Rice Institute

SUMMARYModification by ubiquitination governs the half-lives of thousands of proteins that are fated for elimination by either the proteasome or autophagy pathways, depending on the intricate architectures of ubiquitin modification. This system mediates quality control for individual proteins, protein complexes, and organelles, as well as myriad purely regulatory functions. Here we provide a comprehensive survey of the ubiquitin-proteasome system (UPS), the scope of which is at present poorly defined. The UPS, with the inclusion of pathways involving ubiquitin-like modifiers, comprises in our estimate over 1400 distinct proteins in humans, a vast set of activities whose collective impact on the biology of the cell is pervasive. The UPS is an integral component of the proteostasis network (PN), the remainder of which we have also surveyed in recent studies. With the addition of molecular chaperones, proteins from autophagy-lysosome pathway, and related activities, the PN includes in total over 3100 components by our estimates. Comprehensive and systematic definition of these pathways should support a range of ongoing investigations in the areas of genomics, proteomics, biochemistry, cell biology, and disease research.

Abstract Animal behavioural diversity ultimately stems from variation in neural circuitry, yet how central neural circuits evolve remains poorly understood. Studies of neural circuit evolution often focus on a few elements within a network. However, addressing fundamental questions in evolutionary neuroscience, such as whether some elements are more evolvable than others, requires a more global and unbiased approach. Here, we used synapse-level comparative connectomics to examine how an entire olfactory circuit evolves. We compared the full antennal lobe connectome of the larvae of two closely related Drosophila species, D. melanogaster and D. erecta , which differ in their ecological niches and odour-driven behaviours. We found that evolutionary change is unevenly distributed across the network. Some features, including neuron types, neuron numbers and interneuron-to-interneuron connectivity, are highly conserved. These conserved elements delineate a core circuit blueprint presumably required for fundamental olfactory processing. Superimposed on this scaffold, we find rewiring changes that mirror each species’ ecologies, including a systematic shift in the excitation-to-inhibition balance in the feedforward pathways. We further show that some neurons have changed more than others, and that even within individual neurons some synaptic elements remain conserved while others display major species-specific changes, suggesting evolutionary hot-spots within the circuit. Our findings reveal constrained and adaptable elements within olfactory networks, and establish a framework for identifying general principles in the evolution of neural circuits underlying behaviour.

Abstract Chronic pain is a global epidemic that disproportionately affects Black, Indigenous, and other people of color as well as individuals of lower socioeconomic status. Unfortunately, the mechanisms that cause and sustain disparities in pain outcomes remain underexamined. This review highlights recent insights into epigenetics as a uniquely suited biological mechanism linking environmental stressors and pain disparities. Emerging evidence suggests that epigenetic modification of genes in pathways involved in stress dysregulation and neuroinflammation may play a central role in racial pain disparities and internalized stigma. These findings indicate that differential environmental exposure (ie, chronic stress) induces epigenetic changes (mediators) that explain pain disparities. Another putative mechanism by which differential epigenetic modifications contribute to pain disparities is epigenetic age acceleration. Emerging evidence suggests that epigenetic age acceleration mediates the relationship between lower socioeconomic status (household income, food insecurity, and neighborhood deprivation) and worse pain outcomes. Epigenetic modifications are dynamic and reversible, leaning toward pharmacological and nonpharmacological interventions. Logically, these will contribute to tailored interventions for pain management and equity in pain management. Finally, we cannot ignore that social and structural forces are the root causes of pain disparities. Thus, there is a need for policy changes addressing these forces.

Mitochondria play critical roles in energy production and cellular metabolism. Despite the Warburg effect, mitochondria are crucial for the survival and proliferation of cancer cells. Heat Shock Factor 1 (HSF1), a key transcription factor in the cellular heat shock response, promotes malignancy and metastasis when aberrantly activated. To understand the multifaceted roles of HSF1 in cancer, we performed a genome-wide CRISPR screen to identify epistatic interactors of HSF1 in cancer cell proliferation. The verified interactors of HSF1 include those involved in DNA replication and repair, transcriptional and post-transcriptional gene expression, and mitochondrial functions. Specifically, we found that HSF1 promotes cell proliferation, mitochondrial biogenesis, respiration, and ATP production in a manner dependent on TIMM17A, a subunit of the inner membrane translocase. HSF1 upregulates the steady-state level of the short-lived TIMM17A protein via its direct target genes, HSPD1 and HSPE1, which encode subunits of the mitochondrial chaperonin complex and are responsible for protein refolding once imported into the matrix. The HSF1-HSPD1/HSPE1-TIMM17A axis remodels the mitochondrial proteome to promote mitochondrial translation and energy production, thereby supporting robust cell proliferation. Our work reveals a mechanism by which mitochondria adjust protein uptake according to the folding capacity in the matrix by altering TIM complex composition.

Tender Coconut Water (TCW) is a nutrient-rich dietary supplement that contains bioactive secondary metabolites and phytohormones with anti-oxidative and anti-inflammatory properties. Studies on TCW's anti-cancer properties are limited and the mechanism of its anti-cancer effects have not been defined. In the present study, we investigate TCW for its anti-cancer properties and, using untargeted metabolomics, we identify components form TCW with potential anti-cancer activity. Cell viability assay, BrdU incorporation assay, soft-agar assay, flow-cytometery, and Western blotting were used to analyze TCW's anticancer properties and to identify mechanism of action. Liquid chromatography- Tandem Mass Spectroscopy (LC-MS/MS) was used to identify TCW components. TCW decreased the viability and anchorage-independent growth of HepG2 hepatocellular carcinoma (HCC) cells and caused S-phase cell cycle arrest. TCW inhibited AKT and ERK phosphorylation leading to reduced ZEB1 protein, increased E-cadherin, and reduced N-cadherin protein expression in HepG2 cells, thus reversing the 'epithelial-to-mesenchymal' (EMT) transition. TCW also decreased the viability of Hep3B hepatoma, HCT-15 colon, MCF-7 and T47D luminal A breast cancer (BC) and MDA-MB-231 and MDA-MB-468 triplenegative BC cells. Importantly, TCW did not inhibit the viability of MCF-10A normal breast epithelial cells. Untargeted metabolomics analysis of TCW identified 271 metabolites, primarily lipids and lipid-like molecules, phenylpropanoids and polyketides, and organic oxygen compounds. We demonstrate that three components from TCW: 3-hydroxy-1-(4-hydroxyphenyl)propan-1-one, iondole-3-carbox aldehyde and caffeic acid inhibit the growth of cancer cells. TCW and its components exhibit anti-cancer effects. TCW inhibits the viability of HepG2 hepatocellular carcinoma cells by reversing the EMT process through inhibition of AKT and ERK signalling.

Czechoslovakia in the 1950s and 1960s was controlled by the Communist Party, which strictly determined cultural policy. The book market was centrally planned and based on the reduction or negation of market mechanisms. In this study, I show the ways in which the Party in power tried to determine the optimal way of calculating authors' royalties in order to achieve a "fair" payment system and to limit "unearned" profit. Similarly, I examine what factors were taken into account in setting a uniform selling price for the book, which was not to be based on actual financial costs or the level of reader demand, but was to take into account the social value of the book and represent a "fair price for readers". Although the governing bodies of the Ministry of Culture tried to find a very precise and transparent way of calculating royalties and the selling price of a book, they had to gradually take into account more and more exceptions and specific circumstances relating to particular types of books or book genres. This demolished their ideas of a possible "ideal calculation" of a "fair price". The result was a system that had to be revised many times and was nearly never respected because of the number of exceptions. The study is based on research into archival material from the Ministry of Culture and demonstrates well the way in which literature and other book production was considered in the 1950s and 1960s. It shows how great discrepancy was generated between the utopian idea and its actual implementation in practice.

Introduction: Diabetic patients frequently experience a serious complication known as impaired wound healing, which increases the likelihood of foot infection and limb amputation. Investigators have been looking for novel methods to treat diabetic foot ulcers (DFUs) recently. Case Report: A 75-year-old woman with type one diabetes mellitus (DM) has been accepted. There was a sizable (40 cm2 full-thickness cutaneous wound) in the plantar part of her right foot (Wagner Ulcer Grade Classification System: grade 3) which had not been treated by the usual treatment for DFUs. In this present case, we used amniotic fluid gel (AF gel) and photobiomodulation therapy (PBMT) (400 mW/cm2; 810 nm, once a week for 16 weeks) to treat and speed up the healing of a harsh DFU. The size of the ulcer area significantly decreased as combination therapy progressed, and within 16 weeks, the wound was healed and the pain was reduced. Conclusion: This revealed contextual analysis demonstrated the useful effect of the mix of PBMT and AF gel on a serious DFU. To confirm the findings, we recommend conducting additional clinical trials in a clinical setting. In addition, it is recommended that additional research using preclinical models uncover the mechanism of action of the combination therapy.

Unplanned extubations (UEs) in injured patients are potentially fatal, but etiology and patient characteristics are not well described. We have been prospectively characterizing the etiology of UEs after we identified a high rate of UEs and implemented an educational program to address it. This period of monitoring included the years of the COVID-19 pandemic that produced high rates of workforce turnover in many hospitals, dramatically affecting nursing and respiratory therapy services. We hypothesized that frequency of UEs would depend on the etiology and that the workforce changes produced by the COVID-19 pandemic would increase UEs. This study was a prospective tracking and retrospective review of trauma registry and performance improvement data from 2012-2021. UE subjects were younger, were more frequently male, were diagnosed more frequently with pneumonia (38% vs 27%), and had longer hospital (19 d vs 15 d) and ICU length of stay (LOS) (12 d vs 10 d) (all P < .05). Most UEs were due to patient factors (self-extubation) that decreased after education, while UEs from other etiologies (mechanical, provider) were stable. Subjects with UEs from mechanical or provider etiologies had longer ICU LOS, higher mortality, and were less likely to be discharged home. The COVID-19 pandemic was associated with more total patient admissions and more days of ventilator use, but the rate of UEs was not changed. UEs were decreased by education with ongoing tracking, and UEs from patient factors were associated with better outcome than other etiologies. Workforce changes produced by the COVID-19 pandemic did not change the rate of UEs.