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1.
Cell ; 185(19): 3568-3587.e27, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36113428

RESUMO

Computational analysis of cellular activity has developed largely independently of modern transcriptomic cell typology, but integrating these approaches may be essential for full insight into cellular-level mechanisms underlying brain function and dysfunction. Applying this approach to the habenula (a structure with diverse, intermingled molecular, anatomical, and computational features), we identified encoding of reward-predictive cues and reward outcomes in distinct genetically defined neural populations, including TH+ cells and Tac1+ cells. Data from genetically targeted recordings were used to train an optimized nonlinear dynamical systems model and revealed activity dynamics consistent with a line attractor. High-density, cell-type-specific electrophysiological recordings and optogenetic perturbation provided supporting evidence for this model. Reverse-engineering predicted how Tac1+ cells might integrate reward history, which was complemented by in vivo experimentation. This integrated approach describes a process by which data-driven computational models of population activity can generate and frame actionable hypotheses for cell-type-specific investigation in biological systems.


Assuntos
Habenula , Recompensa , Dinâmica Populacional
2.
Cell ; 181(2): 396-409.e26, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32220308

RESUMO

Decades after the motor homunculus was first proposed, it is still unknown how different body parts are intermixed and interrelated in human motor cortical areas at single-neuron resolution. Using multi-unit recordings, we studied how face, head, arm, and leg movements are represented in the hand knob area of premotor cortex (precentral gyrus) in people with tetraplegia. Contrary to traditional expectations, we found strong representation of all movements and a partially "compositional" neural code that linked together all four limbs. The code consisted of (1) a limb-coding component representing the limb to be moved and (2) a movement-coding component where analogous movements from each limb (e.g., hand grasp and toe curl) were represented similarly. Compositional coding might facilitate skill transfer across limbs, and it provides a useful framework for thinking about how the motor system constructs movement. Finally, we leveraged these results to create a whole-body intracortical brain-computer interface that spreads targets across all limbs.


Assuntos
Lobo Frontal/fisiologia , Córtex Motor/anatomia & histologia , Córtex Motor/fisiologia , Adulto , Mapeamento Encefálico , Lobo Frontal/anatomia & histologia , Corpo Humano , Humanos , Córtex Motor/metabolismo , Movimento/fisiologia
3.
Mol Cell ; 82(7): 1261-1277.e9, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-35305311

RESUMO

The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.


Assuntos
Glucose , Hexoquinase/metabolismo , Animais , Glucose/metabolismo , Glicólise , Hexoquinase/genética , Camundongos , Mitocôndrias/metabolismo , Via de Pentose Fosfato
4.
Nat Rev Neurosci ; 25(4): 213-236, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38443626

RESUMO

The study of the cortical control of movement experienced a conceptual shift over recent decades, as the basic currency of understanding shifted from single-neuron tuning towards population-level factors and their dynamics. This transition was informed by a maturing understanding of recurrent networks, where mechanism is often characterized in terms of population-level factors. By estimating factors from data, experimenters could test network-inspired hypotheses. Central to such hypotheses are 'output-null' factors that do not directly drive motor outputs yet are essential to the overall computation. In this Review, we highlight how the hypothesis of output-null factors was motivated by the venerable observation that motor-cortex neurons are active during movement preparation, well before movement begins. We discuss how output-null factors then became similarly central to understanding neural activity during movement. We discuss how this conceptual framework provided key analysis tools, making it possible for experimenters to address long-standing questions regarding motor control. We highlight an intriguing trend: as experimental and theoretical discoveries accumulate, the range of computational roles hypothesized to be subserved by output-null factors continues to expand.


Assuntos
Córtex Motor , Humanos , Córtex Motor/fisiologia , Movimento/fisiologia , Neurônios/fisiologia
5.
Nature ; 620(7976): 1031-1036, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37612500

RESUMO

Speech brain-computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speech into text1,2 or sound3,4. Early demonstrations, although promising, have not yet achieved accuracies sufficiently high for communication of unconstrained sentences from a large vocabulary1-7. Here we demonstrate a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant-who can no longer speak intelligibly owing to amyotrophic lateral sclerosis-achieved a 9.1% word error rate on a 50-word vocabulary (2.7 times fewer errors than the previous state-of-the-art speech BCI2) and a 23.8% word error rate on a 125,000-word vocabulary (the first successful demonstration, to our knowledge, of large-vocabulary decoding). Our participant's attempted speech was decoded  at 62 words per minute, which is 3.4 times as fast as the previous record8 and begins to approach the speed of natural conversation (160 words per minute9). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for restoring rapid communication to people with paralysis who can no longer speak.


Assuntos
Interfaces Cérebro-Computador , Próteses Neurais , Paralisia , Fala , Humanos , Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/reabilitação , Córtex Cerebral/fisiologia , Microeletrodos , Paralisia/fisiopatologia , Paralisia/reabilitação , Vocabulário
6.
Annu Rev Neurosci ; 43: 249-275, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32640928

RESUMO

Significant experimental, computational, and theoretical work has identified rich structure within the coordinated activity of interconnected neural populations. An emerging challenge now is to uncover the nature of the associated computations, how they are implemented, and what role they play in driving behavior. We term this computation through neural population dynamics. If successful, this framework will reveal general motifs of neural population activity and quantitatively describe how neural population dynamics implement computations necessary for driving goal-directed behavior. Here, we start with a mathematical primer on dynamical systems theory and analytical tools necessary to apply this perspective to experimental data. Next, we highlight some recent discoveries resulting from successful application of dynamical systems. We focus on studies spanning motor control, timing, decision-making, and working memory. Finally, we briefly discuss promising recent lines of investigation and future directions for the computation through neural population dynamics framework.


Assuntos
Encéfalo/fisiologia , Biologia Computacional , Aprendizado Profundo , Rede Nervosa/fisiologia , Animais , Biologia Computacional/métodos , Humanos , Neurônios/fisiologia , Dinâmica Populacional
7.
Nature ; 602(7896): 274-279, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35082444

RESUMO

The brain's remarkable ability to learn and execute various motor behaviours harnesses the capacity of neural populations to generate a variety of activity patterns. Here we explore systematic changes in preparatory activity in motor cortex that accompany motor learning. We trained rhesus monkeys to learn an arm-reaching task1 in a curl force field that elicited new muscle forces for some, but not all, movement directions2,3. We found that in a neural subspace predictive of hand forces, changes in preparatory activity tracked the learned behavioural modifications and reassociated4 existing activity patterns with updated movements. Along a neural population dimension orthogonal to the force-predictive subspace, we discovered that preparatory activity shifted uniformly for all movement directions, including those unaltered by learning. During a washout period when the curl field was removed, preparatory activity gradually reverted in the force-predictive subspace, but the uniform shift persisted. These persistent preparatory activity patterns may retain a motor memory of the learned field5,6 and support accelerated relearning of the same curl field. When a set of distinct curl fields was learned in sequence, we observed a corresponding set of field-specific uniform shifts which separated the associated motor memories in the neural state space7-9. The precise geometry of these uniform shifts in preparatory activity could serve to index motor memories, facilitating the acquisition, retention and retrieval of a broad motor repertoire.


Assuntos
Aprendizagem , Córtex Motor , Destreza Motora , Animais , Aprendizagem/fisiologia , Macaca mulatta/fisiologia , Córtex Motor/fisiologia , Destreza Motora/fisiologia , Movimento/fisiologia , Músculo Esquelético/fisiologia
8.
Nature ; 593(7858): 249-254, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33981047

RESUMO

Brain-computer interfaces (BCIs) can restore communication to people who have lost the ability to move or speak. So far, a major focus of BCI research has been on restoring gross motor skills, such as reaching and grasping1-5 or point-and-click typing with a computer cursor6,7. However, rapid sequences of highly dexterous behaviours, such as handwriting or touch typing, might enable faster rates of communication. Here we developed an intracortical BCI that decodes attempted handwriting movements from neural activity in the motor cortex and translates it to text in real time, using a recurrent neural network decoding approach. With this BCI, our study participant, whose hand was paralysed from spinal cord injury, achieved typing speeds of 90 characters per minute with 94.1% raw accuracy online, and greater than 99% accuracy offline with a general-purpose autocorrect. To our knowledge, these typing speeds exceed those reported for any other BCI, and are comparable to typical smartphone typing speeds of individuals in the age group of our participant (115 characters per minute)8. Finally, theoretical considerations explain why temporally complex movements, such as handwriting, may be fundamentally easier to decode than point-to-point movements. Our results open a new approach for BCIs and demonstrate the feasibility of accurately decoding rapid, dexterous movements years after paralysis.


Assuntos
Interfaces Cérebro-Computador , Encéfalo/fisiologia , Comunicação , Escrita Manual , Humanos , Redes Neurais de Computação , Traumatismos da Medula Espinal , Fatores de Tempo
9.
Nature ; 591(7851): 604-609, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33473215

RESUMO

In dynamic environments, subjects often integrate multiple samples of a signal and combine them to reach a categorical judgment1. The process of deliberation can be described by a time-varying decision variable (DV), decoded from neural population activity, that predicts a subject's upcoming decision2. Within single trials, however, there are large moment-to-moment fluctuations in the DV, the behavioural significance of which is unclear. Here, using real-time, neural feedback control of stimulus duration, we show that within-trial DV fluctuations, decoded from motor cortex, are tightly linked to decision state in macaques, predicting behavioural choices substantially better than the condition-averaged DV or the visual stimulus alone. Furthermore, robust changes in DV sign have the statistical regularities expected from behavioural studies of changes of mind3. Probing the decision process on single trials with weak stimulus pulses, we find evidence for time-varying absorbing decision bounds, enabling us to distinguish between specific models of decision making.


Assuntos
Tomada de Decisões/fisiologia , Modelos Neurológicos , Animais , Comportamento de Escolha/fisiologia , Discriminação Psicológica , Julgamento , Macaca/fisiologia , Movimento (Física) , Percepção de Movimento , Estimulação Luminosa , Fatores de Tempo
10.
BMC Biol ; 22(1): 108, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714997

RESUMO

BACKGROUND: Populations of the plant pathogenic fungus Verticillium dahliae display a complex and rich genetic diversity, yet the existence of sexual reproduction in the fungus remains contested. As pivotal genes, MAT genes play a crucial role in regulating cell differentiation, morphological development, and mating of compatible cells. However, the functions of the two mating type genes in V. dahliae, VdMAT1-1-1, and VdMAT1-2-1, remain poorly understood. RESULTS: In this study, we confirmed that the MAT loci in V. dahliae are highly conserved, including both VdMAT1-1-1 and VdMAT1-2-1 which share high collinearity. The conserved core transcription factor encoded by the two MAT loci may facilitate the regulation of pheromone precursor and pheromone receptor genes by directly binding to their promoter regions. Additionally, peptide activity assays demonstrated that the signal peptide of the pheromone VdPpg1 possessed secretory activity, while VdPpg2, lacked a predicted signal peptide. Chemotactic growth assays revealed that V. dahliae senses and grows towards the pheromones FO-a and FO-α of Fusarium oxysporum, as well as towards VdPpg2 of V. dahliae, but not in response to VdPpg1. The findings herein also revealed that VdMAT1-1-1 and VdMAT1-2-1 regulate vegetative growth, carbon source utilization, and resistance to stressors in V. dahliae, while negatively regulating virulence. CONCLUSIONS: These findings underscore the potential roles of VdMAT1-1-1 and VdMAT1-2-1 in sexual reproduction and confirm their involvement in various asexual processes of V. dahliae, offering novel insights into the functions of mating type genes in this species.


Assuntos
Genes Fúngicos Tipo Acasalamento , Genes Fúngicos Tipo Acasalamento/genética , Ascomicetos/genética , Ascomicetos/fisiologia , Feromônios/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Verticillium
11.
Phytopathology ; 114(1): 61-72, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37530500

RESUMO

Endophytes play important roles in promoting plant growth and controlling plant diseases. Verticillium wilt is a vascular wilt disease caused by Verticillium dahliae, a widely distributed soilborne pathogen that causes significant economic losses on cotton each year. In this study, an endophyte KRS015, isolated from the seed of the Verticillium wilt-resistant Gossypium hirsutum 'Zhongzhimian No. 2', was identified as Bacillus subtilis by morphological, phylogenetic, physiological, and biochemical analyses. The volatile organic compounds (VOCs) produced by KRS015 or its cell-free fermentation extract had significant antagonistic effects on various pathogenic fungi, including V. dahliae. KRS015 reduced Verticillium wilt index and colonization of V. dahliae in treated cotton seedlings significantly; the disease reduction rate was ∼62%. KRS015 also promoted plant growth, potentially mediated by the growth-related cotton genes GhACL5 and GhCPD-3. The cell-free fermentation extract of KRS015 triggered a hypersensitivity response, including reactive oxygen species (ROS) and expression of resistance-related plant genes. VOCs from KRS015 also inhibited germination of conidia and the mycelial growth of V. dahliae, and were mediated by growth and development-related genes such as VdHapX, VdMcm1, Vdpf, and Vel1. These results suggest that KRS015 is a potential agent for controlling Verticillium wilt and promoting growth of cotton.


Assuntos
Acremonium , Ascomicetos , Verticillium , Bacillus subtilis/genética , Filogenia , Doenças das Plantas/microbiologia , Verticillium/fisiologia , Gossypium/genética , Extratos Vegetais , Resistência à Doença/fisiologia , Regulação da Expressão Gênica de Plantas
12.
BMC Biol ; 21(1): 166, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37542270

RESUMO

BACKGROUND: The extracellular space between the cell wall and plasma membrane is a battlefield in plant-pathogen interactions. Within this space, the pathogen employs its secretome to attack the host in a variety of ways, including immunity manipulation. However, the role of the plant secretome is rarely studied for its role in disease resistance. RESULTS: Here, we examined the secretome of Verticillium wilt-resistant Gossypium hirsutum cultivar Zhongzhimian No.2 (ZZM2, encoding 95,327 predicted coding sequences) to determine its role in disease resistance against the wilt causal agent, Verticillium dahliae. Bioinformatics-driven analyses showed that the ZZM2 genome encodes 2085 secreted proteins and that these display disequilibrium in their distribution among the chromosomes. The cotton secretome displayed differences in the abundance of certain amino acid residues as compared to the remaining encoded proteins due to the localization of these putative proteins in the extracellular space. The secretome analysis revealed conservation for an allotetraploid genome, which nevertheless exhibited variation among orthologs and comparable unique genes between the two sub-genomes. Secretome annotation strongly suggested its involvement in extracellular stress responses (hydrolase activity, oxidoreductase activity, and extracellular region, etc.), thus contributing to resistance against the V. dahliae infection. Furthermore, the defense response genes (immunity marker NbHIN1, salicylic acid marker NbPR1, and jasmonic acid marker NbLOX4) were activated to varying degrees when Nicotina benthamiana leaves were agro-infiltrated with 28 randomly selected members, suggesting that the secretome plays an important role in the immunity response. Finally, gene silencing assays of 11 members from 13 selected candidates in ZZM2 displayed higher susceptibility to V. dahliae, suggesting that the secretome members confer the Verticillium wilt resistance in cotton. CONCLUSIONS: Our data demonstrate that the cotton secretome plays an important role in Verticillium wilt resistance, facilitating the development of the resistance gene markers and increasing the understanding of the mechanisms regulating disease resistance.


Assuntos
Ascomicetos , Verticillium , Gossypium/genética , Resistência à Doença/genética , Secretoma , Verticillium/metabolismo , Doenças das Plantas/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
13.
BMC Biol ; 21(1): 237, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37904147

RESUMO

BACKGROUND: Melanin plays important roles in morphological development, survival, host-pathogen interactions and in the virulence of phytopathogenic fungi. In Verticillum dahliae, increases in melanin are recognized as markers of maturation of microsclerotia which ensures the long-term survival and stress tolerance, while decreases in melanin are correlated with increased hyphal growth in the host. The conserved upstream components of the VdCmr1-regulated pathway controlling melanin production in V. dahliae have been extensively identified, but the direct activators of this pathway are still unclear. RESULTS: We identified two genes encoding conserved C2H2-type zinc finger proteins VdZFP1 and VdZFP2 adjacent to VdPKS9, a gene encoding a negative regulator of both melanin biosynthesis and microsclerotia formation in V. dahliae. Both VdZFP1 and VdZFP2 were induced during microsclerotia development and were involved in melanin deposition. Their localization changed from cytoplasmic to nuclear in response to osmotic pressure. VdZFP1 and VdZFP2 act as modulators of microsclerotia melanization in V. dahliae, as confirmed by melanin biosynthesis inhibition and supplementation with the melanin pathway intermediate scytalone in albino strains. The results indicate that VdZFP1 and VdZFP2 participate in melanin biosynthesis by positively regulating VdCmr1. Based on the results obtained with yeast one- and two-hybrid (Y1H and Y2H) and bimolecular fluorescence complementation (BiFC) systems, we determined the melanin biosynthesis relies on the direct interactions among VdZFP1, VdZFP2 and VdCmr1, and these interactions occur on the cell walls of microsclerotia. Additionally, VdZFP1 and/or VdZFP2 mutants displayed increased sensitivity to stress factors rather than alterations in pathogenicity, reflecting the importance of melanin in stress tolerance of V. dahliae. CONCLUSIONS: Our results revealed that VdZFP1 and VdZFP2 positively regulate VdCmr1 to promote melanin deposition during microsclerotia development, providing novel insight into the regulation of melanin biosynthesis in V. dahliae.


Assuntos
Ascomicetos , Verticillium , Melaninas , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Verticillium/genética , Dedos de Zinco , Doenças das Plantas/microbiologia
14.
Plant Dis ; : PDIS01240193RE, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38506911

RESUMO

Verticillium wilt, caused by Verticillium dahliae, is one of the most devastating soilborne diseases of lettuce (Lactuca sativa L.). There are three races of V. dahliae, and each race has been characterized by markers representing race-specific effectors. Race 1 is differentiated by the presence of the functional secretory Ave1 effector. Similarly, races 2 and 3 are differentiated by effectors VdR2e and VdR3e, respectively. Although the presence of race 1 in coastal California was well established, the presence of effector-based races 2 and 3 was uncertain. This study therefore focused on characterizing 727 isolates collected from 142 ranches of symptomatic lettuce and other crops from coastal California. Based on this evaluation, 523 isolates were designated as race 1, 20 isolates as race 2, 23 isolates as race 3, and 17 as race undefined. Isolates representing other Verticillium species totaled 110, and 34 were non-Verticillium fungal species. Because the use of resistant cultivars is a key strategy to manage this disease, we evaluated 48 lettuce germplasm lines and 1 endive (Cichorium endivia L.) line, comprising commercial cultivars and breeding lines, including the race 1-resistant heirloom cultivar La Brillante and the susceptible cultivar Salinas as controls. Resistance against races 1, 2, and 3 along with VdLs17, a virulent isolate of V. dahliae from lettuce that is currently not assigned to a race, was evaluated in replicated greenhouse experiments. Two crisphead lettuce lines, HL28 and HL29, exhibited resistance against race 1 and a partial resistance against race 2, whereas all other lines were highly susceptible to races 1 and 2 and VdLs17. The majority of lines exhibited higher resistance to race 3 relative to the other two races. This study documents the current distribution of the different races in coastal California. In addition, the sources of resistance currently being developed should be effective or partially effective against these races for targeted deployment as soon as they are available.

15.
J Surg Orthop Adv ; 33(1): 29-32, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38815075

RESUMO

Bracing reduces the need for surgical intervention in patients with adolescent idiopathic scoliosis (AIS). However, bracing outcomes with variable body mass index (BMI) are understudied. The authors sought to determine the association of BMI with bracing outcomes. The authors performed a retrospective cohort study of 104 patients presenting with AIS. Initial Risser score, hours of bracing per day, BMI percentile, and curve magnitude pre- and postbracing were collected. There was no detectable difference between years of brace wear or primary curve magnitude at time of presentation between both groups. Overall, 29% (25/87) of underweight/normal weight patients and 59% (10/17) of overweight/obese patients had curves ≥ 45 degrees at the end of bracing (p = 0.016). Odds of having a curve ≥ 45 degrees after bracing were 3.5 (95% confidence interval: 1.2 to 10.3, p = 0.021) times higher for overweight/obese patients compared with underweight/normal weight patients. Increased overlying adipose tissue may reduce the corrective forces required to straighten the spine. (Journal of Surgical Orthopaedic Advances 33(1):029-032, 2024).


Assuntos
Índice de Massa Corporal , Braquetes , Escoliose , Humanos , Adolescente , Estudos Retrospectivos , Feminino , Masculino , Criança , Resultado do Tratamento , Sobrepeso/complicações , Magreza , Obesidade/complicações
16.
Mol Plant Microbe Interact ; 36(1): 68-72, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36463398

RESUMO

Verticillium wilt, caused by the fungal pathogen Verticillium dahliae, is the major cause of disease-related yield losses in cotton (Gossypium hirsutum). Despite these losses, the major cultivars of G. hirsutum remain highly susceptible to Verticillium wilt. The lack of understanding on the genetic basis for Verticillium wilt resistance may further hinder progress in deploying elite cultivars with proven resistance, such as the wilt resistant G. hirsutum cultivar Zhongzhimian No. 2. To help remedy this knowledge gap, we sequenced the whole genome of Zhongzhimian No. 2 and assembled it from a combination of PacBio long reads, Illumina short reads, and high-throughput chromosome conformation capture technologies. The final assembly of the genome was 2.33 Gb, encoding 95,327 predicted coding sequences. The GC content was 34.39% with 99.2% of the bases anchored to 26 pseudo-chromosomes that ranged from 53.8 to 127.7 Mb. This resource will help gain a detailed understanding of the genomic features governing high yield and Verticillium wilt resistance in this cultivar. Comparative genomics will be particularly helpful, since there are several published genomes of other Gossypium species. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.


Assuntos
Gossypium , Verticillium , Gossypium/microbiologia , Verticillium/genética , Genes de Plantas , Resistência à Doença/genética , Doenças das Plantas/microbiologia , Regulação da Expressão Gênica de Plantas
17.
Blood ; 137(23): 3291-3305, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33657221

RESUMO

Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R- patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.


Assuntos
Ciclofosfamida/efeitos adversos , Infecções por Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Ciclofosfamida/administração & dosagem , Infecções por Citomegalovirus/induzido quimicamente , Infecções por Citomegalovirus/mortalidade , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
18.
Haematologica ; 108(1): 98-109, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35833303

RESUMO

Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis, <2 lines of intervening therapy between CAR T and alloHCT and complete response at time of alloHCT were associated with better outcomes. In conclusion, alloHCT after CAR T failure can provide durable remissions in a subset of patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Estudos Retrospectivos , Recidiva Local de Neoplasia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/etiologia , Transplante Homólogo , Antígenos CD19
19.
Theor Appl Genet ; 136(9): 180, 2023 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-37548768

RESUMO

KEY MESSAGE: GWAS identified 19 QTLs for resistance to Sclerotinia minor, 11 of them co-locating with red leaf color. Lower disease incidence was observed in red and dark red accessions. Lettuce (Lactuca sativa L.), one of the most economically important vegetables grown primarily in moderate climates around the world, is susceptible to many diseases including lettuce drop caused by the soilborne fungus Sclerotinia minor. Complete resistance to S. minor has not been identified in cultivated lettuce or its wild relatives. We conducted five experiments over 4 years with the diversity panel of almost 500 lettuce accessions to evaluate their response to the pathogen in an artificially infested field. The lowest disease incidence (DI) was observed in cultivars Eruption, Infantry, and Annapolis (median DI of 12.1-17.5%), while the highest DI was recorded for cultivars Reine des Glaces, Wayahead, and line FL. 43007 (median DI of 81.0-95.2%). Overall, significantly lower DI was observed in red and dark red accessions compared to those with a lower anthocyanin content. Genome-wide association mapping identified 19 QTLs for resistance to S. minor, 21 for the presence of red leaf color or its variations caused by the anthocyanin content, and one for the green color intensity. Eleven of the QTLs for disease resistance were located within 10 Mb of the loci associated with red color or anthocyanin content identified in this diversity panel. The frequent, non-random co-location of QTLs, together with the lower DI observed in red and dark red accessions suggests that lettuce interaction with S. minor may be partly influenced by anthocyanins. We have identified RLL2 and ANS, the genes of the anthocyanin biosynthesis pathway that co-locate with resistance QTLs, as candidates for functional studies to ascertain the involvement of anthocyanins in lettuce resistance against S. minor. Resistance QTLs closely linked with QTLs for anthocyanin content could be used to develop lettuce with a relatively high partial resistance and red color, while those not associated with anthocyanins could be used to develop partially resistant cultivars of green color.


Assuntos
Antocianinas , Lactuca , Lactuca/genética , Lactuca/microbiologia , Antocianinas/metabolismo , Estudo de Associação Genômica Ampla , Mapeamento Cromossômico
20.
Chemphyschem ; 24(12): e202300074, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-36917010

RESUMO

Structurally simple rod-like π-conjugated mesogens with thiophene directly connected to phenyl, biphenyl, and fluorenone rings with terminal chains are synthesized respectively. The occurrence of smectic A/smectic C phases is concurred by a hot-stage optical polarising microscope (HOPM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The static 1D and 2D 13 C nuclear magnetic resonance (NMR) studies in the liquid crystalline phase are carried out to find the alignment-induced chemical shifts (AIS) and 13 C-1 H dipolar couplings. The orientational order parameters of the mesogens determined from 13 C-1 H dipolar couplings disclose that the long axis is not only collinear to the C3-C4 bond of the thiophene ring but also for the local axes of phenyl and biphenyl rings. For fluorenone-based mesogen, the molecular biaxiality is found to be high owing to the increased breadth of the molecule. The study unveils that the orientation of thiophene and the phenyl rings is similar in the current mesogens in stark contrast to mesogens, where thiophene is connected to phenyl rings through linking groups.


Assuntos
Imageamento por Ressonância Magnética , Tiofenos , Espectroscopia de Ressonância Magnética , Compostos de Bifenilo
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