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1.
Cell ; 187(3): 676-691.e16, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38306983

RESUMEN

Behavior relies on activity in structured neural circuits that are distributed across the brain, but most experiments probe neurons in a single area at a time. Using multiple Neuropixels probes, we recorded from multi-regional loops connected to the anterior lateral motor cortex (ALM), a circuit node mediating memory-guided directional licking. Neurons encoding sensory stimuli, choices, and actions were distributed across the brain. However, choice coding was concentrated in the ALM and subcortical areas receiving input from the ALM in an ALM-dependent manner. Diverse orofacial movements were encoded in the hindbrain; midbrain; and, to a lesser extent, forebrain. Choice signals were first detected in the ALM and the midbrain, followed by the thalamus and other brain areas. At movement initiation, choice-selective activity collapsed across the brain, followed by new activity patterns driving specific actions. Our experiments provide the foundation for neural circuit models of decision-making and movement initiation.


Asunto(s)
Movimiento , Neuronas , Encéfalo/fisiología , Movimiento/fisiología , Neuronas/fisiología , Tálamo/fisiología , Memoria
2.
Chembiochem ; 25(3): e202300671, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38055197

RESUMEN

The proteasome degrades proteins, which is essential for cellular homeostasis. Ubiquitin independent proteolysis degrades highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation of misfolded proteins. In this work, cyclic peptide proteasome stimulators (CyPPSs) that enhance the clearance of misfolded proteins were discovered. In the initial screen of predicted natural products (pNPs), several cyclic peptides were found to stimulate the 20S core particle (20S CP). Development of a robust structural activity relationship led to the identification of potent, cell permeable CyPPSs. In vitro assays revealed that CyPPSs stimulate degradation of highly disordered and misfolded proteins without affecting ordered proteins. Furthermore, using a novel flow-based assay for proteasome activity, several CyPPSs were found to stimulate the 20S CP in cellulo. Overall, this work describes the development of CyPPSs as chemical tools capable of stimulating the proteasome and provides strong support for proteasome stimulation as a therapeutic strategy for neurodegenerative diseases.


Asunto(s)
Enfermedades Neurodegenerativas , Complejo de la Endopetidasa Proteasomal , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/metabolismo , Proteolisis , Proteínas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico
3.
Phys Rev Lett ; 132(23): 230401, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38905661

RESUMEN

The combination of optical tweezer arrays with strong interactions-via dipole exchange of molecules and Van der Waals interactions of Rydberg atoms-has opened the door for the exploration of a wide variety of quantum spin models. A next significant step will be the combination of such settings with mobile dopants. This will enable one to simulate the physics believed to underlie many strongly correlated quantum materials. Here, we propose an experimental scheme to realize bosonic t-J models via encoding the local Hilbert space in a set of three internal atomic or molecular states. By engineering antiferromagnetic (AFM) couplings between spins, competition between charge motion and magnetic order similar to that in high-T_{c} cuprates can be realized. Since the ground states of the 2D bosonic AFM t-J model we propose to realize have not been studied extensively before, we start by analyzing the case of two dopants-the simplest instance in which their bosonic statistics plays a role-and compare our results to the fermionic case. We perform large-scale density matrix renormalization group calculations on six-legged cylinders, and find a strong tendency for bosonic holes to form stripes. This demonstrates that bosonic, AFM t-J models may contain similar physics as the collective phases in strongly correlated electrons.

4.
J Pediatr Orthop ; 44(4): 213-220, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38270343

RESUMEN

INTRODUCTION: Complications following operative treatment of pediatric femoral neck fractures include nonunion, coxa vara, and avascular necrosis (AVN). Proximal femoral locking plates (PFLPs) provide a fixed-angle construct that may reduce the rates of coxa vara, but their use in pediatric femoral neck fractures has not been studied. The purpose of this study was to evaluate rates of union, coxa vara, and AVN in traumatic pediatric femoral neck fractures treated with PFLP or cannulated screws (CS). METHODS: We retrospectively reviewed all traumatic, nonpathologic Delbet II/III femoral neck fractures in patients below 18 years of age treated with PFLP or CS. All cases had ≥6 months of radiographic follow-up to evaluate for osseous union and AVN. Changes in proximal femoral alignment were determined by measuring injured and contralateral femoral neck-shaft angle and articulotrochanteric distance (ATD) between 6 and 12 months postoperatively. RESULTS: Forty-two patients were identified with mean age at surgery of 10.7±2.9 years (range 3.3 to 16.3 years) and mean follow-up of 36±27 months. Sixteen patients (38%) underwent PFLP fixation, whereas 26 patients (62%) underwent CS fixation. When compared with the CS cohort, the PFLP cohort had a greater proportion of males (87.5% vs. 50%, P =0.02) and Delbet III fractures (68.8% vs. 15.4%, P <0.001). There was no difference between PFLP and CS cohorts with respect to rates of union (81% vs. 88%, respectively, P =0.66), AVN (25% vs. 35%, respectively, P =0.73), or secondary surgery (62% vs 62%, P =0.95). There was no significant difference in neck-shaft angle between injured and contralateral hips in those patients treated with PFLP ( P =0.93) or CS ( P =0.16). However, the ATD was significantly decreased in hips treated with CS compared with the contralateral hip (18.4±4.6 vs. 23.3±4.2 mm, P =0.001), with no significant difference in the PFLP group ( P =0.57). CONCLUSIONS: This study suggests that the use of a PFLP in Delbet II/III femoral neck fractures does not appear to significantly increase nonunion rates or AVN and maintains anatomic ATD when compared with screw fixation. LEVEL OF EVIDENCE: Level III-therapeutic study.


Asunto(s)
Coxa Vara , Fracturas del Cuello Femoral , Osteonecrosis , Masculino , Humanos , Niño , Lactante , Estudios Retrospectivos , Fracturas del Cuello Femoral/cirugía , Placas Óseas , Fijación Interna de Fracturas/métodos , Cuello Femoral , Resultado del Tratamiento
5.
Am J Bot ; 110(7): e16202, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37305986

RESUMEN

PREMISE: Biomass accumulation over years in vertical stems of trees leads to hypoallometric scaling between stem and leaf biomass within this growth form, while for herbaceous species, biomass allocation between these organ types typically exhibits isometry. However, biomass accumulation in herbs can occur in belowground perennating organs (e.g., rhizomes) that are, contrary to aboveground parts of herbs, long-lived. Although ecologically important, biomass allocation and accumulation in rhizomes (and similar organs) have mostly not been studied. METHODS: We assembled data on biomass investments into plant organs for 111 rhizomatous herbs based on a literature survey and greenhouse experiment. We estimated the proportion of whole-plant biomass invested into rhizomes and, using allometric relationships, analyzed scaling between rhizome and leaf biomass and whether it is more variable than for other organs. RESULTS: On average, rhizomes comprise 30.2% of the total plant biomass. The proportion allocated to rhizomes does not change with plant size. Scaling between rhizome and leaf biomass is isometric, and allocation to rhizomes is not more variable than allocation to other organs. CONCLUSIONS: Rhizomatous herbs accumulate substantial biomass in rhizomes, and rhizome biomass scales isometrically with leaves, contrary to the hypoallometric relationship between stem and leaves in trees. This difference suggests that the rhizome biomass is in balance with aboveground biomass-a resource of carbon for rhizome formation that, at the same time, is dependent on carbon stored in rhizomes for its seasonal regrowth.


Asunto(s)
Rizoma , Árboles , Biomasa , Plantas , Hojas de la Planta , Carbono
6.
Nature ; 551(7679): 232-236, 2017 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-29120427

RESUMEN

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal-oxide-semiconductor (CMOS) processing-compatible low-impedance TiN sites that tile a single 10-mm long, 70 × 20-µm cross-section shank. The 6 × 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour.


Asunto(s)
Electrodos , Neuronas/fisiología , Silicio/metabolismo , Animales , Corteza Entorrinal/citología , Corteza Entorrinal/fisiología , Femenino , Masculino , Ratones , Movimiento/fisiología , Corteza Prefrontal/citología , Corteza Prefrontal/fisiología , Ratas , Semiconductores , Vigilia/fisiología
7.
J Nematol ; 54(1): 20220009, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35860518

RESUMEN

DNA barcoding with the mitochondrial COI gene reveals distinct haplotype subgroups within the monophyletic and parthenogenetic nematode species, Mesocriconema xenoplax. Biological attributes of these haplotype groups (HG) have not been explored. An analysis of M. xenoplax from 40 North American sites representing both native plant communities and agroecosystems was conducted to identify possible subgroup associations with ecological, physiological, or geographic factors. A dataset of 132 M. xenoplax specimens was used to generate sequences of a 712 bp region of the cytochrome oxidase subunit I gene. Maximum-likelihood and Bayesian phylogenies recognized seven COI HG (≥99/0.99 posterior probability/bootstrap value). Species delimitation metrics largely supported the genetic integrity of the HG. Discriminant function analysis of HG morphological traits identified stylet length, total body length, and stylet knob width as the strongest distinguishing features among the seven groups, with stylet length as the strongest single distinguishing morphological feature. Multivariate analysis identified land cover, ecoregion, and maximum temperature as predictors of 53.6% of the total variation (P = 0.001). Within land cover, HG categorized under "herbaceous," "woody wetlands," and "deciduous forest" were distinct in DAPC and RDA analyses and were significantly different (analysis of molecular variance P = 0.001). These results provide empirical evidence for molecular, morphological, and ecological differentiation associated with HG within the monophyletic clade that represents the species Mesocriconema xenoplax.

8.
Genome ; 64(3): 232-241, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32526150

RESUMEN

Nematodes are frequently cited as underrepresented in faunistic surveys using DNA barcoding with COI. This underrepresentation is generally attributed to a limited presence of nematodes in DNA databases which, in turn, is often ascribed to structural variability and high evolutionary rates in nematode mitochondrial genomes. Empirical evidence, however, indicates that many taxa are readily amplified with primer sets specifically targeted to different nematode families. Here we report the development of a COI reference library of 1726 specimens in the terrestrial plant parasitic nematode superfamily Criconematoidea. Specimens collected during an ecoregion survey of North America were individually photographed, measured, and PCR amplified to produce a 721 bp region of COI for taxonomic analysis. A neighbor-joining tree structured the dataset into 179 haplotype groups that generally conformed to morphospecies in traditional analysis or Barcode Index Numbers (BINs) in the BOLD system, although absent formal BIN membership due to insufficient overlap with the Folmer region of COI. Approximately one-third of the haplotype groups could be associated with previously described species. The geographic distribution of criconematid nematode species suggests a structure influenced by the major habitat types in the United States and Canada. All sequences collected in the ecoregion survey are deposited in BOLD.


Asunto(s)
Rabdítidos/clasificación , Animales , Biodiversidad , Canadá , Código de Barras del ADN Taxonómico , Bases de Datos de Ácidos Nucleicos , Haplotipos , Plantas/parasitología , Rabdítidos/genética , Estados Unidos
9.
J Nematol ; 50(3): 399-412, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30451423

RESUMEN

DNA barcoding with a new cytochrome oxidase c subunit 1 primer set generated a 721 to 724 bp fragment used for the identification of 322 Meloidogyne specimens, including 205 new sequences combined with 117 from GenBank. A maximum likelihood analysis grouped the specimens into 19 well-supported clades and four single-specimen lineages. The "major" tropical apomictic species ( Meloidogyne arenaria , Meloidogyne incognita , Meloidogyne javanica ) were not discriminated by this barcode although some closely related species such as Meloidogyne konaensis were characterized by fixed diagnostic nucleotides. Species that were collected from multiple localities and strongly characterized as discrete lineages or species include Meloidogyne enterolobii , Meloidogyne partityla , Meloidogyne hapla , Meloidogyne graminicola , Meloidogyne naasi , Meloidogyne chitwoodi , and Meloidogyne fallax . Seven unnamed groups illustrate the limitations of DNA barcoding without the benefit of a well-populated reference library. The addition of these DNA sequences to GenBank and the Barcode of Life Database (BOLD) should stimulate and facilitate root-knot nematode identification and provide a first step in new species discovery.

10.
J Nematol ; 49(3): 236-244, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29062146

RESUMEN

In the nematode family Criconematidae, a taxonomy primarily based on cuticle characters has created classifications that are notoriously volatile. Molecular characters may lead to their stabilization. A phylogenetic tree of Criconematoidea was constructed using 166 new near full-length 18S rDNA sequences and 58 sequences from GenBank. Bayesian and maximum likelihood (ML) analyses produced trees with similar topologies. Major features include a strongly supported clade that includes Criconematidae and Hemicycliophoridae, excluding Paratylenchidae and Tylenchulidae. Another well-supported clade groups Criconema, Ogma, Crossonema, and Hemicriconemoides plus Xenocriconemella, combining nematodes with cuticular scales with those without scales at any life stage. Mesocriconema, Discocriconemella limitanea, Hemicaloosia, and Lobocriconema are recognized as monophyletic groups, but Criconemoides is paraphyletic. Both trees support an unexpected sister relationship between Bakernema and Hemicycliophora. The 18S rDNA dataset was insufficient for distinguishing genus boundaries between Criconema, Ogma, and Crossonema. The relationships depicted by the 18S rDNA phylogeny suggest that key morphological characters used in the classification of Criconematidae are not homologous.

11.
J Nematol ; 50(1): 1-24, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-30451437

RESUMEN

Populations of Criconemoides parvus , Discocriconemella hengsungica , and Discocriconemella limitanea , isolated in Hangzhou, China from the rhizosphere soil of woody perennials were characterized morphologically and molecularly. The morphometric data of the Chinese populations were compared with populations from other regions of the world. DNA barcoding with the mitochondrial COI gene confirmed conspecificity of Chinese and Costa Rican populations of D. limitanea . Phylogenetic assessment using a near full-length 18S ribosomal DNA sequence provided weak support for a grouping of Criconemoides parvus from China and C. annulatus from western North America. The phylogenetic position of D. hengsungica from China and an unknown species of Discocriconemella from Thailand relative to D. limitanea suggests that the genus Discocriconemella is not monophyletic. The study provides the first record of D. hengsungica in China and confirms the presence of C. parvus previously reported from China. Biogeographic implications of these nematode distributions are discussed.

12.
J Nematol ; 49(1): 42-66, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28512377

RESUMEN

Nematode surveys of North American grasslands conducted from 2010 to 2015 frequently recovered a species of criconematid nematode morphologically resembling Mesocriconema curvatum. These specimens were recovered from remnant native prairies in the central tallgrass ecoregion of North America, and not from surrounding agroecosystems. Historical records indicate that M. curvatum is a cosmopolitan species feeding on a wide range of agronomic and native plants. DNA barcoding indicates North American grasslands contain at least 10 phylogenetically distinct lineages of Mesocriconema that resemble, but are not, M. curvatum. Analysis of the two most common lineages reveals two distinctly different population structures. The variation in population structure suggests unique evolutionary histories associated with their diversification. These two major lineages share a sympatric distribution and their slight morphological differences contrast with a high level of genetic separation. Based on their genetic divergence, fixed diagnostic nucleotides, population structure, species delimitation metrics, and a sympatric distribution, we believe that one of these distinct lineages warrants formal nomenclatural recognition. Herein, we provide formal recognition for Mesocriconema nebraskense n. sp. and discuss its relationship to other Mesocriconema lineages discovered in native North American grasslands.

13.
J Surg Oncol ; 111(3): 251-7, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25339608

RESUMEN

BACKGROUND AND OBJECTIVES: The effect of postmastectomy radiation therapy (PMRT) on immediately reconstructed abdominal wall-based tissue remains imprecisely defined. We evaluated evidence from all fields involved in care of the breast cancer patient in order to advance a unified recommendation regarding this therapeutic sequence. METHODS: We performed a MEDLINE and manual reference search to identify studies of PMRT with immediate autologous breast reconstruction. Inclusion criteria required studies to describe patients, flaps, and complication rates. Analyses were based on a random effects model. Surgical and radiation oncology literature was reviewed. RESULTS: Eleven retrospective studies of 337 patients with an average follow-up of 18-60 months (out of 268 patients) were selected for inclusion. Overall rates of fat necrosis, revisional surgery, volume loss, and fibrosis/contracture ranged from 16.9% to 35.4%. One out of 260 patients experienced total flap loss. There was an increased probability of fat necrosis in the irradiated breast (OR = 3.13, 95% CI = 1.42-6.89, P = 0.005) among three studies with non-irradiated controls. Five studies evaluated aesthetics with variable outcomes. CONCLUSIONS: There is mixed evidence for the utility of PMRT with immediate autologous abdominal wall breast reconstruction. Further investigation requires prospective studies with collaboration among surgical oncologists, radiation oncologists, and plastic surgeons.


Asunto(s)
Neoplasias de la Mama/radioterapia , Mamoplastia/efectos adversos , Mastectomía/efectos adversos , Procedimientos de Cirugía Plástica/efectos adversos , Complicaciones Posoperatorias/etiología , Oncología por Radiación , Radioterapia Adyuvante/efectos adversos , Neoplasias de la Mama/cirugía , Terapia Combinada , Femenino , Humanos , Metaanálisis como Asunto , Pronóstico , Estudios Retrospectivos
14.
J Neurophysiol ; 111(5): 1132-49, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24353300

RESUMEN

Monitoring representative fractions of neurons from multiple brain circuits in behaving animals is necessary for understanding neuronal computation. Here, we describe a system that allows high-channel-count recordings from a small volume of neuronal tissue using a lightweight signal multiplexing headstage that permits free behavior of small rodents. The system integrates multishank, high-density recording silicon probes, ultraflexible interconnects, and a miniaturized microdrive. These improvements allowed for simultaneous recordings of local field potentials and unit activity from hundreds of sites without confining free movements of the animal. The advantages of large-scale recordings are illustrated by determining the electroanatomic boundaries of layers and regions in the hippocampus and neocortex and constructing a circuit diagram of functional connections among neurons in real anatomic space. These methods will allow the investigation of circuit operations and behavior-dependent interregional interactions for testing hypotheses of neural networks and brain function.


Asunto(s)
Conducta Animal/fisiología , Corteza Cerebral/fisiología , Electrodos Implantados , Red Nerviosa/fisiología , Neuronas/fisiología , Procesamiento de Señales Asistido por Computador , Animales , Corteza Cerebral/cirugía , Masculino , Ratones , Red Nerviosa/cirugía , Ratas , Ratas Long-Evans , Programas Informáticos
15.
Emerg Med J ; 31(5): 374-9, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-23513235

RESUMEN

INTRODUCTION: Many studies have demonstrated a rise in troponin and brain natriuretic peptide (BNP) levels following prolonged and/or strenuous exercise. Only one study looked at athletes who collapse and this showed no difference in cardiac biomarkers between those who collapsed and those who completed without requiring medical attention. We set out to describe and quantify the changes in troponin and BNP in three groups of non-elite runners at the 2009 London marathon: those with and without known structural heart disease (SHD) and those who collapsed on completion. METHODS: The first group (recruited group, RG) was recruited at the prerace exhibition. This group had two subsets, runners with SHD and without (non-SHD). A second group was recruited from those who collapsed (collapsed group, CG). Blood was taken for troponin I (TnI), troponin T (TnT), high sensitivity TnT (HSTnT) and BNP. RESULTS: Cardiac biomarker levels increased in all groups following the marathon. No statistically significant difference was seen between the SHD and non-SHD subgroups. When comparing the RG and CG the number and degree of rise was greater in those who collapsed. A trend for the degree of rise of HSTnT was demonstrated. DISCUSSION: We identified runners with troponin levels that, in other circumstances, would raise concern for myocardial necrosis. However absence of adverse clinical sequelae would suggest this rise is physiological. The cause and clinical significance of the increased HSTnT levels seen in those that collapsed is yet to be fully elucidated.


Asunto(s)
Cardiopatías/sangre , Péptido Natriurético Encefálico/sangre , Resistencia Física/fisiología , Carrera/fisiología , Choque/sangre , Troponina/sangre , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Humanos , Londres
16.
bioRxiv ; 2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38260339

RESUMEN

Accurate tracking of the same neurons across multiple days is crucial for studying changes in neuronal activity during learning and adaptation. Advances in high density extracellular electrophysiology recording probes, such as Neuropixels, provide a promising avenue to accomplish this goal. Identifying the same neurons in multiple recordings is, however, complicated by non-rigid movement of the tissue relative to the recording sites (drift) and loss of signal from some neurons. Here we propose a neuron tracking method that can identify the same cells independent of firing statistics, that are used by most existing methods. Our method is based on between-day non-rigid alignment of spike sorted clusters. We verified the same cell identity in mice using measured visual receptive fields. This method succeeds on datasets separated from one to 47 days, with an 84% average recovery rate.

17.
J Orthop Trauma ; 38(2): e71-e77, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38031254

RESUMEN

SUMMARY: Cephalomedullary nail fixation of geriatric intertrochanteric femur fractures is, and will continue to be, performed by most orthopaedic surgeons. The influence of technical factors on outcome is clear, and it is imperative that orthopaedic surgeons use contemporary strategies to achieve adequate reduction and fixation. The lateral patient position on a traction table potentially confers several advantages which surgeons can use to achieve quality outcomes even in patients who have challenging body morphology and/or fracture anatomy. A preferred surgical technique for lateral positioning is presented here and a case series comparing supine versus lateral nailing procedures. Lateral positioning was used more frequently in obese patients and by trauma-trained surgeons, and the results equal or exceed those in supine cases with respect to reduction and placement of fixation. Training surgeons in lateral nailing can deliver a reproducible strategy for reduction and fixation in straightforward and complex cases. By mastering the setup and technique on more simple cases, surgeons can be better prepared for the more complex where advantages of lateral nailing are even more apparent.


Asunto(s)
Fijación Intramedular de Fracturas , Fracturas de Cadera , Humanos , Anciano , Tracción , Fijación Intramedular de Fracturas/métodos , Fracturas de Cadera/cirugía , Fracturas de Cadera/etiología , Posicionamiento del Paciente/métodos , Fémur , Clavos Ortopédicos , Estudios Retrospectivos , Resultado del Tratamiento
18.
J Heart Lung Transplant ; 43(2): 293-302, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37907183

RESUMEN

BACKGROUND: Right heart failure is the major cause of death in pulmonary hypertension. Lung transplantation is the only long-term treatment option for patients who fail medical therapy. Due to the scarcity of donor lungs, there is a critical need to develop durable mechanical support for the failing right heart. A major design goal for durable support is to reduce the size and complexity of devices to facilitate ambulation. Toward this end, we sought to deploy wearable mechanical support technology in a sheep disease model of chronic right heart failure. METHODS: In 6 sheep with chronic right heart failure, a mechanical support system consisting of an extracorporeal blood pump coupled with a gas exchange unit was attached in a right atrium-to-left atrium configuration for up to 7 days. Circuit performance, hematologic parameters, and animal hemodynamics were analyzed. RESULTS: Six subjects underwent the chronic disease model for 56 to 71 days. Three of the subjects survived to the 7-day end-point for circulatory support. The circuit provided 2.8 (0.5) liter/min of flow compared to the native pulmonary blood flow of 3.5 (1.1) liter/min. The animals maintained physiologically balanced blood gas profile with a sweep flow of 1.2 (1.0) liter/min. Two animals freely ambulated while wearing the circuit. CONCLUSIONS: Our novel mechanical support system provided physiologic support for a large animal model of pulmonary hypertension with right heart failure. The small footprint of the circuit and the low sweep requirement demonstrate the feasibility of this technology to enable mobile ambulatory applications.


Asunto(s)
Oxigenación por Membrana Extracorpórea , Insuficiencia Cardíaca , Corazón Auxiliar , Hipertensión Pulmonar , Humanos , Animales , Ovinos , Hipertensión Pulmonar/terapia , Insuficiencia Cardíaca/cirugía , Hemodinámica/fisiología , Atrios Cardíacos
19.
Brachytherapy ; 23(2): 123-135, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38129211

RESUMEN

BACKGROUND: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. METHODS: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020-1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-ß/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. RESULTS: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2-50.2 fold-increase from baseline), frequency (1.2-1.7), rearrangements (1.2-40.2), and clonality (1.2-15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. CONCLUSION: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.


Asunto(s)
Braquiterapia , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/radioterapia , Cuello del Útero , Infecciones por Papillomavirus/complicaciones , Linfocitos T , Braquiterapia/métodos , Estudios Prospectivos , Recurrencia Local de Neoplasia , Receptores de Antígenos de Linfocitos T , Microambiente Tumoral
20.
bioRxiv ; 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-37662298

RESUMEN

To understand the neural basis of behavior, it is essential to sensitively and accurately measure neural activity at single neuron and single spike resolution. Extracellular electrophysiology delivers this, but it has biases in the neurons it detects and it imperfectly resolves their action potentials. To minimize these limitations, we developed a silicon probe with much smaller and denser recording sites than previous designs, called Neuropixels Ultra (NP Ultra). This device samples neuronal activity at ultra-high spatial density (~10 times higher than previous probes) with low noise levels, while trading off recording span. NP Ultra is effectively an implantable voltage-sensing camera that captures a planar image of a neuron's electrical field. We use a spike sorting algorithm optimized for these probes to demonstrate that the yield of visually-responsive neurons in recordings from mouse visual cortex improves up to ~3-fold. We show that NP Ultra can record from small neuronal structures including axons and dendrites. Recordings across multiple brain regions and four species revealed a subset of extracellular action potentials with unexpectedly small spatial spread and axon-like features. We share a large-scale dataset of these brain-wide recordings in mice as a resource for studies of neuronal biophysics. Finally, using ground-truth identification of three major inhibitory cortical cell types, we found that these cell types were discriminable with approximately 75% success, a significant improvement over lower-resolution recordings. NP Ultra improves spike sorting performance, detection of subcellular compartments, and cell type classification to enable more powerful dissection of neural circuit activity during behavior.

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