATPase, a pharmacologically important pump that transports Ca2+ at the expense of adenosine triphosphate (ATP) hydrolysis. We first tested whether the dissociation of sarcoplasmic reticulum Ca2+-ATPase from its regulatory protein phospholamban is required for small-molecule activation. We found that CDN1163, a validated sarcoplasmic reticulum Ca2+-ATPase activator, does not have significant effects on the stability of the sarcoplasmic reticulum Ca2+-ATPase-phospholamban complex. Time-correlated single photon-counting imaging experiments using the nonhydrolyzable ATP analog β,γ-Methyleneadenosine 5'-triphosphate (AMP-PCP) showed ATP is an allosteric modulator of sarcoplasmic reticulum Ca2+-ATPase, increasing the fraction of catalytically competent structures at physiologically relevant Ca2+ concentrations. Unlike ATP, CDN1163 alone has no significant effects on the Ca2+-dependent shifts in the structural populations of sarcoplasmic reticulum Ca2+-ATPase, and it does not increase the pump's affinity for Ca2+ ions. However, we found that CDN1163 enhances the ATP-mediated modulatory effects to increase the population of catalytically competent sarcoplasmic reticulum Ca2+-ATPase structures. Importantly, this structural shift occurs within the physiological window of Ca2+ concentrations at which sarcoplasmic reticulum Ca2+-ATPase operates. We demonstrated that ATP is both a substrate and modulator of sarcoplasmic reticulum Ca2+-ATPase and showed that CDN1163 and ATP act synergistically to populate sarcoplasmic reticulum Ca2+-ATPase structures that are primed for phosphorylation. This study provides novel insights into the structural mechanisms for sarcoplasmic reticulum Ca2+-ATPase activation by its substrate and a synthetic allosteric modulator.

The dynamics of auditory working memory impairment in logopenic aphasia and Alzheimer’s disease

AbstractBackgroundImpaired auditory verbal working memory is a diagnostic hallmark and integral driver of the clinical phenotype in logopenic aphasia. However, the physiology of the working memory buffer in this syndrome is poorly characterised. Here we addressed the temporal dynamics of auditory verbal working memory in patients with logopenic aphasia and typical Alzheimer’s disease.MethodIn a cohort of patients with logopenic aphasia and typical Alzheimer’s disease and in healthy age‐matched controls, we assessed how temporal manipulations of standard auditory verbal working memory tasks (forward and reverse digit span and phrasal repetition) affected performance. We varied tempo of delivery and inter‐trial gap and performed a detailed analysis of error types. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultCompared with healthy controls, patients with logopenic aphasia and Alzheimer’s disease showed increased sensitivity to temporal manipulation of auditory verbal working memory tasks and error profiles suggesting a dynamic physiological lesion of the working memory buffer. These effects were particularly marked in the logopenic group.ConclusionOur findings open a novel physiological window on working memory dynamics in Alzheimer’s disease syndromes. Further work is warranted to assess how this dynamic deficit impacts communication in patients’ daily lives, how it can best inform management interventions and its potential as a novel, rapid read‐out of neural function in the era of disease‐modifying therapies.

SAT392 A Case Of Idiopathic Intracranial Hypertension in Gender Dysphoria: Is Testosterone The Culprit?

Abstract Disclosure: S. Saad-Omer: None. D. John: None. M. Matos: None. C. Botero Suarez: None. S.K. Suryanarayanan: None. Background: The role of gender affirming Testosterone therapy in female-to-male patients with idiopathic intracranial hypertension (IIH) remains controversial. Case: A 32-year-old transgender male (Female-to-Male) was admitted after ophthalmologic evaluation for difficulties with night vision revealed papilledema. On admission, the patient reported a 2-month history of worsening bifrontal headaches accompanied by nausea, photophobia, and hyperacusis. Physical examination revealed papilledema and photophobia with BMI (34) and BP (132/86mmHg). CT Head was normal. Lumbar puncture showed an opening pressure of 22 cm water consistent with elevated intracranial pressure. Cerebrospinal fluid (CSF) lab results were grossly unremarkable. He reported being on 4 pumps daily of testosterone gel 1% (50mg) which was started approximately 3 months prior to admission with the last dose administered the day prior to admission. Initial labs showed bioavailable testosterone of 48.7 ng/dl, sex hormone binding globulin 29 nmol/l, free testosterone 24.2ng/dl, albumin 4.4g/dl, total testosterone 178ng/dl, estradiol 67pg/ml, FSH 6.7 mIU/ml, and LH 3.66 IU/ml. MRI Brain and Orbits revealed signs consistent with intracranial hypertension with no masses or bleeding to suggest an alternative cause. He was treated with Solumedrol, Acetazolamide, a brief course of Topiramate. Due to the suspected role of testosterone therapy in development of IIH, it was held during hospitalization. The risks and benefits of testosterone were discussed with the patient and he elected to restart it for gender affirmation at the time of discharge. However, his severe headache recurred after one week and he was asked to hold therapy for 30 days. He had no significant symptomatic improvement while off testosterone and therapy was resumed. Discussion: Several theories have been proposed to explain the occurrence of IIH in transgender patients with the leading hypothesis suggesting a “physiological window” of abnormal hormone levels, shared by women with elevated androgen levels and men with low androgen levels, where the risk of developing IIH is increased. Testosterone levels in women who have hyperandrogenism is similar to those in men with hypoandrogenism and these levels are likely contributing to the increase in volume of visceral fat and decrease in the size of muscles. It is therefore feasible that IIH is a distinct neuro-metabolic complication of circulating testosterone levels within this range. Conclusion: Our patient reported no symptomatic improvement despite withholding testosterone therapy for 30 days. Given the scarcity of evidence, it is important to discuss the potential risk of IIH with transgender patients, but not to withhold gender affirming hormone therapy for these patients. More research is required to better explore the mechanism of this association and possible methods to prevent its occurrence. Presentation: Saturday, June 17, 2023

Therapeutic Delivery of Nanoscale Sulfur to Suppress Disease in Tomatoes: In Vitro Imaging and Orthogonal Mechanistic Investigation.

Nanoscale sulfur can be a multifunctional agricultural amendment to enhance crop nutrition and suppress disease. Pristine (nS) and stearic acid coated (cS) sulfur nanoparticles were added to soil planted with tomatoes (Solanum lycopersicum) at 200 mg/L soil and infested with Fusarium oxysporum. Bulk sulfur, ionic sulfate, and healthy controls were included. Orthogonal end points were measured in two greenhouse experiments, including agronomic and photosynthetic parameters, disease severity/suppression, mechanistic biochemical and molecular end points including the time-dependent expression of 13 genes related to two S bioassimilation and pathogenesis-response, and metabolomic profiles. Disease reduced the plant biomass by up to 87%, but nS and cS amendment significantly reduced disease as determined by area-under-the-disease-progress curve by 54 and 56%, respectively. An increase in planta S accumulation was evident, with size-specific translocation ratios suggesting different uptake mechanisms. In vivo two-photon microscopy and time-dependent gene expression revealed a nanoscale-specific elemental S bioassimilation pathway within the plant that is separate from traditional sulfate accumulation. These findings correlate well with time-dependent metabolomic profiling, which exhibited increased disease resistance and plant immunity related metabolites only with nanoscale treatment. The linked gene expression and metabolomics data demonstrate a time-sensitive physiological window where nanoscale stimulation of plant immunity will be effective. These findings provide mechanistic understandings of nonmetal nanomaterial-based suppression of plant disease and significantly advance sustainable nanoenabled agricultural strategies to increase food production.

An Interplay of Light and Smoke Compounds in Photoblastic Seeds.

Light increases the germinability of positively photoblastic seeds and inhibits the germination of negative ones. In an area where plant-generated smoke from fire is a periodically occurring environmental factor, smoke chemicals can affect the germination of seeds, including those that are photoblastically sensitive. Moreover, as smoke and its compounds, mostly karrikin 1, KAR1, have been used for priming the seeds of many species, including photoblastic ones, a systematic review of papers dealing with the phenomenon was conducted. The review indicates that the unification of experimental treatments (light spectrum, intensity and photoperiod, and KAR1 concentration within the species) could improve the quality of global research on the impact of smoke chemicals on photoblastic seeds, also at the molecular level. The review also reveals that the physiologically active concentration of KAR1 varies in different species. Moreover, the physiological window of KAR’s impact on germination can be narrow due to different depths of primary seed dormancy. Another concern is the mode of action of different smoke sources and formulations (aerosol smoke, smoke-saturated water), or pure smoke chemicals. The reason for this concern is the additive or synergetic effect of KARs, cyanohydrins, nitrates and other compounds, and the presence of a germination inhibitor, trimethylbutenolide (TMB) in smoke and its formulations. Obviously, environmental factors that are characteristic of the local environment need to be considered. From a practical perspective, seeds germinating faster in response to smoke chemicals can outcompete other seeds. Hence, a thorough understanding of this phenomenon can be useful in the restoration of plant habitats and the protection of rare species, as well as yielding an improvement in plants that are sown directly to the field. On the other hand, the application of smoke compounds can induce “suicidal germination” in the photoblastic seeds that are buried in the soil and deplete the soil seed bank of the local population of unwanted species.

A importância do equilíbrio entre flexibilidade e estabilidade neuronal na formação de memórias

The neurobiological mechanisms behind memory formation remain unknown. Synapses are essential neuronal sub-compartments for the transmission of information within neuronal networks. Hebbian and homeostatic plasticity mechanisms, are two types of processes that play a role on synaptic modifications during the formation of memories. The interaction between these types of plasticity controls the balance between neuronal flexibility and stability to keep neuronal activity within a physiological window. Thus, it is important to better understand these mechanisms and identify the basic units of this system as they may be involved in the onset of neurological disorders. Here, I shed light on the impact of these mechanisms in the early phase of Alzheimer’s disease.

Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation.

Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-transport response to β-adrenergic stimulation, thus modulating cardiac output during the fight-or-flight response. In the sarcoplasmic reticulum membrane, PLN binds to the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), keeping this enzyme's function within a narrow physiological window. PLN phosphorylation by cAMP-dependent protein kinase A or increase in Ca2+ concentration reverses the inhibitory effects through an unknown mechanism. Using oriented-sample solid-state NMR spectroscopy and replica-averaged NMR-restrained structural refinement, we reveal that phosphorylation of PLN's cytoplasmic regulatory domain signals the disruption of several inhibitory contacts at the transmembrane binding interface of the SERCA-PLN complex that are propagated to the enzyme's active site, augmenting Ca2+ transport. Our findings address long-standing questions about SERCA regulation, epitomizing a signal transduction mechanism operated by posttranslationally modified bitopic membrane proteins.

The face of future: Face expressions during future thinking.

Future thinking, which is the ability to project oneself forward in time to pre-experience an event, is intimately associated with emotions. We investigated whether emotional future thinking can activate emotional facial expressions. We invited 43 participants to imagine future scenarios, cued by the words "happy," "sad," and "city." Future thinking was video recorded and analysed with a facial analysis software to classify whether facial expressions (i.e., happy, sad, angry, surprised, scared, disgusted, and neutral facial expression) of participants were neutral or emotional. Analysis demonstrated higher levels of happy facial expressions during future thinking cued by the word "happy" than "sad" or "city." In contrast, higher levels of sad facial expressions were observed during future thinking cued by the word "sad" than "happy" or "city." Higher levels of neutral facial expressions were observed during future thinking cued by the word "city" than "happy" or "sad." In the three conditions, the neutral facial expressions were high compared with happy and sad facial expressions. Together, emotional future thinking, at least for future scenarios cued by "happy" and "sad," seems to trigger the corresponding facial expression. Our study provides an original physiological window into the subjective emotional experience during future thinking.

Mutations Linked to Dilated Cardiomyopathy Perturb the Topology and Regulatory Response of Phospholamban

Phospholamban (PLN), a small 52-residue membrane protein expressed in cardiac tissue, functions as a regulatory subunit to the 110 kDa sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) calcium pump. The SERCA-PLN complex is responsible for restoring high SR Ca2+ concentrations prior to each cardiomyocyte contraction, in which PLN maintains SERCA's activity within a tight physiological window. PLN binds SERCA via a transmembrane protein-protein interaction that suppresses the affinity of SERCA's Ca2+ sites, but this effect is relieved upon phosphorylation of PLN's cytoplasmic extension by protein kinase A (PKA) upon β-adrenergic stimulation. PLN mutations that alter its activity or interfere with phosphorylation are linked to hereditary forms of dilated cardiomyopathy (DCM), although the reasons for this remain unclear due to a lack of structural data for the SERCA-PLN complex. Using structural restraints from high-resolution magic-angle spinning (MAS) and oriented sample (OS) solid-state NMR (ssNMR) spectroscopy, we have constructed dynamic models of the SERCA-PLN complex that capture a topological allosteric mechanism for PLN-driven communication of cytoplasmic regulatory stimuli to SERCA's Ca2+ binding sites. Further OS-ssNMR measurements and activity assays of DCM mutants of PLN displayed an altered topology and a dampened response to phosphorylation, which was consistent with our dynamic models and suggest disease onset may occur from an impaired β-adrenergic pathway. Overall, our recent observations by OS-ssNMR and modelling demonstrate that structural topology (i.e., helical tilt, rotation and secondary structure) is a critical determinant of SERCA regulation by PLN as well as by other homologous regulatory partners expressed in non-cardiac tissues.

Controversy of physiological vs. pharmacological effects of BMP signaling: Constitutive activation of BMP type IA receptor-dependent signaling in osteoblast lineage enhances bone formation and resorption, not affecting net bone mass.

Bone morphogenetic proteins (BMPs) were first described over 50years ago as potent inducers of ectopic bone formation when administrated subcutaneously. Preclinical studies have extensively examined the osteoinductive properties of BMPs in vitro and new bone formation in vivo. BMPs (BMP-2, BMP-7) have been used in orthopedics over 15years. While osteogenic function of BMPs has been widely accepted, our previous studies demonstrated that loss-of-function of BMP receptor type IA (BMPR1A), a potent receptor for BMP-2, increased net bone mass by significantly inhibiting bone resorption in mice, indicating a positive role of BMP signaling in bone resorption. The physiological role of BMPs (i.e. osteogenic vs. osteoclastogenic) is still largely unknown. The purpose of this study was to investigate the physiological role of BMP signaling in endogenous long bones during adult stages. For this purpose, we conditionally and constitutively activated the Smad-dependent canonical BMP signaling thorough BMPR1A in osteoblast lineage cells using the mutant mice (Col1CreER™:caBmpr1a). Because trabecular bones were largely increased in the loss-of-function mouse study for BMPR1A, we hypothesized that the augmented BMP signaling would affect endogenous trabecular bones. In the mutant bones, the Smad phosphorylation was enhanced within physiological level three-fold while the resulting gross morphology, bodyweights, bone mass/shape/length, serum calcium/phosphorus levels, collagen cross-link patterns, and healing capability were all unchanged. Interestingly, we found; 1) increased expressions of both bone formation and resorption markers in femoral bones, 2) increased osteoblast and osteoclast numbers together with dynamic bone formation parameters by trabecular bone histomorphometry, 3) modest bone architectural phenotype with reduced bone quality (i.e. reduced trabecular bone connectivity, larger diametric size but reduced cortical bone thickness, and reduced bone mechanical strength), and 4) increased expression of SOST, a downstream target of the Smad-dependent BMPR1A signaling, in the mutant bones. This study is clinically insightful because gain-of-function of BMP signaling within a physiological window does not increase bone mass while it alters molecular and cellular aspects of osteoblast and osteoclast functions as predicted. These findings help explain the high-doses of BMPs (i.e. pharmacological level) in clinical settings required to substantially induce a bone formation, concurrent with potential unexpected side effects (i.e. bone resorption, inflammation) presumably due to a broader population of cell-types exposed to the high-dose BMPs rather than osteoblastic lineage cells.

Effect of Panchagavya foliar spray on the plant metabolism and grain yield of Tenai under rainfed condition

The crop growth and development are constantly influenced by environmental conditions such as stresses which are the most important yield reducing factors in the world. Millets cultivation is the most important agricultural operation in the country, not only in terms of food security, but also in creating better livelihoods, opportunities for rural population. Water stress and other abiotic stresses can dramatically limit and reduce the plant growth and productivity. In the frame of physiological window, mild drought induces regulation of water loss and uptake in plants allowing maintenance of their leaf relative water content within the limits where the photosynthetic capacity shows no or little changes. But severe drought induces unfavourable changes in plants, leading to inhibition of photosynthesis and growth. The use of bioregulators is the quickest and surest way of boosting crop production under rainfed condition. Panchagavya is an organic product blended from five different cow products, commonly applied to crop plants in organic farming. It is used as foliar spray, soil application and seed treatment. It can act as growth promoter and immunity booster. The organic Panchagavya foliar spray significantly influenced various physiological and biochemical parameters. A field experiment was conducted at Centre of Excellence in Millets, Athiyandal, Tiruvannamalai, during Kharif, 2017 to study the effect of Panchagavya foliar spray for enhancing the productivity of tenai under rainfed situation. In a water shortage conditions, application of enriched FYM +Recommended dose of fertilizer + 3%Panchagavya foliar spray improves plant height, no. of tillers per plant, total dry matter partitioning, SPAD chlorophyll content and highest grain yield (1739.0 kg ha-1) of tenai under rainfed condition.

Plant Biostimulant Effects of Baker’s Yeast Vinasse and Selenium on Tomatoes through Foliar Fertilization

The application of selenium (Se) to tomatoes enhances accumulation of bioactive compounds. The physiological window of Se is very narrow, and Se overdose reduces the yield. Glycine betaine was shown to reduce Se’s negative effects on plants and to potentiate its beneficial effects. In this study, baker’s yeast vinasse (BYV), as an affordable source of glycine betaine, was tested for its interaction with Se in an optimized foliar fertilizer. The application dose was selected after a laboratory experiment, wherein assays on plant height, leaves surfaces, stomatal conductance, and chlorophyll fluorescence were done. The Se and BYV supplemented foliar fertilizers were tested for their effects on accumulation of bioactives in drip-irrigated tomatoes cultivated in a greenhouse. Under laboratory conditions, assays demonstrated Se and BYV induced effects on tomatoes plants. Both the stomatal conductance and photosynthesis efficiency increased compared to a water treated control. The greenhouse experiment demonstrated that BYV and Se addition increases the number of tomato fruits in the “extra” marketable class and enhances the accumulation of ascorbic acid, carotenes, polyphenols, and flavonoids. The effects depend on the composition of the foliar fertilizer, the most significant effects being recorded for the foliar applied product with the highest BYV and nitrogen content.

To compare the blood pressure and heart rate during course of various types of anesthesia in wistar rat: A novel experiences

Background: Rats are commonly used animals in development of newer drugs, rectification of toxicity and to record the various alterations in physiological parameters following pharmacological and non pharmacological interventions.Aim and Objectives: The purpose of this study was to identify the best physiological window during anesthesia. Therefore, we compared the effect of anesthesia using combination of ketamine and xylazine (KX) and thiopental sodium (intraperitoneally) on blood pressure and heart rate in adult male Wistar rats. Material and Methods: Twelve, male Wistar rats with a mean body weight of 260 ± 15 g were acquired. Thiopental sodium and cocktail of ketamine and xylazine (KX) were administered (ip) in group- I and group-II respectively. The systolic blood pressure and heart rate was recorded in both the groups till the awakening phase.Results: We found that there was a constant SBP and HR in Ketamine/Xylezine groups that are from 30 to 90 minutes after injection of anesthesia while this window was not observed in thiopental group.Conclusion: Our study concludes that the best time to observe the effect of newer drug during period between 30- 90 minutes after anesthesia.Asian Journal of Medical Sciences Vol.9(6) 2018 37-39

Quantifying the Effects of Different Treadmill Training Speeds and Durations on the Health of Rat Knee Joints

BackgroundWalking and running provide cyclical loading to the knee which is thought essential for joint health within a physiological window. However, exercising outside the physiological window, e.g. excessive cyclical loading, may produce loading conditions that could be detrimental to joint health and lead to injury and, ultimately, osteoarthritis. The purpose of this study was to assess the effects of a stepwise increase in speed and duration of treadmill training on knee joint integrity and to identify the potential threshold for joint damage.MethodsTwenty-four Sprague-Dawley rats were randomized into four groups: no exercise, moderate duration, high duration, and extra high duration treadmill exercise. The treadmill training consisted of a 12-week progressive program. Following the intervention period, histologic serial sections of the left knee were graded using a modified Mankin Histology Scoring System. Mechanical testing of the tibial plateau cartilage and RT-qPCR analysis of mRNA from the fat pad, patellar tendon, and synovium were performed for the right knee. Kruskal-Wallis testing was used to assess differences between groups for all variables.ResultsThere were no differences in cartilage integrity or mechanical properties between groups and no differences in mRNA from the fat pad and patellar tendon. However, COX-2 mRNA levels in the synovium were lower for all animals in the exercise intervention groups compared to those in the no exercise group.ConclusionsTherefore, these exercise protocols did not exceed the joint physiological window and can likely be used safely in aerobic exercise intervention studies without affecting knee joint health.

To bridge or not to bridge the multisensory time gap: bimanual coordination to sound and touch with temporal lags.

Living in a complex and multisensory environment involves constant interaction between perception and action. There is evidence that multisensory integration is governed by temporal factors, such as physiological synchrony between cross-modal stimuli favouring multisensory benefit, and the existence of a range of asynchrony between the stimuli which affords their binding (the temporal window of integration). These factors were examined in this study in a bimanual sensorimotor synchronization task with cross-modal stimuli. Participants synchronized each hand to a pair of audio-tactile stimuli, in which the asynchrony between onsets of auditory and tactile stimuli was systematically manipulated. In cross-modal conditions, they were instructed to tap either to the auditory stimuli or to tactile stimuli. The results reported a temporal window of integration of 160ms centred around 40 and 80ms (tactile first). Moreover, the temporal interval between the auditory and tactile stimuli affected the stability of bimanual coordination and of synchronization exclusively when participants were instructed to synchronize with tactile stimuli. Overall, the results indicate that both physiological asynchrony and temporal window of integration apply to cross-modal integration in a bimanual synchronization task. In addition, it shows the effect of auditory dominance onto multisensory temporal processes. This study sheds light on the role of temporal factors in multisensory processes when perception and actions are rhythmic and coupled.

Collateral blood vessels in acute ischemic stroke: a physiological window to predict future outcomes.

Collateral circulation is a physiologic pathway that protects the brain against ischemic injury and can potentially bypass the effect of a blocked artery, thereby influencing ischemic lesion size and growth. Several recent stroke trials have provided information about the role of collaterals in stroke pathophysiology, and collateral perfusion has been recognized to influence arterial recanalization, reperfusion, hemorrhagic transformation, and neurological outcomes after stroke. Our current aim is to summarize the anatomy and physiology of the collateral circulation and to present and discuss a comprehensible review of the related knowledge, particularly the effects of collateral circulation on the time course of ischemic injury and stroke severity, as well as imaging findings and therapeutic implications.

Abstract LB-009: Collagen regulation in postpartum mammary gland involution, a novel breast cancer prevention target

Abstract Collagen is the most abundant extracellular protein in breast tissue and plays a critical role in breast cancer progression. Intravital imaging shows collagen fibers as “highways” for tumor cell invasion, and collagen fibers arranged perpendicular to the tumor border (radial alignment) independently predict breast cancer metastasis. To understand the role of collagen in breast cancer, we argue it is necessary to understand collagen biology in the normal breast. While collagen production has been well studied in the context of wound healing, little is known about its regulation in normal breast physiology. Here we utilize a murine, weaning-induced mammary gland involution model, which is characterized by robust collagen deposition and remodeling, to investigate collagen regulation in the normal mammary gland. During mammary gland involution, we find increased collagen-I, -III, and -V gene expression and high levels of lysyl-oxidase (LOX), a major collagen cross-linker. By SHG analysis, we find collagen fibers around mammary ducts in the involuting gland are more tightly organized than nulliparous gland, with “hot spots” of radial alignment. Collagen is predominantly produced by fibroblasts and we identified mammary fibroblasts as PDGFRα+. Using flow cytometry-based cell sorting and gene expression analysis, PDGFRα+ fibroblasts isolated from the involuting mammary gland have increased gene expression of collagen-I,-III, and LOX. Further, there is ∼2 fold increase in number of PDGFRα+ cells/mg weight of tissue in the involuting gland, suggesting that fibroblasts may be recruited and activated during involution. Increased production of collagen by fibroblasts and radial alignment of collagen are consistent with a tumor promotional microenvironment during mammary gland involution. In fact, our lab has demonstrated pro-tumorigenic attributes of involution in rodent models of postpartum breast cancer, which can be mitigated by non-steroidal anti-inflammatory drug (NSAID) treatment. To investigate the impact of NSAID treatment on collagen during involution, we isolated fibroblasts from mammary glands of animals undergoing involution in the presence and absence of NSAID intervention. Mammary fibroblasts flow sorted from NSAID treated hosts display reduced collagen I, TGFβ1, and MMP-3 gene expression by 30∼60% compared to involution-fibroblasts isolated from untreated mice. Taken together, these data demonstrate that fibroblasts are responsive to COX-2 inhibition and suggest a novel mechanism of NSAIDs action that may be mediated through suppression of collagen deposition. Collagen and breast cancer are inseparable topics, as collagen abundance, architecture and tension impact breast cancer risk and prognosis. Weaning induced mammary gland involution provides a unique physiological window to study collagen regulation. Studying the mechanism of how NSAIDs regulate collagen may provide insight into the use of NSAIDs as a preventative and therapeutic intervention in breast cancer. Citation Format: Qiuchen Guo, Pepper J. Schedin. Collagen regulation in postpartum mammary gland involution, a novel breast cancer prevention target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-009. doi:10.1158/1538-7445.AM2015-LB-009

Popular Rice (Oryza sativa L.) Cultivars Show Contrasting Responses to Heat Stress at Gametogenesis and Anthesis

ABSTRACTStudies on heat tolerance in rice (Oryza sativa L.) have focused on a range of accessions that are currently not grown or cultivated in small localized geographic regions, while popular rice cultivars occupying millions of hectares have not been tested for their response to heat stress. Hence, 18 popular rice cultivars grown across tropical and subtropical regions were subjected to 38°C for 6 h of heat stress at anthesis and five selected contrasting entries were exposed to six consecutive days (6 h each day) of stress coinciding with both gametogenesis and anthesis. Among the tested entries, Ciherang was the most tolerant, after both 6 h at anthesis and 6 d of stress across both gametogenesis and anthesis, whereas Moroberekan and KDML‐105 were the most susceptible. Using a quick and easy phenotyping protocol and by considering all the sterile spikelets across target panicles, the crucial physiological window “spikelets with exserted anthers but with no ovule enlargement” was identified as the most sensitive stage with exposure to heat stress at both critical reproductive stages. Geographic origin of rice varieties was not clearly related to the degree of tolerance or susceptibility to heat stress because both conditions were observed in cultivars from each target region. Our findings complement other ongoing efforts that are using heat‐tolerant landraces and wild rice as donors to further increase tolerance to sustain global rice production under future warmer climate.