Andres Kriete

Thermodynamically open biological systems not only sustain a life-supporting mutual relationship with their environment by exchanging matter and energy but constantly seek information to navigate probabilistic changes in their surroundings. This work argues that cognition and conscious thought should not be viewed in isolation but rather as parts of an integral control of biological systems to identify and act upon meaningful, semantic information to sustain viability. Under this framework, the development of key cognitive control capacities in centralized nervous systems and the resulting behavior are categorized into distinct Markov decision processes: decision-making with partially observable sensory exteroceptive and interoceptive information, learning and memory, and symbolic communication. It is proposed that the state of conscious thought arises from a control mechanism for speech production resembling actuator control in engineered systems. Also known as the phonological loop, this feedback from the motor to sensory cortex provides a third type of information flowing into the sensory cortex. The continuous, dissipative loop updates the fleeting working memory and provides humans with an advanced layer of control through a sense of self, agency and perception of flow in time. These capacities define distinct degrees of information fitness in the evolution of information-powered organisms.

Comparative oncology is an understudied field of science. We are far from understanding the key mechanisms behind Peto's paradox, i.e., understanding how long-lived and large animals are not subject to a higher cancer burden despite the longer exposure time to mutations and the larger number of cells exposed.In this work, we investigated the scientific evidence on such mechanisms through a systematic mini-review of the literature about the relation of longevity and/or large body mass with physiological, genetic, or environmental traits among mammalian species. More than forty thousand articles were retrieved from three repositories, and 383 of them were screened using an active-learning-based tool. Of those, 36 articles on longevity and 37 on body mass were selected for the review. Such articles were examined focusing on: number and type of species considered, statistical methods used, traits investigated, and observed relationship with longevity and/or body mass. Where applicable, the traits investigated were matched with one or more hallmarks of cancer.We obtained a list of potential candidate traits to explain Peto's paradox related to replicative immortality, cell senescence, genome instability and mutations, proliferative signaling, growth suppression evasion, and cell resistance to death.Our investigation suggests that different strategies have been followed to prevent cancer in large and long-lived species. The large number of papers retrieved emphasizes that more studies can be launched in the future, using more efficient analytical approaches to comprehensively evaluate the convergent biological mechanisms essential for acquiring longevity and large body mass without increasing cancer risk.

Evolution, self-replication and ontogenesis are highly dynamic, irreversible and self-organizing processes dissipating energy. While progress has been made to decipher the role of thermodynamics in cellular fission, it is not yet clear how entropic balances shape organism growth and aging. This paper derives a general dissipation theory for the life-history of organisms. It implies a self-regulated entropy production facilitating exponential growth within a hierarchical and entropy lowering self-organization. The theory predicts ceilings in energy expenditures imposed by geometric constrains, which promote thermal optimality during development, and a dissipative scaling across organisms consistent with ecological scaling laws combining isometric and allometric terms. The theory also illustrates how growing organisms can tolerate damage through continuous extension and production of new dissipative structures low in entropy. However, when organisms reduce their rate of cell division and reach a steady adult state, they become thermodynamically unstable, increase internal entropy by accumulating damage, and age.

This work describes a unique ultrasound (US) exposure system designed to create very localized ( \sim 100 ~\mu \text{m} ) sound fields at operating frequencies that are currently being used for preclinical US neuromodulation. This system can expose small clusters of neuronal tissue, such as cell cultures or intact brain structures in target animal models, opening up opportunities to examine possible mechanisms of action. We modified a dental descaler and drove it at a resonance frequency of 96 kHz, well above its nominal operating point of 28 kHz. A ceramic microtip from an ultrasonic wire bonder was attached to the end of the applicator, creating a 100- \mu \text{m} point source. The device was calibrated with a polyvinylidene difluoride (PVDF) membrane hydrophone, in a novel, air-backed, configuration. The experimental results were confirmed by simulation using a monopole model. The results show a consistent decaying sound field from the tip, well-suited to neural stimulation. The system was tested on an existing neurological model, Drosophila melanogaster, which has not previously been used for US neuromodulation experiments. The results show brain-directed US stimulation induces or suppresses motor actions, demonstrated through synchronized tracking of fly limb movements. These results provide the basis for ongoing and future studies of US interaction with neuronal tissue, both at the level of single neurons and intact organisms.

Having made substantial progress understanding molecules, cells, genes and pathways, aging biology research is now moving toward integration of these parts, attempting to understand how their joint dynamics may contribute to aging. Such a shift of perspective requires the adoption of a formal complex systems framework, a transition being facilitated by large-scale data collection and new analytical tools. Here, we provide a theoretical framework to orient researchers around key concepts for this transition, notably emergence, interaction networks and resilience. Drawing on evolutionary theory, network theory and principles of homeostasis, we propose that organismal function is accomplished by the integration of regulatory mechanisms at multiple hierarchical scales, and that the disruption of this ensemble causes the phenotypic and functional manifestations of aging. We present key examples at scales ranging from sub-organismal biology to clinical geriatrics, outlining how this approach can potentially enrich our understanding of aging.

We have applied a novel and integrative analysis framework for next-generation sequencing (NGS) data to 503 human subjects provided by the Religious Orders Study and Memory and Aging Project (ROSMAP) to examine changes in transcriptomic organization and common variants in association with late-onset Alzheimer’s disease (LOAD). Our framework identified seven reproducible, co-regulated modules after quality control (QC), clinical segregation, preservation filtering, and functional ontology analysis. These modules were specifically enriched in several innate and adaptive immune system processes, the synaptic vesicle cycle, and Hippo signaling. Topological and functional erosion of these modules due to shedding of genes and loss of in-module connectivity was diagnostic of disease progression. Perturbation analysis revealed that only 1% of eQTLs overlapped genes participating in these co-regulated modules. Common variants nevertheless identified components of the immune systems like human leukocyte antigen (HLA) complex and microtubule-associated protein tau (MAPT) regions in association with LOAD. Our results implicate microglial function, adaptive immune response, and the structural degeneration of neurons as contributors to the transcriptional deregulation observed along with common genetic variants in the progression of LOAD.

Stress urinary incontinence (SUI), a serious condition which affects ~56% of postmenopausal women, is the involuntary leakage of urine through urethra during physical activity that causes an increase in abdominal pressure. SUI is associated with a decrease in compliance and volume of urethral tissue, likely due to a reduced proteoglycan: collagen ratio in the extracellular matrix and collagen disorganization. Here, we investigated the use of biomimetic proteoglycans (BPGs) to molecularly engineer urethral tissue of New Zealand White rabbits to examine biocompatibility in vivo. BPG concentrations of 50 mg/mL (n = 6, 1 week) and 200 mg/mL (n = 6, 1 week and n = 6, 6 weeks) dissolved in 1× phosphate‐buffered saline (PBS) were injected transurethrally using a 9 French cystoscope, and were compared to PBS‐injected controls (n = 3, 1 week) and non‐injected controls (n = 2, 1 week). Urethral compression pressure measurements confirm BPG injections did not modify normal urethral pressure, as intended. Histological assessment demonstrated biological tolerance of BPGs in urethra and no inflammatory response was detected after 1 and 6 weeks compared to non‐injected controls. Confocal imaging of fluorescently‐labeled BPG injected urethral specimens demonstrated the integration of BPGs into the interstitial connective tissue and confirmed they were still present after 6 weeks. A general decrease of collagen density was exhibited near injection sites which may be due to increased hydration induced by BPGs. Injection of BPGs is a novel approach that demonstrates potential as molecular treatment for SUI and may be able to reverse some of the degenerative tissue changes of individuals affected by this condition. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: 00B: 000–000, 2019. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2409–2418, 2019.

Background : An increasing amount of evidence demonstrates that immune dysfunction and neuroinflammation contribute to the pathogenesis and progression of late-onset Alzheimer's disease (LOAD). To identify and characterize the transcriptomic and genetic contributors to immune dysfunction in LOAD, we have designed a comprehensive analysis framework for performing clinical segregation analysis, co-expression modeling, functional enrichment, and gene perturbation testing by integrating clinical neuropathological, gene expression, and genotype data.
Methods : We applied our analysis framework to 503 human subjects from the Religious Orders Study and Memory and Aging Project (ROSMAP) to map and compare functional gene networks, transcription factors, and genomic loci studies to decipher their contributions to disease progression.
Results : We identified deregulation in gene networks involving immune response, synaptic function, and Hippo signaling. One module contains 191 genes, including ABI3, CD33, HLA-DRA, HLA-DMB, IL10RA, MS4A4A, TREM2, and TYROBP and is strongly associated with microglial function. Segregation analysis revealed an association between network organization and cognitive decline in these functionally enriched modules. A reduction in co-regulated genes indicates changes in several key signaling nodes associated with microglia activation and inflammatory response. Finally, we identified HLA and MAPT alleles in association with LOAD.
Conclusions : Our results corroborate findings of the involvement of the adaptive and innate immune systems in LOAD pathology and can inform immunotherapies aimed at treating this condition. Finally, this study serves at a paradigm for integrating detailed clinical phenotypes with various -omics data to further resolve molecular endophenotypes in LOAD and other complex diseases.

Urinary incontinence is a significant challenge for women who are affected by it. We propose augmenting the tissue structure to restore normal biomechanics by molecularly engineering the tissue using a novel family of biomimetic proteoglycans (BPGs). This work examines the ability of BPGs to modulate the mechanical and physical properties of porcine urethras
ex vivo
to determine the feasibility of BPGs to be implemented as molecular treatment for stress urinary incontinence (SUI). We investigated compliance by performing a unique radial expansion testing method using urethras from six- to nine-month-old pigs. The urethras were injected with 0.5 ml BPG solution at three sites every approximately 120° (conc.: 25 mg ml
−1
, 50 mg ml
−1
and 75 mg ml
−1
in 1× phosphate-buffered saline (PBS);
n
= 4 per group) and compared them with PBS-injected controls. Young's modulus was calculated by treating the urethra as a thin-walled pressure vessel. A water uptake study was performed by soaking 10 mm urethra biopsy samples that were injected with 0.1 ml BPG solution (conc.: 50 mg ml
−1
, 100 mg ml
−1
and 200 mg ml
−1
in 1× PBS;
n
= 6 per group) in 5 ml PBS for 24 h. Although there was no significant difference in Young's modulus data, there were differences between groups as can be seen in the raw radial expansion testing data. Results showed that BPGs have the potential to increase hydration in samples, and that there was a significant difference in water uptake between BPG-injected samples and the controls (100 mg ml
−1
samples versus PBS samples,
p
< 0.05). This work shows that BPGs have the potential to be implemented as a molecular treatment for SUI, by restoring the diminished proteoglycan content and subsequently increasing hydration and improving the compliance of urethral tissue.

Late-onset Alzheimer's disease (LOAD) and age are significantly correlated such that one-third of Americans beyond 85 years of age are afflicted. We have designed and implemented a pilot study that combines systems biology approaches with traditional next-generation sequencing (NGS) analysis techniques to identify relevant regulatory pathways, infer functional relationships and confirm the dysregulation of these biological pathways in LOAD. Our study design is a most comprehensive systems approach combining co-expression network modeling derived from RNA-seq data, rigorous quality control (QC) standards, functional ontology, and expression quantitative trait loci (eQTL) derived from whole exome (WES) single nucleotide variant (SNV) genotype data. Our initial results reveal several statistically significant, biologically relevant genes involved in sphingolipid metabolism. To validate these findings, we performed a gene set enrichment analysis (GSEA). The GSEA revealed the sphingolipid metabolism pathway and regulation of autophagy in association with LOAD cases. In the execution of this study, we have successfully tested an integrative approach to identify both novel and known LOAD drivers in order to develop a broader and more detailed picture of the highly complex transcriptional and regulatory landscape of age-related dementia.