Control of time-dependent biological processes by temporally patterned input

Temporal patterning of biological variables, in the form of oscillations and rhythms on many time scales, is ubiquitous. Altering the temporal pattern of an input variable greatly affects the output of many biological processes. We develop here a conceptual framework for a quantitative understanding of such pattern dependence, focusing particularly on nonlinear, saturable, time-dependent processes that abound in biophysics, biochemistry, and physiology. We show theoretically that pattern dependence is governed by the nonlinearity of the input–output transformation as well as its time constant. As a result, only patterns on certain time scales permit the expression of pattern dependence, and processes with different time constants can respond preferentially to different patterns. This has implications for temporal coding and decoding, and allows differential control of processes through pattern. We show how pattern dependence can be quantitatively predicted using only information from steady, unpatterned input. To apply our ideas, we analyze, in an experimental example, how muscle contraction depends on the pattern of motorneuron firing.

A chemical genomics approach toward understanding the global functions of the target of rapamycin protein (TOR)

The target of rapamycin protein (TOR) is a highly conserved ataxia telangiectasia-related protein kinase essential for cell growth. Emerging evidence indicates that TOR signaling is highly complex and is involved in a variety of cellular processes. To understand its general functions, we took a chemical genomics approach to explore the genetic interaction between TOR and other yeast genes on a genomic scale. In this study, the rapamycin sensitivity of individual deletion mutants generated by the Saccharomyces Genome Deletion Project was systematically measured. Our results provide a global view of the rapamycin-sensitive functions of TOR. In contrast to conventional genetic analysis, this approach offers a simple and thorough analysis of genetic interaction on a genomic scale and measures genetic interaction at different possible levels. It can be used to study the functions of other drug targets and to identify novel protein components of a conserved core biological process such as DNA damage checkpoint/repair that is interfered with by a cell-permeable chemical compound.

Reverse biochemistry: Use of macromolecular protease inhibitors to dissect complex biological processes and identify a membrane-type serine protease in epithelial cancer and normal tissue

Serine proteases of the chymotrypsin fold are of great interest because they provide detailed understanding of their enzymatic properties and their proposed role in a number of physiological and pathological processes. We have been developing the macromolecular inhibitor ecotin to be a “fold-specific” inhibitor that is selective for members of the chymotrypsin-fold class of proteases. Inhibition of protease activity through the use of wild-type and engineered ecotins results in inhibition of rat prostate differentiation and retardation of the growth of human PC-3 prostatic cancer tumors. In an effort to identify the proteases that may be involved in these processes, reverse transcription–PCR with PC-3 poly(A)+ mRNA was performed by using degenerate oligonucleotide primers. These primers were designed by using conserved protein sequences unique to chymotrypsin-fold serine proteases. Five proteases were identified: urokinase-type plasminogen activator, factor XII, protein C, trypsinogen IV, and a protease that we refer to as membrane-type serine protease 1 (MT-SP1). The cloning and characterization of the MT-SP1 cDNA shows that it encodes a mosaic protein that contains a transmembrane signal anchor, two CUB domains, four LDLR repeats, and a serine protease domain. Northern blotting shows broad expression of MT-SP1 in a variety of epithelial tissues with high levels of expression in the human gastrointestinal tract and the prostate. A His-tagged fusion of the MT-SP1 protease domain was expressed in Escherichia coli, purified, and autoactivated. Ecotin and variant ecotins are subnanomolar inhibitors of the MT-SP1 activated protease domain, suggesting a possible role for MT-SP1 in prostate differentiation and the growth of prostatic carcinomas.

Biological impact on mineral dissolution: Application of the lichen model to understanding mineral weathering in the rhizosphere

Microorganisms modify rates and mechanisms of chemical and physical weathering and clay growth, thus playing fundamental roles in soil and sediment formation. Because processes in soils are inherently complex and difficult to study, we employ a model based on the lichen–mineral system to identify the fundamental interactions. Fixed carbon released by the photosynthetic symbiont stimulates growth of fungi and other microorganisms. These microorganisms directly or indirectly induce mineral disaggregation, hydration, dissolution, and secondary mineral formation. Model polysaccharides were used to investigate direct mediation of mineral surface reactions by extracellular polymers. Polysaccharides can suppress or enhance rates of chemical weathering by up to three orders of magnitude, depending on the pH, mineral surface structure and composition, and organic functional groups. Mg, Mn, Fe, Al, and Si are redistributed into clays that strongly adsorb ions. Microbes contribute to dissolution of insoluble secondary phosphates, possibly via release of organic acids. These reactions significantly impact soil fertility. Below fungi–mineral interfaces, mineral surfaces are exposed to dissolved metabolic byproducts. Through this indirect process, microorganisms can accelerate mineral dissolution, leading to enhanced porosity and permeability and colonization by microbial communities.

Nonuniformity of the constitutive law parameters for shear rupture and quasistatic nucleation to dynamic rupture: a physical model of earthquake generation processes.

Based on the recent high-resolution laboratory experiments on propagating shear rupture, the constitutive law that governs shear rupture processes is discussed in view of the physical principles and constraints, and a specific constitutive law is proposed for shear rupture. It is demonstrated that nonuniform distributions of the constitutive law parameters on the fault are necessary for creating the nucleation process, which consists of two phases: (i) a stable, quasistatic phase, and (ii) the subsequent accelerating phase. Physical models of the breakdown zone and the nucleation zone are presented for shear rupture in the brittle regime. The constitutive law for shear rupture explicitly includes a scaling parameter Dc that enables one to give a common interpretation to both small scale rupture in the laboratory and large scale rupture as earthquake source in the Earth. Both the breakdown zone size Xc and the nucleation zone size L are prescribed and scaled by Dc, which in turn is prescribed by a characteristic length lambda c representing geometrical irregularities of the fault. The models presented here make it possible to understand the earthquake generation process from nucleation to unstable, dynamic rupture propagation in terms of physics. Since the nucleation process itself is an immediate earthquake precursor, deep understanding of the nucleation process in terms of physics is crucial for the short-term (or immediate) earthquake prediction.

The new dysmorphology: application of insights from basic developmental biology to the understanding of human birth defects.

Information obtained from studies of developmental and cellular processes in lower organisms is beginning to make significant contributions to the understanding of the pathogenesis of human birth defects, and it is now becoming possible to treat birth defects as inborn errors of development. Mutations in genes for transcription factors, receptors, cell adhesion molecules, intercellular junctions, molecules involved in signal transduction, growth factors, structural proteins, enzymes, and transporters have been identified in genetically caused human malformations and dysplasias. The identification of these mutations and the analysis of their developmental effects have been greatly facilitated by the existence of natural or engineered models in the mouse and even of related mutations in Drosophila, and in some instances a remarkable conservation of function in development has been observed, even between widely separated species.

Role of the monkey ventrolateral prefrontal cortex in the integration of contextual information for the selection and understanding of goal-directed actions

Action selection and organization are very complex processes that need to exploit contextual information and the retrieval of previously memorized information, as well as the integration of these different types of data. On the basis of anatomical connection with premotor and parietal areas involved in action goal coding, and on the data about the literature it seems appropriate to suppose that one of the most candidate involved in the selection of neuronal pools for the selection and organization of intentional actions is the prefrontal cortex. We recorded single ventrolateral prefrontal (VLPF) neurons activity while monkeys performed simple and complex manipulative actions aimed at distinct final goals, by employing a modified and more strictly controlled version of the grasp-to-eat(a food pellet)/grasp-to-place(an object) paradigm used in previous studies on parietal (Fogassi et al., 2005) and premotor neurons (Bonini et al., 2010). With this task we have been able both to evaluate the processing and integration of distinct (visual and auditory) contextual sequentially presented information in order to select the forthcoming action to perform and to examine the possible presence of goal-related activity in this portion of cortex. Moreover, we performed an observation task to clarify the possible contribution of VLPF neurons to the understanding of others’ goal-directed actions. Simple Visuo Motor Task (sVMT). We found four main types of neurons: unimodal sensory-driven, motor-related, unimodal sensory-and-motor, and multisensory neurons. We found a substantial number of VLPF neurons showing both a motor-related discharge and a visual presentation response (sensory-and-motor neurons), with remarkable visuo-motor congruence for the preferred target. Interestingly the discharge of multisensory neurons reflected a behavioural decision independently from the sensory modality of the stimulus allowing the monkey to make it: some encoded a decision to act/refraining from acting (the majority), while others specified one among the four behavioural alternatives. Complex Visuo Motor Task (cVMT). The cVMT was similar to the sVMT, but included a further grasping motor act (grasping a lid in order to remove it, before grasping the target) and was run in two modalities: randomized and in blocks. Substantially, motor-related and sensory-and-motor neurons tested in the cVMTrandomized were activated already during the first grasping motor act, but the selectivity for one of the two graspable targets emerged only during the execution of the second grasping. In contrast, when the cVMT was run in block, almost all these neurons not only discharged during the first grasping motor act, but also displayed the same target selectivity showed in correspondence of the hand contact with the target. Observation Task (OT). A great part of the neurons active during the OT showed a firing rate modulation in correspondence with the action performed by the experimenter. Among them, we found neurons significantly activated during the observation of the experimenter’s action (action observation-related neurons) and neurons responding not only to the action observation, but also to the presented cue stimuli (sensory-and-action observation-related neurons. Among the neurons of the first set, almost the half displayed a target selectivity, with a not clear difference between the two presented targets; Concerning to the second neuronal set, sensory-and-action related neurons, we found a low target selectivity and a not strictly congruence between the selectivity exhibited in the visual response and in the action observation.

Psychopathy, Moral Understanding and Criminal Responsibility

Peer reviewed

Attentional processes associated with victimization history and posttraumatic symptomatology in women exposed to intimate partner violence

Exposure to intimate partner violence (IPV) puts women at risk for severe and chronic physical and mental health consequences, including elevations in IPV-related psychopathology and increased risk for future victimization. Previous research has examined attention as one of the key information processing mechanisms associated with elevated psychopathology and risk for victimization; however, the nature of attentional processing in response to IPV-related information in women exposed to IPV is poorly understood. Therefore, the current study aimed to further understanding of associations between attentional processing, IPV exposure, and related distress using measures of eye movement and subjective interpretations of IPV-related information. A sample of women exposed to IPV (n = 57) viewed sets of negative, positive, and neutral relationship images for 15 s each while having their eye movements monitored and later provided subjective ratings and interpretations of levels of risk and safety in those images. We examined associations of outcome measures with proximal victimization experiences and IPV-related psychopathology (i.e., depression, posttraumatic stress disorder (PTSD), anxiety, and dissociation). Results indicated a bias to attend to negative relationship images relative to positive and neutral images, though this attention bias fluctuated over time and varied as a function of symptomatology such that depression corresponded with increases in attention to negative images over time and PTSD corresponded with decreases in attention to negative images. The general attention bias for negative images appeared to be explained by rumination on and/or difficulty disengaging from negative images, which was related to general elevations in psychopathology as well as exposure to revictimization by different perpetrators. Subjective interpretations and perception of danger cues were related to victimization history and level and type of IPV-related distress. We replicated these procedures with a sample of undergraduate students without IPV histories or related symptomatology (n = 33) and found that the overall attention bias for negative images was not replicated, despite general similarities in patterns of attention over time. Results therefore indicated associations between attentional processing and IPV exposure and related symptomatology. Implications for models of IPV-related psychopathology and attentional processing as well as directions for future study and interventions are discussed.

Fostering Change: Toward Understanding, Valuing, and Informing the Therapeutic Role of Foster Parents

Foster parents have the potential to effect lasting therapeutic change through their role with the children they temporarily foster. Therapists working with foster parents can understand, support, and inform foster parents in their role based on a commonality that exists between the roles of therapists and foster parents. Similarities at different stages of both the therapeutic and foster parenting relationships are addressed, as well as the use of these relationships in a therapeutic manner. Advantages (for foster parents, foster children, therapists, and the foster care system) of articulating the foster parenting relationship through the lens of the therapeutic relationship are also discussed. Future research into the experience of foster parents in their role will be essential in creating an effective and sustainable system of care for vulnerable children.

Coordination of aproximations in secondary school students’ understanding of limit concept

The aim of this research is to characterize the coordination of the processes of approximation related to the understanding of the limit of a function. We analyze the answers of 64 post-secondary school students to 7 problems considering the dynamic and metric conception of limit of a function. Results indicate that the metric understanding of the limit in terms of inequality supports that the student is capable of coordinating the approximations in the domain and in the range when lateral approximations coincide. However, the student is not capable of this coordination when lateral approximations do not coincide. This indicates that the metric understanding of the limit begins with the previous construction of the dynamic conception in case of coincidence of the lateral approximations in the range.

Legal shifts : shaping expectations of intellectual property protection in an open innovation industrial environment

Projet de recherche réalisé en 2014-2015 avec l'appui du Fonds de recherche du Québec – Société et culture.

The truth lies within: the reconstructive value of inner livores in a homicide case.

Through the widespread use of postmortem computed tomography, inner livores of the lungs have become a frequently observed phenomenon in the field of forensic medicine. Yet their time-dependent development, notably in comparison with the widely studied external livores, remains poorly understood. We present a unique homicide case where the victim was discovered in supine position with correspondent external livores fixed exclusively on the rear side. Yet upon postmortem computed tomography, the victim presented pronounced inner livores within the depending dorsal areas of both lungs but also vertical sedimentation levels solely within the right lung, suggesting an initial right-hand side position and a postmortem re-positioning of the body. Interestingly, this was consistent with tangible hints of postmortem manipulation on-site. It is likely that this repositioning occurred sometime during the early postmortem interval (<6 h) as the external livores have completely rearranged to the final supine position. The presented case suggests different development patterns of inner and outer livores, highlighting the necessity for controlled studies that explore the formation and fixation processes of livor mortis in internal organs. A better understanding of these issues can prove useful in forensic examinations.

Legal shifts : shaping expectations of intellectual property protection in an open innovation industrial environment

Projet de recherche réalisé en 2014-2015 avec l'appui du Fonds de recherche du Québec – Société et culture.

Social Impact of Coca Crops in Colombia. : From socio-territorial processes to new social configurations: the role of land tenure, armed conflict, environment and coca crops.

This paper explores alterations in social dynamics caused by coca crops in Curvaradó and Jiguamiandó, at Choco department in the Colombian Pacific region. The research analyzes the role of armed actors such as paramilitaries and guerrillas in the conformation of new social spaces where local people find resistance as the main tool to survive in chaotic environments. Local power as a politics of resistance is also analyzed. Non-governmental organizations are a key tool to comprehend new social configurations. By doing the analysis and comparison using political ecology as the theoretical background along with concepts of moral economy and everyday resistance, with qualitative research methods. The paper aims to interpret and provide a better understanding of those changes considering social-environmental relations. Findings suggest that those changes in social structure are leading to an understanding, not just of the organization of the area, but also that social dynamics and coca crops cannot be generalized in the country.