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1.
J Fish Biol ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38964773

RESUMO

Meristic characters are often used to differentiate between closely related forms, morphs, and species of fishes, and lend insight into ecology and post-glacial recolonization in taxa with complicated or contentious phylogenies, including the genus Salvelinus. Previous studies of meristics in Salvelinus have focused mostly on individual populations. We collated data from 456 populations/systems across the North American and Russian Arctic and sub-Arctic, and found that counts of pyloric caeca and gill rakers differed consistently between fish visually and/or genetically identified as Arctic char and Dolly Varden across their distributional ranges.

2.
Blood Adv ; 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38968150

RESUMO

Platelet CLEC-2 is a hemITAM-containing receptor which has a critical role in venous thrombosis, but minimal involvement in haemostasis. CLEC-2 can be blocked by Btk inhibitors. Treatment with ibrutinib is associated with increased bleeding due to off-target inhibition of Src family kinases (SFKs). Patients with X-linked agammaglobulinemia (XLA) who lack Btk however do not bleed, suggesting selective Btk inhibition is a viable antithrombotic strategy. We assessed the effects of selective Btk inhibitors PRN1008 (rilzabrutinib) and PRN473 on platelet signalling and function mediated by CLEC-2 and GPVI. We used healthy donor and XLA platelets to determine off-target inhibitor effects. Inferior vena cava (IVC) stenosis and Salmonella infection mouse models were used to assess antithrombotic effects of PRN473 in vivo. PRN1008 and PRN473 potently inhibited CLEC-2-mediated platelet activation to rhodocytin. No off-target inhibition of SFKs was seen. PRN1008 treatment of Btk-deficient platelets resulted in minor additional inhibition of aggregation and tyrosine phosphorylation, likely reflecting inhibition of Tec. No effect on GPCR-mediated platelet function was observed. PRN473 significantly reduced the number of thrombi in podoplanin positive vessels following Salmonella infection and the presence of IVC thrombosis following vein stenosis. The potent inhibition of human platelet CLEC-2, and reduced thrombosis in in vivo models, together with the lack of off-target SFK inhibition and absence of bleeding reported in rilzabrutinib treated immune thrombocytopenia patients, suggest Btk inhibition as a promising antithrombotic strategy.

3.
Pediatr Res ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961165

RESUMO

BACKGROUND: To modify a parent-reported acute otitis media severity of symptoms scale (AOM-SOS) to ensure that it accurately reflects parental concerns. METHODS: Using qualitative interviews with parents of children with acute otitis media (AOM) (n = 24), we generated 39 candidate items for inclusion in the new version of the scale. We determined the importance of each item by enrolling 50 other parents of children with AOM. We selected 15 items with high importance and used them to create a new version of the scale. During successive rounds of cognitive interviews, 3 items were dropped. Two additional items were dropped because they were highly correlated. We evaluated the psychometric properties of the new, 10-item version (version 6.0) in 139 children with AOM. RESULTS: AOM-SOS scores correlated with functional status (r = -0.53), parent assessment of child's pain level (r = 0.69), and overall symptom severity (r = 0.41). The internal consistency of the scale, as measured by Cronbach's alpha, was 0.90. Responsiveness (standardized response mean = 1.82) and test-retest reliability (0.77) were excellent and good, respectively. CONCLUSION: Data presented here support the use of the new version of the scale as a longitudinal measure of symptom burden in clinical trials of children with AOM. IMPACT STATEMENT: The AOM-SOS scale, which now incorporates parental views, can be used to track symptom severity in future efficacy trials in young children with acute otitis media. Data is presented on the validity, reliability, and responsiveness of the AOM-SOS scale. Otitis media is the most frequent indication for antibiotic use in young children. The AOM-SOS is one of the few validated disease specific scales available for use in efficacy trials of children with acute otitis media.

5.
J Gastric Cancer ; 24(3): 267-279, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38960886

RESUMO

PURPOSE: The optimal treatment for gastroesophageal junction adenocarcinoma (GEJA) remains controversial. We evaluated the treatment patterns and outcomes of patients with locally advanced GEJA according to the histological type. MATERIALS AND METHODS: We conducted a single-institution retrospective cohort study of patients with locally advanced GEJA who underwent curative-intent surgical resection between 2010 and 2020. Perioperative therapies as well as clinicopathologic, surgical, and survival data were collected. The results of endoscopy and histopathological examinations were assessed for Siewert and Lauren classifications. RESULTS: Among the 58 patients included in this study, 44 (76%) were clinical stage III, and all received neoadjuvant therapy (72% chemoradiation, 41% chemotherapy, 14% both chemoradiation and chemotherapy). Tumor locations were evenly distributed by Siewert Classification (33% Siewert-I, 40% Siewert-II, and 28% Siewert-III). Esophagogastrectomy (EG) was performed for 47 (81%) patients and total gastrectomy (TG) for 11 (19%) patients. All TG patients received D2 lymphadenectomy compared to 10 (21%) EG patients. Histopathological examination showed the presence of 64% intestinal-type and 36% diffuse-type histology. The frequencies of diffuse-type histology were similar among Siewert groups (37% Siewert-I, 36% Siewert-II, and 33% Siewert-III). Regardless of Siewert type and compared to intestinal-type, diffuse histology was associated with increased intraabdominal recurrence rates (P=0.03) and decreased overall survival (hazard ratio, 2.33; P=0.02). With a median follow-up of 31.2 months, 29 (50%) patients had a recurrence, and the median overall survival was 50.5 months. CONCLUSIONS: Present in equal proportions among Siewert types of esophageal and gastric cancer, a diffuse-type histology was associated with high intraabdominal recurrence rates and poor survival. Histopathological evaluation should be considered in addition to anatomic location in the determination of multimodal GEJA treatment strategies.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Junção Esofagogástrica , Neoplasias Gástricas , Humanos , Masculino , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Adenocarcinoma/classificação , Feminino , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/classificação , Neoplasias Gástricas/cirurgia , Pessoa de Meia-Idade , Junção Esofagogástrica/patologia , Junção Esofagogástrica/cirurgia , Estudos Retrospectivos , Idoso , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/cirurgia , Prognóstico , Gastrectomia , Adulto , Taxa de Sobrevida , Esofagectomia , Idoso de 80 Anos ou mais
7.
PLoS Negl Trop Dis ; 18(7): e0012257, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38991011

RESUMO

BACKGROUND: Promotion of facial cleanliness is recommended for the elimination of blinding trachoma, largely because of observational studies that have found an association between various measures of facial uncleanliness and trachoma. However, when a field grader assesses both facial cleanliness and trachoma, associations may be biased. Assessment of photographs of the face and conjunctiva by masked graders may provide a less biased estimate of the relationship between facial cleanliness and trachoma. METHODS: Face photographs, conjunctival photographs, and conjunctival swabs were obtained on a random sample of 0-9-year-old children from each of 40 communities in Amhara region, Ethiopia. Face photographs were assessed for the presence of seven measures of an unclean face (i.e., wet nasal discharge, dry nasal discharge, wet ocular discharge, dry ocular discharge, food, dust/dirt, and flies) by three independent masked photo-graders. Conjunctival photographs were similarly graded in a masked fashion for signs of clinically active trachoma. Conjunctival swabs were processed for Chlamydia trachomatis DNA. RESULTS: Of 2073 children with complete data, 808 (39%) had evidence of clinically active trachoma, 150 (7%) had evidence of ocular chlamydia infection, and 2524 (91%) had at least one measure of an unclean face. Dry ocular discharge had the strongest association with clinically active trachoma (age- and sex-adjusted prevalence ratio [PR] 1.4, 95% CI 1.2-1.6) and ocular chlamydia infection (PR 1.9, 95%CI 1.3-2.9), although significant associations were observed between each of the measures of facial uncleanliness and trachoma. CONCLUSIONS: Masked assessment of face and conjunctival photographs confirmed prior observational studies that have noted associations between various measures of facial uncleanliness and trachoma. The causal relationship between facial uncleanliness and trachoma is unclear since many features used to measure facial cleanliness (e.g., ocular discharge, nasal discharge, and flies) could be consequences of antecedent ocular chlamydia infection. TRIAL REGISTRATION: NCT02754583, clinicaltrials.gov.

8.
Artigo em Inglês | MEDLINE | ID: mdl-38992473

RESUMO

BACKGROUND: The discriminatory and racist policy of historical redlining in the United States (U.S.) during the 1930s played a role in perpetuating contemporary environmental health disparities. OBJECTIVE: Our objectives were to determine associations between home and school pollutant exposure (fine particulate matter (PM2.5), nitrogen dioxide (NO2)) and respiratory outcomes (Composite Asthma Severity Index (CASI), lung function) among school-aged children with asthma and examine whether associations differed between children who resided and/or attended school in historically redlined compared to non-redlined neighborhoods. METHODS: Children ages 6 to 17 with moderate-to-severe asthma (N=240) from 9 U.S. cities were included. Combined home and school exposure to PM2.5 and NO2 was calculated based on geospatially assessed monthly averaged outdoor pollutant concentrations. Repeated measures of CASI and lung function were collected. RESULTS: Overall, 37.5% of children resided and/or attended schools in historically redlined neighborhoods. Children in historically redlined neighborhoods had greater exposure to NO2 (median: 15.4 vs 12.1 ppb) and closer distance to a highway (median: 0.86 vs 1.23 km), compared to those in non-redlined neighborhoods (p<0.01). Overall, PM2.5 was not associated with asthma severity or lung function. However, among children in redlined neighborhoods, higher PM2.5 was associated with worse asthma severity (p<0.005). No association was observed between pollutants and lung function or asthma severity among children in non-redlined neighborhoods (p>0.005). CONCLUSIONS: Our findings highlight the significance of historical redlining and current environmental health disparities among school-aged children with asthma, specifically, the environmental injustice of PM2.5 exposure and its associations with respiratory health.

9.
Neurosurgery ; 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38985563

RESUMO

BACKGROUND AND OBJECTIVES: Despite growing interest in how patient frailty affects outcomes (eg, in neuro-oncology), its role after transsphenoidal surgery for Cushing disease (CD) remains unclear. We evaluated the effect of frailty on CD outcomes using the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) data set from a collaboration of US academic pituitary centers. METHODS: Data on consecutive surgically treated patients with CD (2011-2023) were compiled using the 11-factor modified frailty index. Patients were classified as fit (score, 0-1), managing well (score, 2-3), and mildly frail (score, 4-5). Univariable and multivariable analyses were conducted to examine outcomes. RESULTS: Data were analyzed for 318 patients (193 fit, 113 managing well, 12 mildly frail). Compared with fit and managing well patients, mildly frail patients were older (mean ± SD 39.7 ± 14.2 and 48.9 ± 12.2 vs 49.4 ± 8.9 years, P < .001) but did not different by sex, race, and other factors. They had significantly longer hospitalizations (3.7 ± 2.0 and 4.5 ± 3.5 vs 5.3 ± 3.5 days, P = .02), even after multivariable analysis (ß = 1.01, P = .007) adjusted for known predictors of prolonged hospitalization (age, Knosp grade, surgeon experience, American Society of Anesthesiologists grade, complications, frailty). Patients with mild frailty were more commonly discharged to skilled nursing facilities (0.5% [1/192] and 4.5% [5/112] vs 25% [3/12], P < .001). Most patients underwent gross total resection (84.4% [163/193] and 79.6% [90/113] vs 83% [10/12]). No difference in overall complications was observed; however, venous thromboembolism was more common in mildly frail (8%, 1/12) than in fit (0.5%, 1/193) and managing well (2.7%, 3/113) patients (P = .04). No difference was found in 90-day readmission rates. CONCLUSION: These results demonstrate that mild frailty predicts CD surgical outcomes and may inform preoperative risk stratification. Frailty-influenced outcomes other than age and tumor characteristics may be useful for prognostication. Future studies can help identify strategies to reduce disease burden for frail patients with hypercortisolemia.

10.
Sci Rep ; 14(1): 15871, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982137

RESUMO

Although epidural spinal cord and muscle stimulation have each been separately used for restoration of movement after spinal cord injury, their combined use has not been widely explored. Using both approaches in combination could provide more flexible control compared to using either approach alone, but whether responses evoked from such combined stimulation can be easily predicted is unknown. We evaluate whether responses evoked by combined spinal and muscle stimulation can be predicted simply, as the linear summation of responses produced by each type of stimulation individually. Should this be true, it would simplify the prediction of co-stimulation responses and the development of control schemes for spinal cord injury rehabilitation. In healthy anesthetized rats, we measured hindlimb isometric forces in response to spinal and muscle stimulation. Force prediction errors were calculated as the difference between predicted and observed co-stimulation forces. We found that spinal and muscle co-stimulation could be closely predicted as the linear summation of the individual spinal and muscle responses and that the errors were relatively low. We discuss the implications of these results to the use of combined muscle and spinal stimulation for the restoration of movement following spinal cord injury.


Assuntos
Contração Isométrica , Músculo Esquelético , Traumatismos da Medula Espinal , Medula Espinal , Animais , Ratos , Medula Espinal/fisiologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/reabilitação , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia , Extremidade Inferior/fisiopatologia , Estimulação Elétrica/métodos , Membro Posterior , Espaço Epidural , Ratos Sprague-Dawley , Estimulação da Medula Espinal/métodos , Feminino , Terapia por Estimulação Elétrica/métodos
11.
Prog Community Health Partnersh ; 18(2): 183-191, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38946564

RESUMO

BACKGROUND: Families of youth involved in the juvenile justice system (YJJ) are integral to YJJ well-being, so it is important to consider the direct input of YJJ families as well as YJJ themselves in justice system reform efforts aiming to improve YJJ health outcomes. OBJECTIVE: Our university research team partnered with one Midwest county's juvenile court, as well as YJJ family members, to form an advisory council to the juvenile court. We report lessons learned through a case study of this council. METHODS: Researchers reviewed and analyzed council records, meeting minutes, and interviews of varied stakeholders, including system representatives, leaders of similar advisory councils, and individuals with lived experience of the juvenile justice system. LESSONS LEARNED: Council sustainability required addressing participation barriers, valuing authentic experiences, seeking out system-based champions, and identifying concrete opportunities for members to be heard. CONCLUSIONS: Investments in community health partnerships with YJJ families could improve system efforts to meet YJJ needs.


Assuntos
Pesquisa Participativa Baseada na Comunidade , Relações Comunidade-Instituição , Delinquência Juvenil , Humanos , Pesquisa Participativa Baseada na Comunidade/organização & administração , Delinquência Juvenil/prevenção & controle , Adolescente , Universidades/organização & administração , Família
12.
medRxiv ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38946965

RESUMO

Severe acute malnutrition (SAM), defined anthropometrically as a weight-for-length z-score more than 3 standard deviations below the mean (WLZ<-3), affects 19 million children under 5-years-old worldwide. Complete anthropometric recovery after standard inventions is rare with children often left with moderate acute malnutrition (MAM; WLZ -2 to -3). Here we conduct a randomized controlled trial (RCT), involving 12-18-month-old Bangladeshi children from urban and rural sites, who after hospital-based treatment for SAM received a 3-month intervention with a microbiota-directed complementary food (MDCF-2) or a ready-to-use supplementary food (RUSF) as they transitioned to MAM. The rate of WLZ improvement was significantly greater with MDCF-2 than the more calorically-dense RUSF, as we observed in a previous RCT of Bangladeshi children with MAM without antecedent SAM. A correlated meta-analysis of aptamer-based measurements of 4,520 plasma proteins in this and the prior RCT revealed 215 proteins positively-associated with WLZ (prominently those involved in musculoskeletal and CNS development) and 44 negatively-associated proteins (related to immune activation), with a significant enrichment in levels of the positively WLZ-associated proteins in the MDCF-2 arm. Characterizing changes in 754 bacterial metagenome-assembled genomes in serially collected fecal samples disclosed the effects of acute rehabilitation for SAM on the microbiome, its transition as each child achieves a state of MAM, and how specific strains of Prevotella copri function at the intersection between MDCF-2 glycan metabolism and the rescue of growth faltering. These results provide a rationale for further testing the generalizability of the efficacy of MDCF and identify biomarkers for defining treatment responses.

13.
Proc Natl Acad Sci U S A ; 121(28): e2318029121, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38950360

RESUMO

Indonesia has experienced rapid primary forest loss, second only to Brazil in modern history. We examined the fates of Indonesian deforested areas, immediately after clearing and over time, to quantify deforestation drivers in Indonesia. Using time-series satellite data, we tracked degradation and clearing events in intact and degraded natural forests from 1991 to 2020, as well as land use trajectories after forest loss. While an estimated 7.8 Mha (SE = 0.4) of forest cleared during this period had been planted with oil palms by 2020, another 8.8 Mha (SE = 0.4) remained unused. Of the 28.4 Mha (SE = 0.7) deforested, over half were either initially left idle or experienced crop failure before a land use could be detected, and 44% remained unused for 5 y or more. A majority (54%) of these areas were cleared mechanically (not by escaped fires), and in cases where idle lands were eventually converted to productive uses, oil palm plantations were by far the most common outcome. The apparent deliberate creation of idle deforested land in Indonesia and subsequent conversion of idle areas to oil palm plantations indicates that speculation and land banking for palm oil substantially contribute to forest loss, although failed plantations could also contribute to this dynamic. We also found that in Sumatra, few lowland forests remained, suggesting that a lack of remaining forest appropriate for palm oil production, together with an extensive area of banked deforested land, may partially explain slowing forest loss in Indonesia in recent years.


Assuntos
Conservação dos Recursos Naturais , Florestas , Indonésia , Árvores/crescimento & desenvolvimento , Agricultura
14.
J Neurooncol ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951457

RESUMO

PURPOSE: Targeted treatment options for non-small cell lung cancer (NSCLC) brain metastases (BMs) may be combined with stereotactic radiosurgery (SRS) to optimize survival. We assessed patient outcomes after SRS for NSCLC BMs, identifying survival trajectories associated with targetable mutations. METHODS: In this retrospective time-dependent analysis, we analyzed median overall survival of patients who received ≥ 1 SRS courses for BM from NSCLC from 2001 to 2021. We compared survival of patients with and without targetable mutations based on clinical variables and treatment. RESULTS: Among the 213 patients included, 87 (40.8%) had targetable mutations-primarily EGFR (22.5%)-and 126 (59.2%) did not. Patients with targetable mutations were more often female (63.2%, p <.001) and nonsmokers (58.6%, p <.001); had higher initial lung-molGPA (2.0 vs. 1.5, p <.001) and lower cumulative tumor volume (3.7 vs. 10.6 cm3, p <.001); and received more concurrent (55.2% vs. 36.5%, p =.007) and total (median 3 vs. 2, p <.001) systemic therapies. These patients had lower mortality rates (74.7% vs. 91.3%, p <.001) and risk (HR 0.298 [95%CI 0.190-0.469], p <.001) and longer median overall survival (20.2 vs. 7.4 months, p <.001), including survival ≥ 3 years (p =.001). Survival was best predicted by SRS with tumor resection in patients with non-targetable mutations (HR 0.491 [95%CI 0.318-757], p =.001) and by systemic therapy with SRS for those with targetable mutations (HR 0.124 [95%CI 0.013-1.153], p =.067). CONCLUSION: The presence of targetable mutations enhances survival in patients receiving SRS for NSCLC BM, particularly when used with systemic therapies. Survival for patients without targetable mutations was longest with SRS and surgical resection. These results inform best practices for managing patients with NSCLC BM based on driver mutation status.

15.
Nat Hum Behav ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951612

RESUMO

In societies without writing, ethnographically known rituals have rarely been tracked back archaeologically more than a few hundred years. At the invitation of GunaiKurnai Aboriginal Elders, we undertook archaeological excavations at Cloggs Cave in the foothills of the Australian Alps. In GunaiKurnai Country, caves were not used as residential places during the early colonial period (mid-nineteenth century CE), but as secluded retreats for the performance of rituals by Aboriginal medicine men and women known as 'mulla-mullung', as documented by ethnographers. Here we report the discovery of buried 11,000- and 12,000-year-old miniature fireplaces with protruding trimmed wooden artefacts made of Casuarina wood smeared with animal or human fat, matching the configuration and contents of GunaiKurnai ritual installations described in nineteenth-century ethnography. These findings represent 500 generations of cultural transmission of an ethnographically documented ritual practice that dates back to the end of the last ice age and that contains Australia's oldest known wooden artefacts.

16.
Arthroplast Today ; 27: 101435, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38946923

RESUMO

Background: Trabecular metal augments (TMAs) have been extensively used in revision total hip arthroplasty (THA) to address acetabular bone defects. However, limited data exists regarding TMA utilization during primary THA. This study aims to assess the clinical and radiographic outcomes of TMAs used during primary THA. Methods: A single-institution retrospective case series of primary THA patients treated with TMA between 2010 and 2019 was performed. Patient demographics, complications, and revisions were recorded. Cup position, center of rotation, leg length, and radiolucent lines were assessed radiographically. The Kaplan-Meier method was used to compute implant survivorship. Results: Twenty-six patients (30 hips) were included with average age of 52.6 ± 15.3 years (range: 22-78) and mean follow-up of 4.1 ± 2.1 years (range: 2.0-8.9). Most TMAs were indicated for developmental dysplasia of the hip (n = 18; 60.0%). On average, hip center of rotation was lowered 1.5 ± 1.3 cm and lateralized 1.2 ± 1.5 cm, while leg length and global offset were increased by 2.4 ± 1.2 cm and 0.4 ± 1.0 cm, respectively. At final follow-up, 3 hips (10.0%) required revision: one (3.3%) for aseptic loosening and 2 (6.7%) for instability. No patients had progressive radiolucent lines at final follow-up. Five-year survival with aseptic loosening and all-cause revision as endpoints was 100% (95% confidence interval: 90.0%-100.0%) and 92.1% (95% confidence interval: 81.3%-100.0%), respectively. One patient required revision for aseptic loosening after the 5-year mark. Conclusions: Trabecular metal augmentation during primary THA demonstrates satisfactory early to mid-term outcomes. TMA is a viable option for complex primary THA when bone loss is encountered or secondary support is required. Level of Evidence: Level IV.

17.
Comput Educ Open ; 6: None, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38947763

RESUMO

Automated writing evaluation (AWE) has shown promise in enhancing students' writing outcomes. However, further research is needed to understand how AWE is perceived by middle school students in the United States, as they have received less attention in this field. This study investigated U.S. middle school students' perceptions of the MI Write AWE system. Students reported their perceptions of MI Write's usefulness using Likert-scale items and an open-ended survey question. We used Latent Dirichlet Allocation (LDA) to identify latent topics in students' comments, followed by qualitative analysis to interpret the themes related to those topics. We then examined whether these themes differed among students who agreed or disagreed that MI Write was a useful learning tool. The LDA analysis revealed four latent topics: (1) students desire more in-depth feedback, (2) students desire an enhanced user experience, (3) students value MI Write as a learning tool but desire greater personalization, and (4) students desire increased fairness in automated scoring. The distribution of these topics varied based on students' ratings of MI Write's usefulness, with Topic 1 more prevalent among students who generally did not find MI Write useful and Topic 3 more prominent among those who found MI Write useful. Our findings contribute to the enhancement and implementation of AWE systems, guide future AWE technology development, and highlight the efficacy of LDA in uncovering latent topics and patterns within textual data to explore students' perspectives of AWE.

18.
Science ; 385(6704): 91-99, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38963839

RESUMO

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in ß-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.


Assuntos
Anemia Falciforme , Antidrepanocíticos , Hemoglobina Fetal , Fatores de Transcrição Kruppel-Like , Proteínas do Tecido Nervoso , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Antidrepanocíticos/química , Antidrepanocíticos/farmacologia , Antidrepanocíticos/uso terapêutico , Cristalografia por Raios X , Descoberta de Drogas , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Macaca fascicularis , Proteínas do Tecido Nervoso/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética
19.
bioRxiv ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38948696

RESUMO

Large-scale networks underpin brain functions. How such networks respond to focal stimulation can help decipher complex brain processes and optimize brain stimulation treatments. To map such stimulation-response patterns across the brain non-invasively, we recorded concurrent EEG responses from single-pulse transcranial magnetic stimulation (i.e., TMS-EEG) from over 100 cortical regions with two orthogonal coil orientations from one densely-sampled individual. We also acquired Human Connectome Project (HCP)-styled diffusion imaging scans (six), resting-state functional Magnetic Resonance Imaging (fMRI) scans (120 mins), resting-state EEG scans (108 mins), and structural MR scans (T1- and T2-weighted). Using the TMS-EEG data, we applied network science-based community detection to reveal insights about the brain's causal-functional organization from both a stimulation and recording perspective. We also computed structural and functional maps and the electric field of each TMS stimulation condition. Altogether, we hope the release of this densely sampled (n=1) dataset will be a uniquely valuable resource for both basic and clinical neuroscience research.

20.
Am J Bot ; : e16370, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38989916

RESUMO

PREMISE: Leafless, heterotrophic plants are prime examples of organismal modification, the genomic consequences of which have received considerable interest. In particular, plastid genomes (plastomes) are being sequenced at a high rate, allowing continual refinement of conceptual models of reductive evolution in heterotrophs. However, numerous sampling gaps exist, hindering the ability to conduct comprehensive phylogenomic analyses in these plants. METHODS: Using floral tissue from an herbarium specimen, we sequenced and analyzed the plastome of Degranvillea dermaptera, a rarely collected, leafless orchid species from South America about which little is known, including its phylogenetic affinities. RESULTS: The plastome is the most reduced of those sequenced among the orchid subfamily Orchidoideae. In Degranvillea, it has lost the majority of genes found in leafy autotrophic species, is structurally rearranged, and has similar gene content to the most reduced plastomes among the orchids. We found strong evidence for the placement of Degranvillea within the subtribe Spiranthinae using models that explicitly account for heterotachy, or lineage-specific evolutionary rate variation over time. We further found evidence of relaxed selection on several genes and of correlations among substitution rates and several other "traits" of the plastome among leafless members of orchid subfamily Orchidoideae. CONCLUSIONS: Our findings advance knowledge on the phylogenetic relationships and paths of plastid genome evolution among the orchids, which have experienced more independent transitions to heterotrophy than any other plant family. This study demonstrates the importance of herbarium collections in comparative genomics of poorly known species of conservation concern.

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