HEGEL’S CRITIQUE OF KANT’S PHILOSOPHY OF BIOLOGY

Thesis (Ph.D.) - Indiana University, Department of Philosophy, 2021Kant’s account of teleology in the Critique of Judgement denied that we could ever have genuine knowledge of living beings; Kant demoted teleological thinking to a heuristic status (albeit a necessary one). Many of Kant’s Idealist successors reacted against this skeptical move, including Goethe and Schelling. Hegel offers the best account of how to think about thoughts of living beings, and his Science of Logic and Philosophy of Nature offer many insights into how we should understand the special nature of living beings in nature and our thoughts about them. My dissertation offers an account of these insights in historical and systematic context

Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeat-rich parasite proteome during malarial fevers

One-fourth of Plasmodium falciparum proteins have asparagine repeats that increase the propensity for aggregation, especially at elevated temperatures that occur routinely in malaria-infected patients. We report that a Plasmodium Asn repeat-containing protein (PFI1155w) formed aggregates in mammalian cells at febrile temperatures, as did a yeast Asn/Gln-rich protein (Sup35). Co-expression of the cytoplasmic P. falciparum heat shock protein 110 (PfHsp110c) prevented aggregation. Human or yeast orthologs were much less effective. All-Asn and all-Gln versions of Sup35 were protected from aggregation by PfHsp110c, suggesting that this chaperone is not limited to handling runs of Asn. PfHsp110c gene knockout parasites were not viable and conditional knockdown parasites died slowly in the absence of protein-stabilizing ligand. When exposed to brief heat shock, these knockdowns were unable to prevent aggregation of PFI1155w or Sup35 and died rapidly. We conclude that PfHsp110c protects the parasite from harmful effects of its asparagine repeat-rich proteome during febrile episodes

Dihydropyrimidine-thiones and clioquinol synergize to target beta-amyloid cellular pathologies through a metal-dependent mechanism

The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer’s disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity. Cotreatment ameliorated Aβ toxicity by reducing Aβ levels and restoring functional vesicle trafficking. Notably, these low doses significantly reduced deleterious off-target effects caused by CQ on mitochondria at higher concentrations. Both single and combinatorial treatments also reduced death of neurons expressing Aβ in a nematode, indicating that DHPM-thiones target a conserved protective mechanism. Furthermore, this conserved activity suggests that expression of the Aβ peptide causes similar cellular pathologies from yeast to neurons. Our identification of a new cytoprotective scaffold that requires metal-binding underscores the critical role of metal phenomenology in mediating Aβ toxicity. Additionally, our findings demonstrate the valuable potential of synergistic compounds to enhance on-target activities, while mitigating deleterious off-target effects. The identification and prosecution of synergistic compounds could prove useful for developing AD therapeutics where combination therapies may be required to antagonize diverse pathologies.D.F.T was funded by NRSA Fellowship NIH 5F32NS061419. D.F.T. and S.L. were supported by WIBR funds in support of research on Regenerative Disease, the Picower/JPB Foundation, and the Edward N. and Della L. Thome Foundation. G.A.C. and S.L. were funded by a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award. L.E.B., R.T., and S.E.S. were funded by NIH GM086180, NIH GM067041, and NIH GM111625. (5F32NS061419 - NRSA Fellowship NIH; WIBR funds in support of research on Regenerative Disease; Picower/JPB Foundation; Edward N. and Della L. Thome Foundation; Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award; GM086180 - NIH; NIH GM067041 - NIH; NIH GM111625 - NIH)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705239/Accepted manuscrip

Ongoing Oxidative Stress Causes Subclinical Neuronal Dysfunction in the Recovery Phase of EAE

Most multiple sclerosis (MS) patients develop over time a secondary progressive disease course, characterized histologically by axonal loss and atrophy. In early phases of the disease, focal inflammatory demyelination leads to functional impairment, but the mechanism of chronic progression in MS is still under debate. Reactive oxygen species generated by invading and resident central nervous system (CNS) macrophages have been implicated in mediating demyelination and axonal damage, but demyelination and neurodegeneration proceed even in the absence of obvious immune cell infiltration, during clinical recovery in chronic MS. Here, we employ intravital NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX1–4, DUOX1, 2) and, thus, to identify the cellular source of oxidative stress in the CNS of mice affected by experimental autoimmune encephalomyelitis (EAE) in the remission phase of the disease. This directly affects neuronal function in vivo, as monitored by cellular calcium levels using intravital FRET–FLIM, providing a possible mechanism of disease progression in MS

Serum and cerebrospinal fluid brain damage markers neurofilament light and glial fibrillary acidic protein correlate with tick-borne encephalitis disease severity—a multicentre study on Lithuanian and Swedish patients

Background and purpose: Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis.// Methods: One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and cerebrospinal fluid (CSF) and serum samples were obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate or severe tick-borne encephalitis. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of the brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL-40, S100B, neurogranin, neurofilament light (NfL) and tau were analysed in CSF and, in addition, NfL, GFAP and S100B levels were measured in serum. The Jonckheere-Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test was used to adjust for age.// Results: Cerebrospinal fluid and serum concentrations of GFAP and NfL correlated with disease severity, independent of age, and with the presence of nerve paralysis. The markers neurogranin, YKL-40, tau and S100B in CSF and S100B in serum were detected, but their concentrations did not correlate with disease severity.// Conclusions: Neuronal cell damage and astroglial cell activation with increased NfL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NfL concentrations in CSF and NfL in serum were also indicative of spinal and/or cranial nerve damage. NfL and GFAP are promising prognostic biomarkers in tick-borne encephalitis, and future studies should focus on determining the association between these biomarkers and long-term sequelae

Cryptic Variation in Morphological Evolution: HSP90 as a Capacitor for Loss of Eyes in Cavefish

In the process of morphological evolution, the extent to which cryptic, preexisting variation provides a substrate for natural selection has been controversial. We provide evidence that heat shock protein 90 (HSP90) phenotypically masks standing eye-size variation in surface populations of the cavefish Astyanax mexicanus. This variation is exposed by HSP90 inhibition and can be selected for, ultimately yielding a reduced-eye phenotype even in the presence of full HSP90 activity. Raising surface fish under conditions found in caves taxes the HSP90 system, unmasking the same phenotypic variation as does direct inhibition of HSP90. These results suggest that cryptic variation played a role in the evolution of eye loss in cavefish and provide the first evidence for HSP90 as a capacitor for morphological evolution in a natural setting

Changes In Nitrogen Use Efficiency And Soil Quality After Five Years Of Managing For High Yield Corn And Soybean

Average corn grain yields in the USA have increased linearly at a rate of 1.7 bu/acre over the past 35 years with a national yield average of 140 bu/acre. Corn yield contest winners and simulation models, however, indicate there is ~100 bu/a in exploitable corn yield gap. Four years (1999-2002) of plant development, grain yield and nutrient uptake were compared in intensive irrigated maize systems representing (a) recommended best management practices for a yield goal of 200 bu/acre (M1) and (b) intensive management aiming at a yield goal of 300 bu/acre (M2). For each management level, three levels of plant density (30000-P1, 37000-P2 and 44000-P3 seed/acre) were compared in a continuous corn and corn- soybean rotation. Over five years, the grain yields increased 11% as a function of management and this effect was manifest under higher plant densities. A high yield of 285 bu/acre was achieved at the M2, P2 treatment in 2003. Higher population resulted in greater demand for N and K per unit grain yield. Over the past five years, nitrogen use efficiency has steadily improved in the M2 treatment due to improvements in soil quality. Intensive management and population levels significantly increased residue carbon inputs with disproportionately lower soil respiration. Closing the yield gap requires higher plant population and improved nutrient management to maintain efficient and profitable improvement in maize production. Soil quality improvements and higher residue inputs under intensive management should make this task easier with time

Influência do treino em esteira na marcha em dupla tarefa em indivíduos com Doença de Parkinson: estudo de caso

The loss in the automaticity of gait hinders the performance of concurrent activities - Dual Task (DT) - in individuals with Parkinson's disease (PD). One hypothesis for the negative interference of DT on gait is related to the limitation of attention resources in the brain for different activities. When the automation of a task occurs, the negative interference of DT on the gait can be minimized. Because the treadmill promotes automaticity of a better locomotion pattern, due to the repetition that promotes motor learning, the study sought to investigate whether treadmill training can improve the performance of gait on DT in people with PD. Three individuals were evaluated in the on-phase of the antiparkinsonian medication regarding the kinematics (Qualisys Motion Capture System) while in gait, simultaneously performing cognitive activities. Subsequently, the subjects performed a 20-minute workout on the treadmill and were reassessed during gait in cognitive activities. There were increases in the length of the cycle (p=0.01), the length of the step (p=0.01) and in total swing time (p=0.03), and a decrease in the total length of support (p=0.03). These results indicate that treadmill training can promote improvement in the performance of DT on gait in individuals with PD. Longitudinal studies with this focus of research are needed.La pérdida en el automatismo de la marcha dificulta la realización de actividades simultáneas - Doble Tarea (DT) - en personas con enfermedad de Parkinson (EP). Una hipótesis para la interferencia negativa de la DT en la marcha está relacionada con la limitación de recursos cerebrales de atención para diferentes actividades. Cuando se produce la automatización de una de las tareas, la interferencia negativa de la DT sobre la marcha podrá ser minimizada. Como la cinta de correr promueve la automaticidad de un mejor patrón locomotor, debido a la repetición que favorece el aprendizaje motor, el estudio trató de investigar si el entrenamiento en cinta de correr puede mejorar el desempeño de marcha en DT en personas con EP. Tres individuos fueron evaluados en la fase on del medicamento antiparkinsoniano en cuanto a la cinemática (Qualisys Motion Capture System), mientras se realizaba la marcha simultáneamente a actividades cognitivas. Posteriormente, los individuos realizaron un entrenamiento de 20 minutos en la cinta y fueron evaluados de nuevo durante la marcha en actividades cognitivas. Hubo aumentos en longitud de la pasada (p=0,01), la longitud del paso (p=0,01) y en el tiempo total del abalanzar (p=0,03) y una disminución de en tiempo total de apoyo (p=0,03). Estos resultados indican que el entrenamiento en cinta puede promover la mejora en el rendimiento de marcha en DT en personas con EP, y que se necesitan estudios longitudinales con este enfoque de investigación.A perda na automaticidade da marcha dificulta a realização de atividades concorrentes - Dupla Tarefa (DT) - em indivíduos com Doença de Parkinson (DP). Uma hipótese para a interferência negativa da DT sobre a marcha está relacionada à limitação de recursos cerebrais atentivos para as diferentes atividades. Caso ocorra a automatização de uma das tarefas, a interferência negativa da DT sobre a marcha poderá ser minimizada. Como a esteira promove automaticidade de um melhor padrão locomotor, devido à repetição que favorece a aprendizagem motora, o estudo buscou investigar se o treino em esteira pode melhorar o desempenho de marcha em DT em pessoas com DP. Três indivíduos foram avaliados na fase on do medicamento antiparkinsoniano quanto à cinemetria (Qualisys Motion Capture System), enquanto realizavam a marcha simultaneamente a atividades cognitivas. Posteriormente, os indivíduos realizaram um treino de 20 minutos na esteira e foram reavaliados durante a marcha em atividades cognitivas. Houve aumentos no comprimento da passada (p=0,01), no comprimento do passo (p=0,01) e no tempo total de apoio (p=0,03). Esses resultados indicam que o treino em esteira pode promover melhora no desempenho de marcha em DT em indivíduos com DP, sendo necessários estudos longitudinais com esse foco de investigação

The amphioxus genome and the evolution of the chordate karyotype

Lancelets ('amphioxus') are the modern survivors of an ancient chordate lineage, with a fossil record dating back to the Cambrian period. Here we describe the structure and gene content of the highly polymorphic approx520-megabase genome of the Florida lancelet Branchiostoma floridae, and analyse it in the context of chordate evolution. Whole-genome comparisons illuminate the murky relationships among the three chordate groups (tunicates, lancelets and vertebrates), and allow not only reconstruction of the gene complement of the last common chordate ancestor but also partial reconstruction of its genomic organization, as well as a description of two genome-wide duplications and subsequent reorganizations in the vertebrate lineage. These genome-scale events shaped the vertebrate genome and provided additional genetic variation for exploitation during vertebrate evolution

Tick-borne Encephalitis from Eating Goat Cheese in a Mountain Region of Austria

We report transmission of tick-borne encephalitis virus (TBEV) in July 2008 through nonpasteurized goat milk to 6 humans and 4 domestic pigs in an alpine pasture 1,500 m above sea level. This outbreak indicates the emergence of ticks and TBEV at increasing altitudes in central Europe and the efficiency of oral transmission of TBEV