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1.
Nature ; 591(7851): 599-603, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33762765

RESUMO

Terrestrial ecosystems remove about 30 per cent of the carbon dioxide (CO2) emitted by human activities each year1, yet the persistence of this carbon sink depends partly on how plant biomass and soil organic carbon (SOC) stocks respond to future increases in atmospheric CO2 (refs. 2,3). Although plant biomass often increases in elevated CO2 (eCO2) experiments4-6, SOC has been observed to increase, remain unchanged or even decline7. The mechanisms that drive this variation across experiments remain poorly understood, creating uncertainty in climate projections8,9. Here we synthesized data from 108 eCO2 experiments and found that the effect of eCO2 on SOC stocks is best explained by a negative relationship with plant biomass: when plant biomass is strongly stimulated by eCO2, SOC storage declines; conversely, when biomass is weakly stimulated, SOC storage increases. This trade-off appears to be related to plant nutrient acquisition, in which plants increase their biomass by mining the soil for nutrients, which decreases SOC storage. We found that, overall, SOC stocks increase with eCO2 in grasslands (8 ± 2 per cent) but not in forests (0 ± 2 per cent), even though plant biomass in grasslands increase less (9 ± 3 per cent) than in forests (23 ± 2 per cent). Ecosystem models do not reproduce this trade-off, which implies that projections of SOC may need to be revised.


Assuntos
Dióxido de Carbono/metabolismo , Sequestro de Carbono , Plantas/metabolismo , Solo/química , Biomassa , Pradaria , Modelos Biológicos
2.
Nature ; 596(7870): 43-53, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34349292

RESUMO

The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile genetic elements that can move from one genomic location to another; in this process, they amplify and increase their presence in genomes, sometimes to very high copy numbers. In this Review we discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans. Retrotransposons have been coevolving with their host genomes since the dawn of life. This relationship has been largely competitive, and transposons have earned epithets such as 'junk DNA' and 'molecular parasites'. Much of our knowledge of the evolution of retrotransposons reflects their activity in the germline and is evident from genome sequence data. Recent research has provided a wealth of information on the activity of retrotransposons in somatic tissues during an individual lifespan, the molecular mechanisms that underlie this activity, and the manner in which these processes intersect with our own physiology, health and well-being.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Doença/genética , Retroelementos/genética , Animais , Dano ao DNA , Inativação Gênica , Genoma Humano/genética , Genômica , Humanos , Imunidade Inata
3.
PLoS Genet ; 20(2): e1011158, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38359090

RESUMO

Elucidating gene function is a major goal in biology, especially among non-model organisms. However, doing so is complicated by the fact that molecular conservation does not always mirror functional conservation, and that complex relationships among genes are responsible for encoding pathways and higher-order biological processes. Co-expression, a promising approach for predicting gene function, relies on the general principal that genes with similar expression patterns across multiple conditions will likely be involved in the same biological process. For Cryptococcus neoformans, a prevalent human fungal pathogen greatly diverged from model yeasts, approximately 60% of the predicted genes in the genome lack functional annotations. Here, we leveraged a large amount of publicly available transcriptomic data to generate a C. neoformans Co-Expression Network (CryptoCEN), successfully recapitulating known protein networks, predicting gene function, and enabling insights into the principles influencing co-expression. With 100% predictive accuracy, we used CryptoCEN to identify 13 new DNA damage response genes, underscoring the utility of guilt-by-association for determining gene function. Overall, co-expression is a powerful tool for uncovering gene function, and decreases the experimental tests needed to identify functions for currently under-annotated genes.


Assuntos
Criptococose , Cryptococcus neoformans , Humanos , Cryptococcus neoformans/genética , Criptococose/genética , Criptococose/microbiologia , Reparo do DNA/genética , Fenótipo , Dano ao DNA/genética , Proteínas Fúngicas/genética
4.
RNA ; 30(8): 1089-1105, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38760076

RESUMO

Many transcription factors (TFs) have been shown to bind RNA, leading to open questions regarding the mechanism(s) of this RNA binding and its role in regulating TF activities. Here, we use biophysical assays to interrogate the k on, k off, and K d for DNA and RNA binding of two model human TFs, ERα and Sox2. Unexpectedly, we found that both proteins exhibit multiphasic nucleic acid-binding kinetics. We propose that Sox2 RNA and DNA multiphasic binding kinetics can be explained by a conventional model for sequential Sox2 monomer association and dissociation. In contrast, ERα nucleic acid binding exhibited biphasic dissociation paired with novel triphasic association behavior, in which two apparent binding transitions are separated by a 10-20 min "lag" phase depending on protein concentration. We considered several conventional models for the observed kinetic behavior, none of which adequately explained all the ERα nucleic acid-binding data. Instead, simulations with a model incorporating sequential ERα monomer association, ERα nucleic acid complex isomerization, and product "feedback" on isomerization rate recapitulated the general kinetic trends for both ERα DNA and RNA binding. Collectively, our findings reveal that Sox2 and ERα bind RNA and DNA with previously unappreciated multiphasic binding kinetics, and that their reaction mechanisms differ with ERα binding nucleic acids via a novel reaction mechanism.


Assuntos
DNA , Receptor alfa de Estrogênio , Ligação Proteica , RNA , Fatores de Transcrição SOXB1 , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/química , Humanos , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/química , DNA/metabolismo , DNA/química , RNA/metabolismo , RNA/química , RNA/genética , Cinética , Sítios de Ligação
5.
Hum Mol Genet ; 32(5): 732-744, 2023 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-36067040

RESUMO

Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia. ALDH18A1 encodes the bifunctional enzyme pyrroline-5-carboxylate synthetase (P5CS) that plays a role in the de novo biosynthesis of proline and ornithine. Here we characterize a previously unreported homozygous ALDH18A1 variant (p.Thr331Pro) in four affected probands from two unrelated families, and demonstrate broad-based alterations in amino acid and antioxidant metabolism. These four patients exhibit variable developmental delay, neurological deficits and loose skin. Functional characterization of the p.Thr331Pro variant demonstrated a lack of any impact on the steady-state level of the P5CS monomer or mitochondrial localization of the enzyme, but reduced incorporation of the monomer into P5CS oligomers. Using an unlabeled NMR-based metabolomics approach in patient fibroblasts and ALDH18A1-null human embryonic kidney cells expressing the variant P5CS, we identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione. Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts, highlighting the functional consequence on another metabolic pathway involved in antioxidant responses in the cell. RNA sequencing of patient fibroblasts revealed transcript abundance changes in several metabolic and extracellular matrix-related genes, adding further insight into pathogenic processes associated with impaired P5CS function. Together these findings shed new light on amino acid and antioxidant pathways associated with ALDH18A1-related disorders, and underscore the value of metabolomic and transcriptomic profiling to discover new pathways that impact disease pathogenesis.


Assuntos
Aminoácidos , Cútis Laxa , Humanos , Antioxidantes , Prolina/metabolismo , Ácido Glutâmico/metabolismo , Cútis Laxa/complicações , Cútis Laxa/genética , Cútis Laxa/patologia , Ornitina
6.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35091469

RESUMO

Sirt6 is a multifunctional enzyme that regulates diverse cellular processes such as metabolism, DNA repair, and aging. Overexpressing Sirt6 extends lifespan in mice, but the underlying cellular mechanisms are unclear. Drosophila melanogaster are an excellent model to study genetic regulation of lifespan; however, despite extensive study in mammals, very little is known about Sirt6 function in flies. Here, we characterized the Drosophila ortholog of Sirt6, dSirt6, and examined its role in regulating longevity; dSirt6 is a nuclear and chromatin-associated protein with NAD+-dependent histone deacetylase activity. dSirt6 overexpression (OE) in flies produces robust lifespan extension in both sexes, while reducing dSirt6 levels shortens lifespan. dSirt6 OE flies have normal food consumption and fertility but increased resistance to oxidative stress and reduced protein synthesis rates. Transcriptomic analyses reveal that dSirt6 OE reduces expression of genes involved in ribosome biogenesis, including many dMyc target genes. dSirt6 OE partially rescues many effects of dMyc OE, including increased nuclear size, up-regulation of ribosome biogenesis genes, and lifespan shortening. Last, dMyc haploinsufficiency does not convey additional lifespan extension to dSirt6 OE flies, suggesting dSirt6 OE is upstream of dMyc in regulating lifespan. Our results provide insight into the mechanisms by which Sirt6 OE leads to longer lifespan.


Assuntos
Longevidade/genética , Sirtuínas/metabolismo , Envelhecimento/fisiologia , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Haploinsuficiência/genética , Histona Desacetilases/economia , Histona Desacetilases/metabolismo , Masculino , Sirtuínas/genética
7.
Biochem Soc Trans ; 52(5): 2035-2045, 2024 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-39221819

RESUMO

Immunotherapy has emerged as a therapeutic option for many cancers. For some tumors, immune checkpoint inhibitors show great efficacy in promoting anti-tumor immunity. However, not all tumors respond to immunotherapies. These tumors often exhibit reduced inflammation and are resistant to checkpoint inhibitors. Therapies that turn these 'cold' tumors 'hot' could improve the efficacy and applicability of checkpoint inhibitors, and in some cases may be sufficient on their own to promote anti-tumor immunity. One strategy to accomplish this goal is to activate innate immunity pathways within the tumor. Here we describe how this can be accomplished by activating double-stranded RNA (dsRNA) sensors. These sensors evolved to detect and respond to dsRNAs arising from viral infection but can also be activated by endogenous dsRNAs. A set of proteins, referred to as suppressors of dsRNA sensing, are responsible for preventing sensing 'self' dsRNA and activating innate immunity pathways. The mechanism of action of these suppressors falls into three categories: (1) Suppressors that affect mature RNAs through editing, degradation, restructuring, or binding. (2) Suppressors that affect RNA processing. (3) Suppressors that affect RNA expression. In this review we highlight suppressors that function through each mechanism, provide examples of the effects of disrupting those suppressors in cancer cell lines and tumors, and discuss the therapeutic potential of targeting these proteins and pathways.


Assuntos
Imunidade Inata , Neoplasias , RNA de Cadeia Dupla , Humanos , RNA de Cadeia Dupla/metabolismo , Neoplasias/terapia , Neoplasias/metabolismo , Animais , Imunoterapia/métodos
8.
J Exp Biol ; 227(12)2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38887874

RESUMO

When you take the time to observe another organism, there is a sort of gravity that can take hold, a mixture of curiosity and connection that expands and strengthens the more you interact with that organism. Yet, in research, a connection with one's study organism can, at times, feel countercultural. Study organisms are sometimes viewed more as tools to conveniently study biological questions. Here, we explicitly highlight the importance of organism-centered research not only in scientific discovery, but also in conservation and in the communication and perception of science.


Assuntos
Gravitação , Animais , Biologia/métodos
9.
AIDS Behav ; 28(10): 3465-3482, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38995442

RESUMO

Research has found that helping others facilitates well-being for Indigenous peoples living with HIV and AIDS, but limited research exists that investigates the mechanism(s) underlying this relationship. Indigenous perspectives posit that helping others facilitates well-being through the development of an individual's spiritual, physical, emotional, and mental aspects (four aspects). Similarly, self-determination theory posits that helping others facilitates well-being by satisfying basic psychological needs. In the present study, we examined if helping others facilitates well-being through the fulfillment of the spiritual, physical, emotional, and mental aspects among Indigenous peoples living with HIV and AIDS. We used a convergent parallel mixed methods design, coupled with a community-engaged approach grounded in the United Nations Greater Involvement of People Living with HIV and AIDS principles and Indigenous and decolonizing research methodologies. Survey (n = 117) and interview data (n = 9) collected by an Indigenous-led HIV/AIDS organization in Canada were employed to examine the relationship between helping, the four aspects, and well-being. Participants were primarily First Nations leaders and mentors who live with HIV/AIDS, with some Métis and Inuit. A parallel multiple mediation model and reflexive thematic analysis were used to analyze the relationship between helping, the four aspects, and well-being. Mixed-methods findings support the idea that helping others promotes well-being by fulfilling the emotional and mental aspects. Qualitative findings demonstrated this relationship for all four aspects. This research may facilitate the development of programs to support Indigenous peoples living with HIV/AIDS well-being and contribute to the literature on integrating Indigenous perspectives and methodologies within psychological research.


Assuntos
Infecções por HIV , Canadenses Indígenas , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canadá/epidemiologia , Comportamento de Ajuda , Infecções por HIV/psicologia , Infecções por HIV/etnologia , Canadenses Indígenas/psicologia , Entrevistas como Assunto , Pesquisa Qualitativa , Apoio Social , Espiritualidade , Inquéritos e Questionários
10.
J Hered ; 115(5): 487-497, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38722259

RESUMO

We present genome assemblies for 18 snake species representing 18 families (Serpentes: Caenophidia): Acrochordus granulatus, Aparallactus werneri, Boaedon fuliginosus, Calamaria suluensis, Cerberus rynchops, Grayia smithii, Imantodes cenchoa, Mimophis mahfalensis, Oxyrhabdium leporinum, Pareas carinatus, Psammodynastes pulverulentus, Pseudoxenodon macrops, Pseudoxyrhopus heterurus, Sibynophis collaris, Stegonotus admiraltiensis, Toxicocalamus goodenoughensis, Trimeresurus albolabris, and Tropidonophis doriae. From these new genome assemblies, we extracted thousands of loci commonly used in systematic and phylogenomic studies on snakes, including target-capture datasets composed of ultraconserved elements (UCEs) and anchored hybrid enriched loci (AHEs), as well as traditional Sanger loci. Phylogenies inferred from the two target-capture loci datasets were identical with each other and strongly congruent with previously published snake phylogenies. To show the additional utility of these non-model genomes for investigative evolutionary research, we mined the genome assemblies of two New Guinea island endemics in our dataset (S. admiraltiensis and T. doriae) for the ATP1a3 gene, a thoroughly researched indicator of resistance to toad toxin ingestion by squamates. We find that both these snakes possess the genotype for toad toxin resistance despite their endemism to New Guinea, a region absent of any toads until the human-mediated introduction of Cane Toads in the 1930s. These species possess identical substitutions that suggest the same bufotoxin resistance as their Australian congenerics (Stegonotus australis and Tropidonophis mairii) which forage on invasive Cane Toads. Herein, we show the utility of short-read high-coverage genomes, as well as improving the deficit of available squamate genomes with associated voucher specimens.


Assuntos
Genoma , Filogenia , Serpentes , Animais , Serpentes/genética , Serpentes/classificação , Colubridae/genética , Colubridae/classificação
11.
Brain Behav Evol ; 99(1): 13-24, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38368854

RESUMO

INTRODUCTION: Domestication is the process of modifying animals for human benefit through selective breeding in captivity. One of the traits that often diverges is the size of the brain and its constituent regions; almost all domesticated species have relatively smaller brains and brain regions than their wild ancestors. Although the effects of domestication on the brain have been investigated across a range of both mammal and bird species, almost nothing is known about the neuroanatomical effects of domestication on the world's most common bird: the chicken (Gallus gallus). METHODS: We compared the quantitative neuroanatomy of the telencephalon of white leghorn chickens with red junglefowl, their wild counterpart, and several wild galliform species. We focused specifically on the telencephalon because telencephalic regions typically exhibit the biggest differences in size in domesticate-wild comparisons. RESULTS: Relative telencephalon size was larger in chickens than in junglefowl and ruffed grouse (Bonasa umbellus). The relative size of telencephalic regions did not differ between chickens and junglefowl, but did differ in comparison with ruffed grouse. Ruffed grouse had larger hyperpallia and smaller entopallial, nidopallial, and striatal volumes than chickens and junglefowl. Multivariate analyses that included an additional three wild grouse species corroborated these findings: chicken and junglefowl have relatively larger nidopallial and striatal volumes than grouse. Conversely, the mesopallial and hyperpallial volumes tended to be relatively smaller in chickens and junglefowl. CONCLUSION: From this suite of comparisons, we conclude that chickens do not follow a pattern of widespread decreases in telencephalic region sizes that is often viewed as typical of domestication. Instead, chickens have undergone a mosaic of changes with some regions increasing and others decreasing in size, and there are few differences between chickens and junglefowl.


Assuntos
Galinhas , Galliformes , Telencéfalo , Animais , Telencéfalo/anatomia & histologia , Galinhas/anatomia & histologia , Galliformes/anatomia & histologia , Especificidade da Espécie , Masculino , Feminino , Tamanho do Órgão , Animais Selvagens/anatomia & histologia , Domesticação
12.
Dev Psychobiol ; 66(2): e22456, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38388195

RESUMO

Reduced play experience over the juvenile period leads to adults with impoverished social skills and to anatomical and physiological aberrations of the neurons found in the medial prefrontal cortex (mPFC). Even rearing rats from high-playing strains with low-playing strains show these developmental consequences. In the present study, we evaluated whether low-playing rats benefit from being reared with higher playing peers. To test this, we reared male Fischer 344 rats (F344), typically thought to be a low-playing strain, with a Long-Evans (LE) peer, a relatively high-playing strain. As juveniles, F344 rats reared with LE rats experienced less play and lower quality play compared to those reared with another F344. As adults, the F344 rats reared with LE partners exhibited poorer social skills and the pyramidal neurons of their mPFC had larger dendritic arbors than F344 rats reared with same-strain peers. These findings show that being reared with a more playful partner does not improve developmental outcomes of F344 rats, rather the discordance in the play styles of F344 and LE rats leads to poorer outcomes.


Assuntos
Neurônios , Córtex Pré-Frontal , Ratos , Animais , Masculino , Ratos Endogâmicos F344 , Ratos Long-Evans , Córtex Pré-Frontal/fisiologia
13.
Occup Med (Lond) ; 74(7): 501-507, 2024 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-39129359

RESUMO

BACKGROUND: The veterinary workplace carries a high risk of staff accidents and injuries, yet there is scant research exploring it in comparison with other comparable fields, such as human medicine. AIMS: To understand how veterinary professionals define injuries and to understand what injuries they do, or do not, deem reportable. METHODS: A cross-sectional survey comprising demographic questions and open-text questions was shared with veterinary practice staff across the UK. Data were analysed descriptively and using an inductive content analysis. RESULTS: There were 740 respondents, who were broadly representative of the veterinary profession. There were differences in how injuries were defined; for example, small animal veterinarians expected injuries to involve blood, while equine and production animal veterinarians were more likely to expect injuries to reduce their ability to perform work and require medical treatment. Many suggested that 'all' workplace injuries should be reported; however, 'minor' injuries were often overlooked, for example, needlestick injuries did not always meet the criteria of being an 'injury'. Injuries caused by staff themselves (e.g. trips) were less likely to be reported than injuries that could be blamed on an external factor (e.g. dog bite). CONCLUSIONS: Collectively, the data suggest a wide-ranging perception of risk of injury in practice, with some harms seen as 'everyday norms'. Veterinary practices should interpret their injury statistics with a high degree of caution. They should explore the microcultures within their practices relating to worker perception of risk, injury and barriers to reporting.


Assuntos
Traumatismos Ocupacionais , Médicos Veterinários , Local de Trabalho , Humanos , Estudos Transversais , Traumatismos Ocupacionais/epidemiologia , Médicos Veterinários/estatística & dados numéricos , Local de Trabalho/normas , Inquéritos e Questionários , Feminino , Reino Unido/epidemiologia , Masculino , Adulto , Acidentes de Trabalho/estatística & dados numéricos , Pessoa de Meia-Idade , Animais , Dor/etiologia
14.
Dev Biol ; 481: 75-94, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34597675

RESUMO

While the epithelial cell cortex displays profound asymmetries in protein distribution and morphology along the apico-basal axis, the extent to which the cytoplasm is similarly polarized within epithelial cells remains relatively unexplored. We show that cytoplasmic organelles within C. elegans embryonic intestinal cells develop extensive apico-basal polarity at the time they establish cortical asymmetry. Nuclei and conventional endosomes, including early endosomes, late endosomes, and lysosomes, become polarized apically. Lysosome-related gut granules, yolk platelets, and lipid droplets become basally enriched. Removal of par-3 activity does not disrupt organelle positioning, indicating that cytoplasmic apico-basal asymmetry is independent of the PAR polarity pathway. Blocking the apical migration of nuclei leads to the apical positioning of gut granules and yolk platelets, whereas the asymmetric localization of conventional endosomes and lipid droplets is unaltered. This suggests that nuclear positioning organizes some, but not all, cytoplasmic asymmetries in this cell type. We show that gut granules become apically enriched when WHT-2 and WHT-7 function is disrupted, identifying a novel role for ABCG transporters in gut granule positioning during epithelial polarization. Analysis of WHT-2 and WHT-7 ATPase mutants is consistent with a WHT-2/WHT-7 heterodimer acting as a transporter in gut granule positioning. In wht-2(-) mutants, the polarized distribution of other organelles is not altered and gut granules do not take on characteristics of conventional endosomes that could have explained their apical mispositioning. During epithelial polarization wht-2(-) gut granules exhibit a loss of the Rab32/38 family member GLO-1 and ectopic expression of GLO-1 is sufficient to rescue the basal positioning of wht-2(-) and wht-7(-) gut granules. Furthermore, depletion of GLO-1 causes the mislocalization of the endolysosomal RAB-7 to gut granules and RAB-7 drives the apical mispositioning of gut granules when GLO-1, WHT-2, or WHT-7 function is disrupted. We suggest that ABC transporters residing on gut granules can regulate Rab dynamics to control organelle positioning during epithelial polarization.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Polaridade Celular , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Organelas/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Organelas/genética
15.
J Biol Chem ; 298(10): 102407, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35988653

RESUMO

Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd). Although intracellular concentrations of N8-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor growth both locally and at distant sites. However, the contribution of N8-AcSpd in this context is unknown. We hypothesized that HDAC10, by converting N8- AcSpd to spermidine, may provide a source of this growth-supporting polyamine in circumstances of reduced polyamine biosynthesis, such as in polyamine-targeting anticancer therapies. Inhibitors of polyamine biosynthesis, including α-difluoromethylornithine (DFMO), inhibit tumor growth, but compensatory uptake of extracellular polyamines has limited their clinical success. Combining DFMO with inhibitors of polyamine uptake have improved the antitumor response. However, acetylated polyamines may use different transport machinery than the parent molecules. Here, we use CRISPR/Cas9-mediated HDAC10-knockout cell lines and HDAC10-specific inhibitors to investigate the contribution of HDAC10 in maintaining tumor cell proliferation. We demonstrate inhibition of cell growth by DFMO-associated polyamine depletion is successfully rescued by exogenous N8-AcSpd (at physiological concentrations), which is converted to spermidine and spermine, only in cell lines with HDAC10 activity. Furthermore, we show loss of HDAC10 prevents both restoration of polyamine levels and growth rescue, implicating HDAC10 in supporting polyamine-associated tumor growth. These data suggest the utility of HDAC10-specific inhibitors as an antitumor strategy that may have value in improving the response to polyamine-blocking therapies. Additionally, the cell-based assay developed in this study provides an inexpensive, high-throughput method of screening potentially selective HDAC10 inhibitors.


Assuntos
Inibidores de Histona Desacetilases , Neoplasias , Espermidina , Humanos , Proliferação de Células , Eflornitina/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Homeostase , Neoplasias/metabolismo , Neoplasias/patologia , Espermidina/antagonistas & inibidores , Espermidina/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia
16.
Phys Rev Lett ; 131(17): 171602, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37955511

RESUMO

We propose a mechanism that couples matter fields to three-dimensional quantum gravity, which can be used for theories with a positive or negative cosmological constant. Our proposal is rooted in the Chern-Simons formulation of three-dimensional gravity and makes use of the Wilson spool, a collection of Wilson loops winding around closed paths of the background. We show that the Wilson spool correctly reproduces the one-loop determinant of a free massive scalar field on rotating black holes in AdS_{3} and Euclidean dS_{3} as G_{N}→0. Moreover, we describe how to incorporate quantum metric fluctuations into this formalism.

17.
J Shoulder Elbow Surg ; 32(3): 512-518, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36283564

RESUMO

BACKGROUND: The use of electrocautery to facilitate passage of a suture needle through bone without the aid of a drill or burr is a novel technique that has potential utility in orthopedic procedures, but there is a scarcity of research to support its utility. The specific aims of this cadaveric biomechanical study were to evaluate (1) the axial force reduction during suture passage using electrocautery when applied to rotator cuff repair, (2) the temperature change caused while using electrocautery, and (3) the failure loads and failure modes of this technique. METHODS: Five matched pairs of fresh frozen humeri were used, classified into 2 groups: with electrocautery on needle (study group) and without electrocautery on needle (control group). Four individual osseous tunnels were made on the greater tuberosity around the insertion of the supraspinatus tendon. Each specimen was sequentially tested in 2 parts: a needle penetration test (part I) to measure the peak axial force and temperature change and a single load-to-failure test (part II) to measure the maximum load to failure as well as the mechanism of failure. A No. 2 FiberWire suture with a straight needle was used. RESULTS: In part I, the mean peak axial force was lower in the study group compared with the control group for all osseous tunnels but was not statistically significant for individual tunnels. However, there was a significant decrease in peak axial force in the study group of 36% compared with the control group overall (P = .033). There was no significant change in temperature of the tunnel site with the use of electrocautery (mean: 0.2 ± 0.3°C, P = .435). In part II, 100% of the samples from each study group experienced bone tunnel failure. Forty percent of the trials in the study group found lower ultimate failure loads compared with the control group (reduction range: 7%-38%). There was no statistically significant difference in the ultimate failure load between either the loop tested or between the 2 study groups (loop 1: P = .352; loop 2: P = .270). CONCLUSION: Suture passage using electrocautery does significantly decrease the peak force needed to pass a needle directly through the greater tuberosity. This technique does not appear to burn the bone or weaken the bone tunnels. This technique may be useful during open rotator cuff repair or shoulder arthroplasty, although clinicians should be cautious when using this technique as its utility depends on bone quality and cortical thickness, and in vivo results may differ.


Assuntos
Lesões do Manguito Rotador , Manguito Rotador , Humanos , Fenômenos Biomecânicos , Cadáver , Manguito Rotador/cirurgia , Lesões do Manguito Rotador/cirurgia , Eletrocoagulação , Suturas , Técnicas de Sutura , Âncoras de Sutura
18.
Molecules ; 28(11)2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37298941

RESUMO

Pain is one of the most prevalent and difficult to manage symptoms in cancer patients, and conventional drugs present a range of adverse reactions. The development of ß-cyclodextrins (ß-CD) complexes has been used to avoid physicochemical and pharmacological limitations due to the lipophilicity of compounds such as p-Cymene (PC), a monoterpene with antinociceptive effects. Our aim was to obtain, characterize, and measure the effect of the complex of p-cymene and ß-cyclodextrin (PC/ß-CD) in a cancer pain model. Initially, molecular docking was performed to predict the viability of complex formation. Afterward, PC/ß-CD was obtained by slurry complexation, characterized by HPLC and NMR. Finally, PC/ß-CD was tested in a Sarcoma 180 (S180)-induced pain model. Molecular docking indicated that the occurrence of interaction between PC and ß-CD is favorable. PC/ß-CD showed complexation efficiency of 82.61%, and NMR demonstrated PC complexation in the ß-CD cavity. In the S180 cancer pain model, PC/ß-CD significantly reduced the mechanical hyperalgesia, spontaneous nociception, and nociception induced by non-noxious palpation at the doses tested (p < 0.05) when compared to vehicle differently from free PC (p > 0.05). Therefore, the complexation of PC in ß-CD was shown to improve the pharmacological effect of the drug as well as reducing the required dose.


Assuntos
Dor do Câncer , Ciclodextrinas , Neoplasias , beta-Ciclodextrinas , Humanos , Camundongos , Animais , Simulação de Acoplamento Molecular , beta-Ciclodextrinas/química , Dor/tratamento farmacológico , Dor/etiologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos/química , Solubilidade
19.
Zoo Biol ; 42(6): 730-743, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37283079

RESUMO

Belugas (Delphinapterus leucas) engage in many forms of play (e.g., object, water, locomotor), but no play is quite as curious as the unusual form of cooperative social play involving mouth-to-mouth interactions. These playful interactions are characterized by two belugas approaching each other head-to-head and interlocking their jaws, clasping one another, as if they were shaking hands. Observed in belugas both in the wild and in managed care, it is seemingly an important type of social play that offers a unique way of socializing with conspecifics. To describe this unusual behavior, a group of belugas in managed care was observed from 2007 to 2019. Although adults participated in mouth-to-mouth interactions, most were initiated and received by young belugas. Both males and females engaged in mouth-to-mouth interactions and did so at similar frequencies. Individual differences in how many mouth-to-mouth interactions were initiated among calves were also observed. Due to the unique, cooperative nature of mouth-to-mouth interactions, which require both social and motor skills, it is hypothesized that these interactions may be used to test social and motor competency.


Assuntos
Beluga , Masculino , Feminino , Animais , Bovinos , Animais de Zoológico , Boca , Programas de Assistência Gerenciada
20.
J Am Chem Soc ; 144(39): 17737-17742, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36165690

RESUMO

We report, for the first time, highly crystalline cyanurate-linked covalent organic frameworks synthesized via dynamic nucleophilic aromatic substitution. The high crystallinity is enabled by the bond exchange reaction (self-correction) between 2,4,6-triphenoxy-1,3,5-triazine and diphenols via reversible SNAr catalyzed by triazabicyclodecene. The CN-COFs contain flexible backbones that exhibit a unique AA'-stacking due to interlayer hydrogen bonding interactions. The isoreticular expansion study demonstrates the general applicability of this synthetic method. The resulting CN-COFs exhibited good stability, as well as high CO2/N2 selectivity.


Assuntos
Estruturas Metalorgânicas , Dióxido de Carbono , Triazinas
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