411 research outputs found
Elucidation of molecular kinetic schemes from macroscopic traces using system identification
Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore the development of methods to extract the dynamics and relationships between the different lower-level (microscopic) processes from the overall (macroscopic) response remains a crucial challenge in the understanding of many aspects of physiology. Here we have devised a hybrid computational-analytical method to accomplish this task, the SYStems-based MOLecular kinetic scheme Extractor (SYSMOLE). SYSMOLE utilizes system-identification input-output analysis to obtain a transfer function between the stimulus and the overall cellular response in the Laplace-transformed domain. It then derives a Markov-chain state molecular kinetic scheme uniquely associated with the transfer function by means of a classification procedure and an analytical step that imposes general biological constraints. We first tested SYSMOLE with synthetic data and evaluated its performance in terms of its rate of convergence to the correct molecular kinetic scheme and its robustness to noise. We then examined its performance on real experimental traces by analyzing macroscopic calcium-current traces elicited by membrane depolarization. SYSMOLE derived the correct, previously known molecular kinetic scheme describing the activation and inactivation of the underlying calcium channels and correctly identified the accepted mechanism of action of nifedipine, a calcium-channel blocker clinically used in patients with cardiovascular disease. Finally, we applied SYSMOLE to study the pharmacology of a new class of glutamate antipsychotic drugs and their crosstalk mechanism through a heteromeric complex of G protein-coupled receptors. Our results indicate that our methodology can be successfully applied to accurately derive molecular kinetic schemes from experimental macroscopic traces, and we anticipate that it may be useful in the study of a wide variety of biological systems
Biological Deacidification Strategies for White Wines
Traditionally, the use of malolactic fermentation gives rise to microbiologically stable wines. However, malolactic fermentation is not free from possible collateral effects that can take place under specific scenarios. The present work tests the influence of different biological deacidification strategies on the volatile and non-volatile components of white must from Germany. The study compared mixed cultures of Lachancea thermotolerans and Schizosaccharomyces pombe and a pure culture of Sc. pombe to the classical biological deacidification process performed by lactic acid bacteria. Strains of Oenococcus oeni and Lactiplantibacillus plantarum were co- or sequentially inoculated with S. cerevisiae to carry out malolactic fermentation. Different fermentation treatments took place at a laboratory scale of 0.6 L in vessels of 0.75 L. The instrumental techniques Fourier-transform mid-infrared spectroscopy (FT-MIR), high performance liquid chromatography (HPLC) and gas chromatography–mass spectrometry (GC-MS) were used to evaluate different chemical parameters in the final wines. The results showed the ability of Sc. pombe to consume malic acid in combination with L. thermotolerans without using S. cerevisiae or lactic acid bacteria. Fermentations involving Sc. pombe consumed all the malic acid, although they reduced the concentrations of higher alcohols, fatty acids and acetic acid. Simultaneous alcoholic and malolactic fermentations reduced malic acid by about 80%, while classical malolactic fermentation reduced it by 100%. Fermentations involving L. thermotolerans produced the highest lactic acid, ester and glycerol concentrations
The impact of luteal phase support on endometrial estrogen and progesterone receptor expression: a randomized control trial
<p>Abstract</p> <p>Background</p> <p>To assess the impact of luteal phase support on the expression of estrogen receptor (ER) alpha and progesterone receptors B (PR-B) on the endometrium of oocyte donors undergoing controlled ovarian hyperstimulation (COH).</p> <p>Methods</p> <p>A prospective, randomized study was conducted in women undergoing controlled ovarian hyperstimulation for oocyte donation. Participants were randomized to receive no luteal support, vaginal progesterone alone, or vaginal progesterone plus orally administered 17 Beta estradiol. Endometrial biopsies were obtained at 4 time points in the luteal phase and evaluated by tissue microarray for expression of ER alpha and PR-B.</p> <p>Results</p> <p>One-hundred and eight endometrial tissue samples were obtained from 12 patients. No differences were found in expression of ER alpha and PR-B among all the specimens with the exception of one sample value.</p> <p>Conclusions</p> <p>The administration of progesterone during the luteal phase of COH for oocyte donor cycles, either with or without estrogen, does not significantly affect the endometrial expression of ER alpha and PR.</p
An analytical tool for elucidating ion-channel molecular mechanisms from macroscopic current traces
Building models to describe the dynamics of macroscopic currents through ion channels has been the object of numerous studies in the literature with the aim of understanding ion-channel function. Following a perturbation, typically a step in voltage or ligand concentration, the response is formed by a combination of different processes such as activation or inactivation that pull the measured quantity (macroscopic current) in the same or opposite directions with different strengths and different time constants. Although this dynamic response can be readily recorded in time, the relationship between the underlying processes cannot be easily teased apart without structural analysis or single-channel recordings. An example is the classic problem of determining from sodium-channel macroscopic traces whether the activation and inactivation processes occur in parallel or inactivation is dependent on previous activation.
We present a mathematical tool to analyze electrophysiological traces and derive molecular kinetic schemes that reflect the interplay between the different processes involved. This tool is based on system-identification algorithms and consists of three modules as summarized in Figure 1. The identifier takes the input and output signals in the time domain and applies autoregressive ARX methods to obtain a transfer function in the Laplace domain yielding a set of poles, zeros and gain that provide a unique signature of the channel response. The classifier capitalizes on this signature to reveal the block diagram associated with the interplay of the processes, that are here described as first order systems in classic engineering terms (a relaxation with one time constant and a gain for each process). Finally, the molecular kinetic converter uses the transfer function together with the block diagram and maps them into a molecular kinetic scheme, a description with states associated with a system of differential equations
1021-97 Impact of diabetes mellitus on thrombolysis in myocardial infarction risk score, procedural utilization, and clinical outcomes in minorities and women as compared to white men with Non-ST-segment elevation acute coronary syndrome
Photoelectron spectra of alkali metal–ammonia microjets: From blue electrolyte to bronze metal
Experimental studies of the electronic structure of excess electrons in liquids—archetypal quantum solutes—have been largely restricted to very dilute electron concentrations. We overcame this limitation by applying soft x-ray photoelectron spectroscopy to characterize excess electrons originating from steadily increasing amounts of alkali metals dissolved in refrigerated liquid ammonia microjets. As concentration rises, a narrow peak at ~2 electron volts, corresponding to vertical photodetachment of localized solvated electrons and dielectrons, transforms continuously into a band with a sharp Fermi edge accompanied by a plasmon peak, characteristic of delocalized metallic electrons. Through our experimental approach combined with ab initio calculations of localized electrons and dielectrons, we obtain a clear picture of the energetics and density of states of the ammoniated electrons over the gradual transition from dilute blue electrolytes to concentrated bronze metallic solutions
Competition-based model of pheromone component ratio detection in the moth
For some moth species, especially those closely interrelated and sympatric, recognizing a specific pheromone component concentration ratio is essential for males to successfully locate conspecific females. We propose and determine the properties of a minimalist competition-based feed-forward neuronal model capable of detecting a certain ratio of pheromone components independently of overall concentration. This model represents an elementary recognition unit for the ratio of binary mixtures which we propose is entirely contained in the macroglomerular complex (MGC) of the male moth. A set of such units, along with projection neurons (PNs), can provide the input to higher brain centres. We found that (1) accuracy is mainly achieved by maintaining a certain ratio of connection strengths between olfactory receptor neurons (ORN) and local neurons (LN), much less by properties of the interconnections between the competing LNs proper. An exception to this rule is that it is beneficial if connections between generalist LNs (i.e. excited by either pheromone component) and specialist LNs (i.e. excited by one component only) have the same strength as the reciprocal specialist to generalist connections. (2) successful ratio recognition is achieved using latency-to-first-spike in the LN populations which, in contrast to expectations with a population rate code, leads to a broadening of responses for higher overall concentrations consistent with experimental observations. (3) when longer durations of the competition between LNs were observed it did not lead to higher recognition accuracy
Stepping Beyond the Newtonian Paradigm in Biology. Towards an Integrable Model of Life: Accelerating Discovery in the Biological Foundations of Science
The INBIOSA project brings together a group of experts across many disciplines
who believe that science requires a revolutionary transformative
step in order to address many of the vexing challenges presented by the
world. It is INBIOSA’s purpose to enable the focused collaboration of an
interdisciplinary community of original thinkers.
This paper sets out the case for support for this effort. The focus of the
transformative research program proposal is biology-centric. We admit
that biology to date has been more fact-oriented and less theoretical than
physics. However, the key leverageable idea is that careful extension of the
science of living systems can be more effectively applied to some of our
most vexing modern problems than the prevailing scheme, derived from
abstractions in physics. While these have some universal application and
demonstrate computational advantages, they are not theoretically mandated
for the living. A new set of mathematical abstractions derived from biology
can now be similarly extended. This is made possible by leveraging
new formal tools to understand abstraction and enable computability. [The
latter has a much expanded meaning in our context from the one known
and used in computer science and biology today, that is "by rote algorithmic
means", since it is not known if a living system is computable in this
sense (Mossio et al., 2009).] Two major challenges constitute the effort.
The first challenge is to design an original general system of abstractions
within the biological domain. The initial issue is descriptive leading to the
explanatory. There has not yet been a serious formal examination of the
abstractions of the biological domain. What is used today is an amalgam;
much is inherited from physics (via the bridging abstractions of chemistry)
and there are many new abstractions from advances in mathematics (incentivized
by the need for more capable computational analyses). Interspersed
are abstractions, concepts and underlying assumptions “native” to biology
and distinct from the mechanical language of physics and computation as
we know them. A pressing agenda should be to single out the most concrete
and at the same time the most fundamental process-units in biology
and to recruit them into the descriptive domain. Therefore, the first challenge
is to build a coherent formal system of abstractions and operations
that is truly native to living systems.
Nothing will be thrown away, but many common methods will be philosophically
recast, just as in physics relativity subsumed and reinterpreted
Newtonian mechanics.
This step is required because we need a comprehensible, formal system to
apply in many domains. Emphasis should be placed on the distinction between
multi-perspective analysis and synthesis and on what could be the
basic terms or tools needed.
The second challenge is relatively simple: the actual application of this set
of biology-centric ways and means to cross-disciplinary problems. In its
early stages, this will seem to be a “new science”.
This White Paper sets out the case of continuing support of Information
and Communication Technology (ICT) for transformative research in biology
and information processing centered on paradigm changes in the epistemological,
ontological, mathematical and computational bases of the science
of living systems. Today, curiously, living systems cannot be said to
be anything more than dissipative structures organized internally by genetic
information. There is not anything substantially different from abiotic
systems other than the empirical nature of their robustness. We believe that
there are other new and unique properties and patterns comprehensible at
this bio-logical level. The report lays out a fundamental set of approaches
to articulate these properties and patterns, and is composed as follows.
Sections 1 through 4 (preamble, introduction, motivation and major biomathematical
problems) are incipient. Section 5 describes the issues affecting
Integral Biomathics and Section 6 -- the aspects of the Grand Challenge
we face with this project. Section 7 contemplates the effort to
formalize a General Theory of Living Systems (GTLS) from what we have
today. The goal is to have a formal system, equivalent to that which exists
in the physics community. Here we define how to perceive the role of time
in biology. Section 8 describes the initial efforts to apply this general theory
of living systems in many domains, with special emphasis on crossdisciplinary
problems and multiple domains spanning both “hard” and
“soft” sciences. The expected result is a coherent collection of integrated
mathematical techniques. Section 9 discusses the first two test cases, project
proposals, of our approach. They are designed to demonstrate the ability
of our approach to address “wicked problems” which span across physics,
chemistry, biology, societies and societal dynamics. The solutions
require integrated measurable results at multiple levels known as “grand
challenges” to existing methods. Finally, Section 10 adheres to an appeal
for action, advocating the necessity for further long-term support of the
INBIOSA program.
The report is concluded with preliminary non-exclusive list of challenging
research themes to address, as well as required administrative actions. The
efforts described in the ten sections of this White Paper will proceed concurrently.
Collectively, they describe a program that can be managed and
measured as it progresses
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