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Abstract Background Breast cancer is a disease characterised by both genetic and epigenetic alterations. Epigenetic silencing of tumour suppressor genes is an early event in breast carcinogenesis and reversion of gene silencing by epigenetic reprogramming can provide clues to the mechanisms responsible for tumour initiation and progression. In this study we apply the reprogramming capacity of oocytes to cancer cells in order to study breast oncogenesis. Results We show that breast cancer cells can be directly reprogrammed by amphibian oocyte extracts. The reprogramming effect, after six hours of treatment, in the absence of DNA replication, includes DNA demethylation and removal of repressive histone marks at the promoters of tumour suppressor genes; also, expression of the silenced genes is re-activated in response to treatment. This activity is specific to oocytes as it is not elicited by extracts from ovulated eggs, and is present at very limited levels in extracts from mouse embryonic stem cells. Epigenetic reprogramming in oocyte extracts results in reduction of cancer cell growth under anchorage independent conditions and a reduction in tumour growth in mouse xenografts. Conclusions This study presents a new method to investigate tumour reversion by epigenetic reprogramming. After testing extracts from different sources, we found that axolotl oocyte extracts possess superior reprogramming ability, which reverses epigenetic silencing of tumour suppressor genes and tumorigenicity of breast cancer cells in a mouse xenograft model. Therefore this system can be extremely valuable for dissecting the mechanisms involved in tumour suppressor gene silencing and identifying molecular activities capable of arresting tumour growth. These applications can ultimately shed light on the contribution of epigenetic alterations in breast cancer and advance the development of epigenetic therapies.

Abstract Background The evolutionary conserved cyclin-dependent kinase phosphatase hCdc14A has been shown to play potential roles in the regulation of mitotic exit and in the centrosome duplication cycle. We have recently shown that hCdc14A also can interact with the tumor suppressor p53 both in vitro and in vivo and specifically dephosphorylates the ser315 site of p53 in vitro. In this study we developed antibodies against hCdc14A to investigate the expression and regulation of hCdc14A in human tissues and cancer cells. Results We show that hCdc14A is differentially expressed in human tissues and in 75 cancer cell lines examined. Treatments with the histone deacetylase inhibitor TSA, the demethylating agent 5-aza-2'-deoxycytodine or the proteasome inhibitor MG132 significantly induced expression of hCdc14A in cell lines expressing low or undetectable levels of hCdc14A. There was a strong bias for low expression of hCdc14A in cancer cell lines harboring wild-type p53, suggesting that high Cdc14A expression is not compatible with wild-type p53 expression. We present evidence for a role for hCdc14A in the dephosphorylation of the ser315 site of p53 in vivo and that hCdc14A forms a complex with Cdk1/cyclin B during interphase but not during mitosis. Conclusion Our results that hCdc14A is differentially expressed in human cancer cells and that hCdc14A can interact with both p53 and the Cdk1/cyclin B complex may implicate that dysregulation of hCdc14A expression may play a role in carcinogenesis.

Abstract Background Clinical practice guidelines are not uniformly successful in influencing clinicians' behaviour toward best practices. Implementability refers to a set of characteristics that predict ease of (and obstacles to) guideline implementation. Our objective is to develop and validate a tool for appraisal of implementability of clinical guidelines. Methods Indicators of implementability were identified from the literature and used to create items and dimensions of the GuideLine Implementability Appraisal (GLIA). GLIA consists of 31 items, arranged into 10 dimensions. Questions from 9 of the 10 dimensions are applied individually to each recommendation of the guideline. Decidability and Executability are critical dimensions. Other dimensions are Global, Presentation and Formatting, Measurable Outcomes, Apparent Validity, Flexibility, Effect on Process of Care, Novelty/Innovation, and Computability. We conducted a series of validation activities, including validation of the construct of implementability, expert review of content for clarity, relevance, and comprehensiveness, and assessment of construct validity of the instrument. Finally, GLIA was applied to a draft guideline under development by national professional societies. Results Evidence of content validity and preliminary support for construct validity were obtained. The GLIA proved to be useful in identifying barriers to implementation in the draft guideline and the guideline was revised accordingly. Conclusion GLIA may be useful to guideline developers who can apply the results to remedy defects in their guidelines. Likewise, guideline implementers may use GLIA to select implementable recommendations and to devise implementation strategies that address identified barriers. By aiding the design and operationalization of highly implementable guidelines, our goal is that application of GLIA may help to improve health outcomes, but further evaluation will be required to support this potential benefit.

Brønsted acids, such as phosphoric acids derived from chiral 1,1'-bi-2-naphthol (BINOL), are important catalysts in the formation of carbon-carbon and carbon-heteroatom bonds, for example. The catalytic activity of these Brønsted acids is strongly linked to their acidity, and as such, the evaluation of compounds to determine pK a values provides insight into their catalytic activity. Herein, a 19 F{ 1 H} NMR methodology is detailed to determine the pK a of a fluorinated binaphthyl-derived phosphinic acid, rac-1, in acetonitrile and in the presence of a fluorinated sulfonamide reference compound (2-4). The approach was tested initially using 2 and 3, with the ΔpK a (0.08) in strong agreement with previously reported values (6.6 for 2 and 6.68/6.73 for 3). Sigmoidal curves of normalised chemical shift change (Δδ) against equivalents of the base phosphazene P 1 - t Bu added overlapped for 2 and 3, but in the case of rac-1 and either 2, 3 or 4, there was significant separation. A variety of different approaches for determining the ΔpK a were compared. Values of pK a determined when the normalised Δδ was 90% were optimal for 2 and 3, whereas a normalised Δδ of 75% was optimal for 4, resulting in the pK a of rac-1 being determined to be 8.47-8.71., (© 2024 The Author(s). Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

Drosophila models for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many of these models use the proliferating tissues of the larval stages of Drosophila development, when tissues are highly mitotically active, or stem cells are abundant. Fewer Drosophila tumorigenesis models use adult animals to initiate tumor formation when many tissues are largely terminally differentiated and postmitotic. The Drosophila accessory glands are prostate-like tissues and a model for some aspects of prostate tumorigenesis using this tissue has been explored. In this model, oncogenic signaling was induced during the proliferative stage of accessory gland development, raising the question of how oncogenic activity would impact the terminally differentiated and postmitotic adult tissue. Here, we show that oncogenic signaling in the adult Drosophila accessory gland leads to activation of a conserved pro-tumorigenic program, similar to that observed in mitotic larval tissues, but in the absence of proliferation. Oncogenic signaling in the adult postmitotic gland leads to tissue hyperplasia with nuclear anaplasia and aneuploidy through endoreduplication, which increases polyploidy and occasionally results in non-mitotic neoplastic-like extrusions. We compare gene expression changes in our Drosophila model with that of endocycling prostate cancer cells induced by chemotherapy, which potentially mediate tumor recurrence after treatment. Similar signaling pathways are activated in the Drosophila gland and endocycling cancer cells, suggesting the adult accessory glands provide a useful model for aspects of prostate cancer progression that do not involve cellular proliferation., Competing Interests: Conflicts of Interest: Kenneth Pienta discloses that he is a consultant to Cue Biopharma Inc., an equity holder in PEEL therapeutics, an equity holder in Keystone Biopharma Inc, and an equity holder in Kreftect, Inc. Sarah Amend discloses that she is an equity holder in Keystone Biopharma Inc.

The place of living organisms in the natural world is a nearly perennial question in philosophy and the sciences; how can inanimate matter yield animate beings? A dominant answer for several centuries has been to treat organisms as sophisticated machines, studying them with the mechanistic physics and chemistry that have given rise to technology and complex machines. Since the early 20th century, many scholars have sought instead to naturalize biology through thermodynamics, recognizing the precarious far-from-equilibrium state of organisms. Erwin Bauer was an early progenitor of this perspective with ambitions of "general laws for the movement of living matter". In addition to taking a thermodynamic perspective, Bauer recognized that organisms are fundamentally behaving systems, and that explaining the physics of life requires explaining the origins of intentionality, adaptability, and self-regulation. Bauer, like some later scholars, seems to advocate for a "new physics", one that extends beyond mechanics and classical thermodynamic, one that would be inclusive of living systems. In this historical review piece, we explore some of Bauer's ideas and explain how similar concepts have been explored in modern non-equilibrium thermodynamics and dissipative structure theory. Non-living dissipative structures display end-directedness, self-maintenance, and adaptability analogous to organisms. These findings also point to an alternative framework for the life sciences, that treats organisms not as machines but as sophisticated dissipative structures. We evaluate the differences between mechanistic and thermodynamic perspectives on life, and what each theory entails for understanding the behavior of organisms., Competing Interests: Declaration of Competing interest We declare no conflicts of interest for this publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A physical system to generate a PPG-mimicking signal was designed and validated using everyday low-cost components to aid in medical sensor design. The pulse waveform was created by driving a working fluid into a silicone tube and changing the pressure within it. The corresponding waveform mimics a PPG signal through an artery, is adaptable, and repeatable. The working fluid is interchangeable allowing for change of blood analyte concentrations for development and testing of PPG-based sensors. The system was validated by black ink water compared to water and air compared to water testing to confirm optical transparency of the tube. The produced PPG signal, pulse rate and pressure change were compared to that seen in subjects. Optical transparency for 660 nm - 1550 nm wavelengths of light was validated with the signal, pulse rate and total compliance matching subject data. Thus, the system can mimic arterial pulses, creating a valid PPG signal that can be detected by PPG-based sensors.Clinical Relevance- Provides a low-cost, adaptable, physical PPG signal generator for research and development of optical medical sensor technologies.

Spectroscopy is utilised extensively in medical sensing technology. Typically, hand-held spectroscopy equipment uses miniature narrow-band light emitting diodes (LEDs) and photodiodes to emit and detect light, respectively. Photodiodes typically absorb light across a wide spectra so measurements can be corrupted by surrounding light. LEDs in the visible spectrum have a narrower spectral response and can be used in place of a traditional photodiode. However, the absorption characteristics of near infrared (NIR) spectrum LEDs is unknown. A discrete, low-cost spectrophotometer was designed to assess spectral response for 8 narrow band NIR LEDs. The normalised and raw spectral response determined the optimum detector for 1050 nm - 1300 nm is the 1450 nm LED, and the optimum detector for 1450 nm - 1650 nm emissions is the 1650 nm LED.Clinical relevance - Understanding the spectral response of narrow-band LEDs in the NIR spectrum will aid development of NIR hand-held spectroscopy medical devices.

Background: People with Opioid Use Disorder (PWOUD) represent an underserved and marginalized population for whom treatment gaps exist. Low-barrier programs like mobile care units and street outreach programs have yielded increased access to buprenorphine and social services, however, OUD pertinent co-occurring behavioral health and medical conditions are frequently left unaddressed. A novel, tailored, comprehensive care delivery model may reduce disparities and improve access to care across a range of pathologies in this historically difficult to reach population and enhance efforts to provide universal treatment access in a harm reduction setting., Methods: Descriptive data were collected and analyzed regarding patient demographics, retention in treatment and services rendered at a new, wrap-around, low-barrier buprenorphine clinic established at an existing harm reduction site in New Mexico between August 1, 2020, and August 31, 2021., Results: 203 people used any service at the newly implemented program, 137 of whom specifically obtained medical and/or behavioral health care services including prescriptions for buprenorphine at least once from the physician onsite. Thirty-seven unique medical and psychiatric conditions were treated, representing a total of 565 separate encounters. The most common service utilized was buprenorphine treatment for opioid use disorder (81%), followed by treatment for post-traumatic stress disorder (62%), anxiety (44.5%) and depression (40.9%). Retention in buprenorphine treatment was 31.2% at 6 months., Conclusions: An innovative, multidisciplinary, buprenorphine-centric care model, which targets a wide range of OUD pertinent pathologies while employing a harm reduction approach, can enhance utilization of these services among an underserved PWOUD population in a manner which moves our health system toward universal OUD treatment access thereby potentially reducing overdose and existing disparities., (© 2023. The Author(s).)

Purpose: Limited research exists on the time course of long-term retinal and cerebral deficits in diabetic rodents. Previously, we examined short term (4-8 weeks) deficits in the Goto-Kakizaki (GK) rat model of Type II diabetes. Here, we investigated the long-term (1-8 months) temporal appearance of functional deficits (retinal, cognitive, and motor), retinal vascular pathology, and retinal dopamine levels in the GK rat., Methods: In GK rats and Wistar controls, retinal neuronal function (electroretinogram), cognitive function (Y-maze), and motor function (rotarod) were measured at 1, 2, 4, 6, and 8 months of age. In addition, we evaluated retinal vascular function (functional hyperemia) and glucose and insulin tolerance. Retinas from rats euthanized at ≥8 months were assessed for vascular pathology. Dopamine and DOPAC levels were measured via HPLC in retinas from rats euthanized at 1, 2, 8, and 12 months., Results: Goto-Kakizaki rats exhibited significant glucose intolerance beginning at 4 weeks and worsening over time ( p < 0.001). GK rats also showed significant delays in flicker and oscillatory potential implicit times ( p < 0.05 to p < 0.001) beginning at 1 month. Cognitive deficits were observed beginning at 6 months ( p < 0.05), but no motor deficits. GK rats showed no deficits in functional hyperemia and no increase in acellular retinal capillaries. Dopamine levels were twice as high in GK vs. Wistar retinas at 1, 2, 8, and 12 months ( p < 0.001)., Conclusion: As shown previously, retinal deficits were detectable prior to cognitive deficits in GK rats. While retinal neuronal function was compromised, retinal vascular pathology was not observed, even at 12+ months. High endogenous levels of dopamine in the GK rat may be acting as an anti-angiogenic and providing protection against vascular pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Allen, Khayat, Feola, Win, Grubman, Chesler, He, Dixon, Kern, Iuvone, Thule and Pardue.)

All organisms depend on a supply of energetic resources to power behavior and the irreversible entropy-producing processes that sustain them. Dissipative structure theory has often been a source of inspiration for better understanding the thermodynamics of biology, yet real organisms are inordinately more complex than most laboratory systems. Here we report on a simulated chemical dissipative structure that operates as a proto cell. The simulated swimmer moves through a 1D environment collecting resources that drive a nonlinear reaction network interior to the swimmer. The model minimally represents properties of a simple organism including rudimentary foraging and chemotaxis and an analog of a metabolism in the nonlinear reaction network. We evaluated how dynamical stability of the foraging dynamics (i.e., swimming and chemotaxis) relates to the rate of entropy production. Results suggested a relationship between dynamical steady states and entropy production that was tuned by the relative coordination of foraging and metabolic processes. Results include evidence in support of and contradicting one formulation of a maximum entropy production principle. We discuss the status of this principle and its relevance to biology.

Do communicative actions such as gestures fundamentally differ in their control mechanisms from other actions? Evidence for such fundamental differences comes from a classic gesture-speech coordination experiment performed with a person (IW) with deafferentation (McNeill, 2005). Although IW has lost both his primary source of information about body position (i.e., proprioception) and discriminative touch from the neck down, his gesture-speech coordination has been reported to be largely unaffected, even if his vision is blocked. This is surprising because, without vision, his object-directed actions almost completely break down. We examine the hypothesis that IW's gesture-speech coordination is supported by the biomechanical effects of gesturing on head posture and speech. We find that when vision is blocked, there are micro-scale increases in gesture-speech timing variability, consistent with IW's reported experience that gesturing is difficult without vision. Supporting the hypothesis that IW exploits biomechanical consequences of the act of gesturing, we find that: (1) gestures with larger physical impulses co-occur with greater head movement, (2) gesture-speech synchrony relates to larger gesture-concurrent head movements (i.e. for bimanual gestures), (3) when vision is blocked, gestures generate more physical impulse, and (4) moments of acoustic prominence couple more with peaks of physical impulse when vision is blocked. It can be concluded that IW's gesturing ability is not based on a specialized language-based feedforward control as originally concluded from previous research, but is still dependent on a varied means of recurrent feedback from the body., (© 2022. The Author(s).)

Purpose: The purpose of this study was to extend our understanding of how aging affects normal retina function and morphology in wild-type C57BL/6J mice, by analyzing electrophysiological recordings and in vivo and post mortem anatomy., Methods: Electroretinograms (ERGs), spectral domain optical coherence tomography (SD-OCT), and confocal scanning laser ophthalmoscope (cSLO) in vivo images were obtained from mice between the ages of 2 and 32 months in four groups: group 1 (<0.5 years), group 2 (1.0-1.5 years), group 3 (1.5-2.0 years), and group 4 (>2.0 years). Afterward, mouse bodies and eyes were weighed. Eyes were stained with hematoxylin and eosin (H&E) and cell nuclei were quantified., Results: With aging, mice showed a significant reduction in both a- and b-wave ERG amplitudes in scotopic and photopic conditions. Additionally, total retina and outer nuclear layer (ONL) thickness, as measured by SD-OCT images, were significantly reduced in older groups. The cSLO images showed an increase in auto-fluorescence at the photoreceptor-RPE interface as age increases. H&E cell nuclei quantification showed significant reduction in the ONL in older ages, but no differences in the inner nuclear layer (INL) or ganglion cell layer (GCL)., Conclusions: By using multiple age groups and extending the upper age limit of our animals to approximately 2.65 years (P970), we found that natural aging causes negative effects on retinal function and morphology in a gradual, rather than abrupt, process. Future studies should investigate the exact mechanisms that contribute to these gradual declines in order to discover pathways that could potentially serve as therapeutic targets.

Gestures and speech are clearly synchronized in many ways. However, previous studies have shown that the semantic similarity between gestures and speech breaks down as people approach transitions in understanding. Explanations for these gesture-speech mismatches, which focus on gestures and speech expressing different cognitive strategies, have been criticized for disregarding gestures' and speech's integration and synchronization. In the current study, we applied three different perspectives to investigate gesture-speech synchronization in an easy and a difficult task: temporal alignment, semantic similarity, and complexity matching. Participants engaged in a simple cognitive task and were assigned to either an easy or a difficult condition. We automatically measured pointing gestures, and we coded participant's speech, to determine the temporal alignment and semantic similarity between gestures and speech. Multifractal detrended fluctuation analysis was used to determine the extent of complexity matching between gestures and speech. We found that task difficulty indeed influenced gesture-speech synchronization in all three domains. We thereby extended the phenomenon of gesture-speech mismatches to difficult tasks in general. Furthermore, we investigated how temporal alignment, semantic similarity, and complexity matching were related in each condition, and how they predicted participants' task performance. Our study illustrates how combining multiple perspectives, originating from different research areas (i.e., coordination dynamics, complexity science, cognitive psychology), provides novel understanding about cognitive concepts in general and about gesture-speech synchronization and task difficulty in particular., (© 2021 The Authors. Cognitive Science published by Wiley Periodicals LLC on behalf of Cognitive Science Society (CSS).)

Coordination within and between organisms is one of the most complex abilities of living systems, requiring the concerted regulation of many physiological constituents, and this complexity can be particularly difficult to explain by appealing to physics. A valuable framework for understanding biological coordination is the coordinative structure , a self-organized assembly of physiological elements that collectively performs a specific function. Coordinative structures are characterized by three properties: (1) multiple coupled components, (2) soft-assembly, and (3) functional organization. Coordinative structures have been hypothesized to be specific instantiations of dissipative structures, non-equilibrium, self-organized, physical systems exhibiting complex pattern formation in structure and behaviors. We pursued this hypothesis by testing for these three properties of coordinative structures in an electrically-driven dissipative structure. Our system demonstrates dynamic reorganization in response to functional perturbation, a behavior of coordinative structures called reciprocal compensation . Reciprocal compensation is corroborated by a dynamical systems model of the underlying physics. This coordinated activity of the system appears to derive from the system's intrinsic end-directed behavior to maximize the rate of entropy production. The paper includes three primary components: (1) empirical data on emergent coordinated phenomena in a physical system, (2) computational simulations of this physical system, and (3) theoretical evaluation of the empirical and simulated results in the context of physics and the life sciences. This study reveals similarities between an electrically-driven dissipative structure that exhibits end-directed behavior and the goal-oriented behaviors of more complex living systems.

It is commonly understood that hand gesture and speech coordination in humans is culturally and cognitively acquired, rather than having a biological basis. Recently, however, the biomechanical physical coupling of arm movements to speech vocalization has been studied in steady-state vocalization and monosyllabic utterances, where forces produced during gesturing are transferred onto the tensioned body, leading to changes in respiratory-related activity and thereby affecting vocalization F0 and intensity. In the current experiment (n = 37), we extend this previous line of work to show that gesture-speech physics also impacts fluent speech. Compared with nonmovement, participants who are producing fluent self-formulated speech while rhythmically moving their limbs demonstrate heightened F0 and amplitude envelope, and such effects are more pronounced for higher-impulse arm versus lower-impulse wrist movement. We replicate that acoustic peaks arise especially during moments of peak impulse (i.e., the beat) of the movement, namely around deceleration phases of the movement. Finally, higher deceleration rates of higher-mass arm movements were related to higher peaks in acoustics. These results confirm a role for physical impulses of gesture affecting the speech system. We discuss the implications of gesture-speech physics for understanding of the emergence of communicative gesture, both ontogenetically and phylogenetically., (© 2020 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Mitochondria are dynamic organelles that produce energy and molecular precursors that are essential for myelin synthesis. Unlike in neurons, mitochondria in oligodendrocytes increase intracellular movement in response to glutamatergic activation and are more susceptible to oxidative stress than in astrocytes or microglia. The signaling pathways that regulate these cell type-specific mitochondrial responses in oligodendrocytes are not understood. Here, we visualized mitochondria migrating through thin cytoplasmic channels crossing myelin basic protein-positive compacted membranes and localized within paranodal loop cytoplasm. We hypothesized that local extracellular enrichment of netrin-1 might regulate the recruitment and function of paranodal proteins and organelles, including mitochondria. We identified rapid recruitment of mitochondria and paranodal proteins, including neurofascin 155 (NF155) and the netrin receptor deleted in colorectal carcinoma (DCC), to sites of contact between oligodendrocytes and netrin-1-coated microbeads in vitro. We provide evidence that Src-family kinase activation and Rho-associated protein kinase (ROCK) inhibition downstream of netrin-1 induces mitochondrial elongation, hyperpolarization of the mitochondrial inner membrane, and increases glycolysis. Our findings identify a signaling mechanism in oligodendrocytes that is sufficient to locally recruit paranodal proteins and regulate the subcellular localization, morphology, and function of mitochondria., (© 2020 Wiley Periodicals LLC.)

Self-organization in nonequilibrium systems has been known for over 50 years. Under nonequilibrium conditions, the state of a system can become unstable and a transition to an organized structure can occur. Such structures include oscillating chemical reactions and spatiotemporal patterns in chemical and other systems. Because entropy and free-energy dissipating irreversible processes generate and maintain these structures, these have been called dissipative structures. Our recent research revealed that some of these structures exhibit organism-like behavior, reinforcing the earlier expectation that the study of dissipative structures will provide insights into the nature of organisms and their origin. In this article, we summarize our study of organism-like behavior in electrically and chemically driven systems. The highly complex behavior of these systems shows the time evolution to states of higher entropy production. Using these systems as an example, we present some concepts that give us an understanding of biological organisms and their evolution.

Expressive moments in communicative hand gestures often align with emphatic stress in speech. It has recently been found that acoustic markers of emphatic stress arise naturally during steady-state phonation when upper-limb movements impart physical impulses on the body, most likely affecting acoustics via respiratory activity. In this confirmatory study, participants (N = 29) repeatedly uttered consonant-vowel (/pa/) mono-syllables while moving in particular phase relations with speech, or not moving the upper limbs. This study shows that respiration-related activity is affected by (especially high-impulse) gesturing when vocalizations occur near peaks in physical impulse. This study further shows that gesture-induced moments of bodily impulses increase the amplitude envelope of speech, while not similarly affecting the Fundamental Frequency (F0). Finally, tight relations between respiration-related activity and vocalization were observed, even in the absence of movement, but even more so when upper-limb movement is present. The current findings expand a developing line of research showing that speech is modulated by functional biomechanical linkages between hand gestures and the respiratory system. This identification of gesture-speech biomechanics promises to provide an alternative phylogenetic, ontogenetic, and mechanistic explanatory route of why communicative upper limb movements co-occur with speech in humans.

Purpose: The present study tested the hypothesis that connexin-36 (Cx36) and gap junctions between photoreceptor cells contribute to the circadian rhythm of the photopic electroretinogram (ERG) b-wave amplitude., Methods: Cone-specific disruption of Cx36 was obtained in mice with a floxed Gjd2 gene and human red/green pigment promoter (HRGP)-driven Cre recombinase. Standard ERG, spectral-domain optical coherence tomography (SD-OCT) and histochemical methods were used., Results: HRGPcreGjd2fl/fl mice had a selective reduction in Cx36 protein in the outer plexiform layer; no reduction in Cx36 was observed in the inner plexiform layer. Cx36 disruption had no effect on the number of cones, the thickness of the photoreceptor layer, or the scotopic ERG responses. However, there was a reduction of the photopic ERG circadian rhythm, with b-wave amplitudes in the day and the night locked in the daytime, light-adapted state. In HRGPcreGjd2+/+and Gjd2fl/fl controls, the circadian rhythm of light-adapted ERG persisted, similar to that in wild type mice., Conclusions: Cx36 regulation contributes to the circadian rhythm of light-adapted ERG; in the absence of photoreceptor gap junctions, mice appear to be in a fully light-adapted state regardless of the time of day. The higher amplitudes and reduced circadian regulation of the b-wave of HRGPcreGjd2fl/fl mice may be due to increased synaptic strength at the cone to ON bipolar cell synapse due to electrotonic isolation of the terminals lacking gap junctions.

We show that the human voice has complex acoustic qualities that are directly coupled to peripheral musculoskeletal tensioning of the body, such as subtle wrist movements. In this study, human vocalizers produced a steady-state vocalization while rhythmically moving the wrist or the arm at different tempos. Although listeners could only hear and not see the vocalizer, they were able to completely synchronize their own rhythmic wrist or arm movement with the movement of the vocalizer which they perceived in the voice acoustics. This study corroborates recent evidence suggesting that the human voice is constrained by bodily tensioning affecting the respiratory-vocal system. The current results show that the human voice contains a bodily imprint that is directly informative for the interpersonal perception of another's dynamic physical states., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Stimulus-response compatibility effects illustrate the mutual depen-dence of perception and action processes. Ellis and Tucker (2000) showed that object identification was facilitated when the response required a grip that was compatible with the stimulus. In the current study, we extend grip-compatibility effects to perception of the Necker cube. Participants reported the perceived orientation of a Necker cube by orienting a hand-held cube into a compatible or an incompatible position. Participants in the incompatible condition were quickly attracted to the FRB (front-side right bottom) percept, consistent with previous work. However, participants in the compatible condition showed an extended period of metastability, switching between the two perceptual states about equally. A second experiment replicated these results and showed that a control condition in which responses were made with a key press produced intermediate levels of metastability. These results are interpreted in terms of the dynamics of bistable perception.

There is increasing evidence that hand gestures and speech synchronize their activity on multiple dimensions and timescales. For example, gesture's kinematic peaks (e.g., maximum speed) are coupled with prosodic markers in speech. Such coupling operates on very short timescales at the level of syllables (200 ms), and therefore requires high-resolution measurement of gesture kinematics and speech acoustics. High-resolution speech analysis is common for gesture studies, given that field's classic ties with (psycho)linguistics. However, the field has lagged behind in the objective study of gesture kinematics (e.g., as compared to research on instrumental action). Often kinematic peaks in gesture are measured by eye, where a "moment of maximum effort" is determined by several raters. In the present article, we provide a tutorial on more efficient methods to quantify the temporal properties of gesture kinematics, in which we focus on common challenges and possible solutions that come with the complexities of studying multimodal language. We further introduce and compare, using an actual gesture dataset (392 gesture events), the performance of two video-based motion-tracking methods (deep learning vs. pixel change) against a high-performance wired motion-tracking system (Polhemus Liberty). We show that the videography methods perform well in the temporal estimation of kinematic peaks, and thus provide a cheap alternative to expensive motion-tracking systems. We hope that the present article incites gesture researchers to embark on the widespread objective study of gesture kinematics and their relation to speech.

Purpose: To determine predictors of best-corrected postoperative visual acuity (VA) in patients who underwent surgical intervention for macula-off rhegmatogenous retinal detachment., Materials and Methods: Primary macula-off retinal detachments from the University of Colorado Primary Rhegmatogenous Retinal Detachment Database (2012-2017) were reviewed. The primary outcome measure was a postoperative VA of 20/40 or better at least 6 months after surgery. Patient demographics, medical history, duration of central vision loss before surgery, examination findings, operative technique, and postoperative findings were analyzed as possible predictors of postoperative visual recovery to 20/40 or better. Chi-square or Fisher's exact test was used to compare categorical variables, and Wilcoxon rank sum test was used for continuous variables. A multivariable logistic regression analysis was used to determine the adjusted odds ratios and 95% confidence intervals for variables that were significant in the univariable analyses. Statistical significance was set at p < 0.05., Results: One hundred thirty-one patients met inclusion criteria. Eighty-one (61.8%) patients achieved a postoperative VA of 20/40 or better 6 or more months after surgery. Patients with a single retinal break were more likely than patients with more than one break to reach a postoperative VA of 20/40 or better (76.9% vs. 55.4%, p = 0.021). Patients with a better preoperative logMAR VA had better postoperative VA (p = 0.021). Duration of central vision loss prior to surgical repair was not related to final postoperative VA in this particular study., Conclusion: Postoperative recovery of visual acuity to 20/40 or better was significantly more common in patients with a single retinal break as well as in patients with better preoperative visual acuity. Duration of central vision loss prior to surgical repair was not significantly associated with postoperative VA.

The phenomenon of gesture-speech synchrony involves tight coupling of prosodic contrasts in gesture movement (e.g., peak velocity) and speech (e.g., peaks in fundamental frequency; F0). Gesture-speech synchrony has been understood as completely governed by sophisticated neural-cognitive mechanisms. However, gesture-speech synchrony may have its original basis in the resonating forces that travel through the body. In the current preregistered study, movements with high physical impact affected phonation in line with gesture-speech synchrony as observed in natural contexts. Rhythmic beating of the arms entrained phonation acoustics (F0 and the amplitude envelope). Such effects were absent for a condition with low-impetus movements (wrist movements) and a condition without movement. Further, movement-phonation synchrony was more pronounced when participants were standing as opposed to sitting, indicating a mediating role for postural stability. We conclude that gesture-speech synchrony has a biomechanical basis, which will have implications for our cognitive, ontogenetic, and phylogenetic understanding of multimodal language. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

From flocks of birds and sheep to colonies of bacteria, complex patterns and self-motion are found in all hierarchies of nature. Artificial nonliving systems provide useful insight, since living systems are complicated and may involve cognitive issues not found in nonliving matter. Herein, we report naturally flocking irregularly shaped benzoquinone (BQ) particles on the air-water interface that cross a gate. In this open system designed with absence of external control, the particle flock moves by Marangoni "surfing" driven by slow dissolution of weakly surface active BQ postulated to create inhomogeneous interfacial tension fields. The particle flocks move collectively through a gate placed in the air-water interface to the side that has higher interfacial tension. Position-sensitive surface tension measurements used for the first time in a multiparticle Marangoni motion system show unequivocally that flock motion and gate crossing proceed to areas of slightly higher interfacial tension. Flock crossing is accompanied by a low-high differential interfacial tension change from one side of the gate to the other, with the flock moving to the side with higher interfacial tension. Thus, the flocks move because they are foraging for interfacial free energy.

Physical systems open to a flow of energy can exhibit spontaneous symmetry breaking and self-organization. These nonequilibrium self-organized systems are known as dissipative structures. We study the oscillatory mode of an electrically driven dissipative structure. Our system consists of aluminum beads in shallow oil, which, when subjected to a high voltage, self-organize into connected 'tree' structures. The tree structures serve as pathways for the conduction of charge to ground. This system shows a variety of spatio-temporal behaviors, such as oscillating movement of the tree structures. Utilizing a dynamical systems model of the electromagnetic phenomena, we explore a potential mechanism underlying the system's behavior and use the model to make additional empirical predictions. The model reproduces the oscillatory behavior observed in the real system, and the behavior of the real system is consistent with predictions from the model under various constraints. From the empirical results and the mathematical model, we observe a tendency for the system to select modes of behavior with increased dissipation, or higher rates of entropy production, in accord with the proposed Maximum Entropy Production (MEP) Principle., Competing Interests: The authors have declared that no competing interests exist.

Collective self-motion of particulate systems provides novel opportunities for developing flocking and sensing functions from seemingly inanimate objects. In this paper, we report videos documenting spontaneous collective flocking of multiple irregularly shaped macroscopic benzoquinone (BQ) particles at the air-water interface. Self-propulsion occurs due to the Gibbs-Marangoni effect surface tension gradients generated by the BQ particles. The air-water interface develops inhomogeneous interfacial tension fields created by differential dissolution at points and edges of BQ particles, causing interfacial tension variations along the solid-liquid-air interfaces. Responses of irregularly shaped BQ particles to these driving forces do not result in random motion but lead to a cooperative hydrodynamic flocking. Curiously, the flocking behavior was very evident for irregularly shaped particles but not observed for symmetric circular BQ disks. The flock responds to changes in its local environment as it forages for interfacial free energy. It exhibits warm and cool thermotaxis and thus can sense local temperature changes. Also, though a single magnetic bead is not confined to a part of the Petri dish by an applied magnetic field, when this magnetic bead is a member of a flock in which all of the other beads are not magnetic, the flock as a whole moves and hovers around the region where the field is maximum. In other words, the magnetic bead becomes a kind of "sensor" for the flock to respond to a magnetic field, the response being a drift in the direction of the field.

The modern constraints of drug discovery demand a rigorous validation process of all new reactions prior to widespread implementation. To this end, sulfinates (now marketed as Diversinates) have seen alacritous adoption by the medicinal chemistry community, as evidenced by the recent outpour of both patent and primary reports. Featuring more than 50 examples, this review seeks to highlight those particularly compelling cases published in the past 5 years, with an eye toward the identification of robust and predictable trends in reactivity.

Gesture-speech synchrony re-stabilizes when hand movement or speech is disrupted by a delayed feedback manipulation, suggesting strong bidirectional coupling between gesture and speech. Yet it has also been argued from case studies in perceptual-motor pathology that hand gestures are a special kind of action that does not require closed-loop re-afferent feedback to maintain synchrony with speech. In the current pre-registered within-subject study, we used motion tracking to conceptually replicate McNeill's () classic study on gesture-speech synchrony under normal and 150 ms delayed auditory feedback of speech conditions (NO DAF vs. DAF). Consistent with, and extending McNeill's original results, we obtain evidence that (a) gesture-speech synchrony is more stable under DAF versus NO DAF (i.e., increased coupling effect), (b) that gesture and speech variably entrain to the external auditory delay as indicated by a consistent shift in gesture-speech synchrony offsets (i.e., entrainment effect), and (c) that the coupling effect and the entrainment effect are co-dependent. We suggest, therefore, that gesture-speech synchrony provides a way for the cognitive system to stabilize rhythmic activity under interfering conditions., (© 2019 The Authors. Cognitive Science published by Wiley Periodicals, Inc. on behalf of Cognitive Science Society.)

Collective behavior can be defined as the ability of humans to coordinate with others through a complex environment. Sports offer exquisite examples of this dynamic interplay, requiring decision making and other perceptual-cognitive skills to adjust individual decisions to the team self-organization and vice versa. Considering players of a team as periodic phase oscillators, synchrony analyses can be used to model the coordination of a team. Nonetheless, a main limitation of current models is that collective behavior is context independent. In other words, players on a team can be highly synchronized without this corresponding to a meaningful coordination dynamics relevant to the context of the game. Considering these issues, the aim of this study was to develop a method of analysis sensitive to the context for evidence-based measures of collective behavior., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Interpersonal coordination is an essential aspect of daily life, and crucial to performance in cooperative and competitive team sports. While empirical research has investigated interpersonal coordination using a wide variety of analytical tools and frameworks, to date very few studies have employed multifractal techniques to study the nature of interpersonal coordination across multiple spatiotemporal scales. In the present study we address this gap., Methods: We investigated the dynamics of a simple dyadic interpersonal coordination task where each participant manually controlled a virtual object in relation to that of his or her partner. We tested whether the resulting hand-movement time series exhibits multi-scale properties and whether those properties are associated with successful performance., Results: Using the formalism of multifractals, we show that the performance on the coordination task is strongly multi-scale, and that the multi-scale properties appear to arise from interaction-dominant dynamics. Further, we find that the measure of across-scale interactions, multifractal spectrum width, predicts successful performance at the level of the dyad., Conclusion: The results are discussed with respect to the implications of multifractals and interaction-dominance for understanding control in an interpersonal context.

Self-motion of physical-chemical systems is a promising avenue for studying and developing mechanical functions with inanimate systems. In this paper, we investigate spontaneous motion of collections of solid macroscopic benzoquinone (BQ) disks at the air-water interface without intervention of chemical reactions. The BQ particles slowly dissolve and create heterogeneous interfacial tension fields on the water surface that drive the motion. Spontaneous, continuous locomotion was observed between multiple BQ particles, along with coupling, collisions, cycling and collective foraging for interfacial free energy. Analysis of the motion suggests co-operative behavior depends strongly on particle shape.

Background. Bilateral reduction mammoplasty is a common plastic surgery procedure that can be complicated by unfavorable scar formation along incision sites. Surgical adhesives can be utilized as an alternative or as an adjunct to conventional suture closures to help achieve good wound tension and provide an adequate barrier with excellent cosmesis. The recently introduced DERMABOND PRINEO Skin Closure System Skin Closure System combines the skin adhesive 2-octyl cyanoacrylate with a self-adhering polyester-based mesh. Proposed benefits of wound closure with DERMABOND PRINEO Skin Closure System, used with or without sutures, include its watertight seal, easy removal, microbial barrier, even distribution of tension, and reduction in wound closure time. Although allergic reactions to 2-octyl cyanoacrylate have been reported, few allergic reactions to DERMABOND PRINEO Skin Closure System have been noted in the literature. This case series describes three patients who experienced an allergic reaction to DERMABOND PRINEO Skin Closure System after undergoing elective bilateral reduction mammoplasties at our institution to further explore this topic. Methods. Retrospective chart review of bilateral reduction mammoplasty patients who received DERMABOND PRINEO Skin Closure System dressing at our institution was performed. Results. Three patients were identified as having a rash in reaction to DERMABOND PRINEO Skin Closure System after bilateral reduction mammoplasty. All three patients required systemic steroid treatment to resolve the rash. One patient was identified as having a prior adhesive reaction. Conclusions. DERMABOND PRINEO Skin Closure System has demonstrated its efficacy in optimizing scar healing and appearance. However, as we demonstrate these three allergic reactions to DERMABOND PRINEO Skin Closure System, caution must be utilized in its usage, namely, in patients with a prior adhesive allergy and in sites where moisture or friction may be apparent.

Intermodal integration required for perceptual learning tasks is rife with individual differences. Participants vary in how they use perceptual information to one modality. One participant alone might change her own response over time. Participants vary further in their use of feedback through one modality to inform another modality. Two experiments test the general hypothesis that perceptual-motor fluctuations reveal both information use within modality and coordination among modalities. Experiment 1 focuses on perceptual learning in dynamic touch, in which participants use exploratory hand-wielding of unseen objects to make visually guided length judgments and use visual feedback to rescale their judgments of the same mechanical information. Previous research found that the degree of fractal temporal scaling (i.e., "fractality") in hand-wielding moderates the use of mechanical information. Experiment 1 shows that head-sway fractality moderates the use of visual information. Further, experience with feedback increases head-sway fractality and prolongs its effect on later hand-wielding fractality. Experiment 2 replicates effects of head-sway fractality moderating use of visual information in a purely visual-judgment task. Together, these findings suggest that fractal fluctuations may provide a modal-general window onto not just how participants use perceptual information but also how well they may integrate information among different modalities., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

Hypertrophic pyloric stenosis is a very common surgical problem in infants. It occurs most often in otherwise well babies with normal gestation and birth history. Rarely, pyloric stenosis has been described in babies with history of prior abdominal surgery. Below we discuss the management of hypertrophic pyloric stenosis in a child who remained hospitalized, recovering from repair of a congenital abdominal wall defect.

Movement science has traditionally understood high-dimensional fluctuations as either antithetical or irrelevant to low-dimensional control. However, fluctuations incident to changeful, sometimes unpredictable stimulation must somehow reshape low-dimensional aspects of control through perception. The movement system's fluctuations may reflect cascade dynamics in which many-sized events interact nonlinearly across many scales. Cascades yield fractal fluctuations, and fractality of fluctuations may provide a window on the interactions across scale supporting perceptual processes. To test these ideas, we asked adult human participants to judge whole or partial length for unseen rods (with and without added masses). The participants' only experience with the objects came from supporting them across their shoulders during quiet standing. First, the degree of fractal temporal correlations in trial-by-trial series of planar Euclidean displacements in center of pressure (COP) significantly improved prediction of subsequent trial-by-trial judgments, above and beyond prediction by traditional predictors of haptic perception and conventional measures of COP variability. Second, comparison with linear surrogate data indicated the presence of nonlinear interactions across scale in these time series. These results demonstrate that high-dimensional fluctuations may serve a crucial role in the cascade dynamics supporting apparently low-dimensional control strategies.

The present protocol details the synthesis of zinc bis(alkanesulfinate)s that can be used as general reagents for the formation of radical species. The zinc sulfinates described herein are generated from the corresponding sulfonyl chlorides by treatment with zinc dust. The products may be used crude, or a simple purification procedure may be performed to minimize incorporation of water and zinc chloride. Although the synthesis of the zinc sulfinate salts can generally be completed within 3 h, workup can take up to 24 h and purification can take up to 3 h. Following the steps in this protocol would enable the user to generate a small toolkit of zinc sulfinate reagents over the course of 1 week.

The present work documents reanalysis of previous research by Priplata and colleagues (Priplata et al., 2002) into the effects of subthreshold vibratory stimulation to the plantar surface of the foot on postural stability during quiet standing. In stochastic resonance, stimulating a nonlinear system with noise can promote system stability. Stochastic resonance has been proposed to have clinical applications as an intervention that might help to stabilize posture. Insoles designed to stimulate the plantar surface of the foot with uncorrelated white-noise fluctuations have been shown to reduce a number of standard measures of postural variability. An important remaining concern is that the efficacy of stochastic-resonance applications is subject to strong individual differences. Our reanalysis of data from Priplata et al.'s original study provides evidence that effects of uncorrelated fluctuations in subthreshold vibratory stimulation are moderated by temporally correlated fluctuations in postural sway. We suggest how future development might capitalize on this finding to fine-tune existing stochastic-resonance applications to posture., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.

Self-organized criticality purports to build multi-scaled structures out of local interactions. Evidence of scaling in various domains of biology may be more generally understood to reflect multiplicative interactions weaving together many disparate scales. The self-similarity of power-law scaling entails homogeneity: fluctuations distribute themselves similarly across many spatial and temporal scales. However, this apparent homogeneity can be misleading, especially as it spans more scales. Reducing biological processes to one power-law relationship neglects rich cascade dynamics. We review recent research into multifractality in executive-function cognitive tasks and propose that scaling reflects not criticality but instead interactions across multiple scales and among fluctuations of multiple sizes.

Molecular scaffolds containing alkylfluorine substituents are desired in many areas of chemical research from materials to pharmaceuticals. Herein, we report the invention of a new reagent (Zn(SO(2)CF(2)H)(2), DFMS) for the innate difluoromethylation of organic substrates via a radical process. This mild, operationally simple, chemoselective, and scalable difluoromethylation method is compatible with a range of nitrogen-containing heteroarene substrates of varying complexity as well as select classes of conjugated π-systems and thiols. Regiochemical comparisons suggest that the CF(2)H radical generated from the new reagent possesses nucleophilic character., (© 2012 American Chemical Society)