Spontaneous cerebrovascular reactivity at rest in older adults with and without mild cognitive impairment and memory deficits.

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest. Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors. Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline.

The effects of clays on bacterial community composition during arthropod decay.

Fossilization, or the transition of an organism from the biosphere to the geosphere, is a complex mechanism involving numerous biological and geological variables. Bacteria are one of the most significant biotic players to decompose organic matter in natural environments, early on during fossilization. However, bacterial processes are difficult to characterize as many different abiotic conditions can influence bacterial efficiency in degrading tissues. One potentially important variable is the composition and nature of the sediment on which a carcass is deposited after death. We experimentally examined this by decaying the marine shrimp Palaemon varians underwater on three different clay sediments. Samples were then analyzed using 16S ribosomal RNA sequencing to identify the bacterial communities associated with each clay system. Results show that samples decaying on the surface of kaolinite have a lower bacterial diversity than those decaying on the surface of bentonite and montmorillonite, which could explain the limited decay of carcasses deposited on this clay. However, this is not the only role played by kaolinite, as a greater proportion of gram-negative over gram-positive bacteria is observed in this system. Gram-positive bacteria are generally thought to be more efficient at recycling complex polysaccharides such as those forming the body walls of arthropods. This is the first experimental evidence of sediments shaping an entire bacterial community. Such interaction between sediments and bacteria might have contributed to arthropods' exquisite preservation and prevalence in kaolinite-rich Lagerstätten of the Cambrian Explosion. Supplementary Information: The online version contains supplementary material available at 10.1186/s13358-024-00324-7.

Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production.

Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.

Underrepresentation of black individuals in pivotal trials for novel anticancer drugs: Potential consequence of using estimated creatinine clearance to assess kidney function?

BACKGROUND: Black individuals are historically underrepresented in oncology clinical trials. One potential reason for this is the prevalence of kidney disease in Black individuals, utilization of estimated creatinine clearance as a surrogate for glomerular filtration rate (GFR) in oncology, and GFR-based trial eligibility criteria. We characterized the representation of racial minorities in anticancer agent pivotal trials and examined if GFR-based trial eligibility criteria impact the proportion of Black individuals in trial populations. METHODS: We constructed a data repository for anticancer drugs FDA-approved 2015-2019 and associated pivotal trials, from which we extracted trial population racial compositions and GFR-based trial eligibility criteria. We calculated the participation-to-incidence ratio (PIR) and participation-to-mortality ratio (PMR) for a variety of cancer sites, where PIR or PMR >1.2 and < 0.8 indicate overrepresentation and underrepresentation, respectively. We evaluated the relationship between GFR eligibility cutoffs and the proportion of Black enrollees with Spearman rank correlation coefficient. RESULTS: We assessed 24,698 patients in 74 trials. Black individuals were underrepresented in all trials (PIR ≤0.48, PMR ≤0.50). For trials with GFR-based eligibility criteria (n = 49), a lower GFR cutoff was modestly associated with a higher proportion of Black enrollees (r = -0.29, p = 0.039). This relationship was strengthened for trials that only used estimated creatinine clearance to estimate GFR (r = -0.43, p = 0.004). CONCLUSIONS: GFR-related eligibility, and specifically the use of estimated creatinine clearance, may contribute to Black individuals being disproportionately excluded from cancer clinical trials. This highlights the need for implementation of contemporary GFR equations and other interventions to boost racial minority trial enrollment.

Understanding Factors that Influence Parents' Provision of Beverages to Their Children: A Qualitative Evidence Synthesis.

OBJECTIVE: Understand parental perceptions of beverages and factors influencing the beverage choices they make for their children. DATA SOURCE: A literature search was conducted using PubMed, Scopus, and CINAHL. STUDY INCLUSION AND EXCLUSION CRITERIA: Included studies contained qualitative data examining parents' perceptions of beverages or factors that influence their child's beverage consumption, were conducted in the United States between 2000 and 2022, written in English, and enrolled parents of children aged 18 years or younger. DATA EXTRACTION: Authors, titles, study aims, methods, qualitative results, and representative quotations were extracted using Covidence. DATA SYNTHESIS: Qualitative findings were independently coded by two coders. Codes were compared and discrepancies resolved through discussion with a third team member. Themes and sub-themes were identified, and representative quotations selected. RESULTS: 13 studies met inclusion criteria. Five major themes emerged: 1) factors that influence parents' provision of beverages to their children, 2) parents' concerns about sugar-sweetened beverages (SSBs), 3) barriers to limiting children's SSB consumption, 4) strategies to lower children's SSB consumption, and 5) parents' perceptions of beverage healthfulness. CONCLUSION: Though most parents are aware of unfavorable health effects of frequent SSB intake, environmental and sociocultural factors pose barriers to limiting their child's SSB consumption. Changes to policy and the food environment are needed to initiate and sustain reductions in SSB intake, along with continued nutrition education efforts.

Outcomes of r/r B-cell NHL patients with limited (<5 Sites) pre-CART Disease Bridged With or Without Radiotherapy.

Unirradiated relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) patients who undergo anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized pre-CART disease. This study reports on the outcomes of r/r NHL patients with limited (<5 involved sites) disease bridged with or without radiotherapy (BRT). A multi-center retrospective review of 150 patients with r/r NHL who received CART with <5 disease sites prior to leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study endpoints included relapse free-survival (RFS), event-free survival (EFS) and overall survival (OS). Prior to CART infusion, 48 (32%) patients received BRT and 102 (68%) did not. The median follow-up was 21 months. Following CART infusion, BRT patients had higher objective response (92% vs 78%, p=0.046) and sustained complete response (54% vs 33%, p=0.015) rates. Local relapse in sites present prior to CART was lower in the BRT group (21% vs. 46%, p=0.003). BRT patients had improved 2-year RFS (53% vs 44%, p=0.023) and 2-year EFS (37% vs 34%, p=0.039) compared to no BRT patients. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared to 42% in those who did not (p=0.002). BRT prior to CART for patients with limited (<5 involved disease sites) r/r NHL improves response rate, local control, RFS, and EFS without causing significant toxicities.

Positionally distinct interferon stimulated dermal immune acting fibroblasts promote neutrophil recruitment in Sweet's syndrome.

Sweet's syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet's syndrome revealed a prominent interferon signature in Sweet's syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet's syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet's syndrome through recognition of type I interferons.

Assessing Pain and Functional Outcomes of Percutaneous Stabilization of Metastatic Pelvic Lesions via Photodynamic Nails: A Bi-Institutional Investigation of Orthopaedic Outcomes.

Background: Minimally invasive surgical interventions for metastatic invasion of the pelvis have become more prevalent and varied. Our group hypothesized that the use of percutaneous photodynamic nails (PDNs) would result in decreased pain, improved functional outcomes and level of ambulation, and decreased use of opioid pain medication. Methods: We performed a retrospective chart review of patients with metastatic pelvic bone disease undergoing stabilization with PDNs (IlluminOss Medical) at 2 institutions. Functional outcome measures assessed include the Combined Pain and Ambulatory Function (CPAF), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function, and PROMIS Global Health-Physical. Pain was assessed using a visual analog scale (VAS). Outcomes were assessed preoperatively and at 6 weeks, 3 months, 6 months, and 1 year following surgery. Results: A total of 39 patients treated with PDNs were included. No cases of surgical site infection or implant failure were identified. The median pain VAS score decreased from 8 preoperatively to 0 at the 6-week time point (p < 0.0001). The median CPAF score improved from 5.5 points preoperatively to 7 points at the 3-month mark (p = 0.0132). A significant improvement in physical function was seen at 6 months in the PROMIS Physical Function (p = 0.02) and at both 6 months (p = 0.01) and 1 year (p < 0.01) for the PROMIS Global Health-Physical. The rate of patients prescribed opioid analgesia dropped from 100% preoperatively to 20% at 6 months following surgery (p < 0.001). By 6 weeks, all patients were fully weight-bearing and able to walk independently with or without assistive devices. Conclusions: Percutaneous stabilization of metastatic periacetabular defects using PDNs is a safe and effective palliative procedure that has been shown to improve patient mobility and provide early pain relief. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Self-guided digital behavioural therapy versus active control for fibromyalgia (PROSPER-FM): a phase 3, multicentre, randomised controlled trial.

BACKGROUND: International guidelines have recommended cognitive behavioural therapy, including acceptance and commitment therapy (ACT), as it offers validated benefits for managing fibromyalgia; however, it is inaccessible to most patients. We aimed to evaluate the effect of a 12-week, self-guided, smartphone-delivered digital ACT programme on fibromyalgia management. METHODS: In the PROSPER-FM randomised clinical trial conducted at 25 US community sites, adult participants aged 22-75 years with fibromyalgia were recruited and randomly assigned (1:1) to the digital ACT group or an active control group that offered daily symptom tracking and monitoring and access to health-related and fibromyalgia-related educational materials. Randomisation was done with a web-based system in permuted blocks of four at the site level. We used a blind-to-hypothesis approach in which participants were informed they would be randomly assigned to one of two potentially effective therapies under evaluation. Research staff were not masked to group allocation, with the exception of a masked statistics group while preparing statistical programming for the interim analysis. The primary endpoint was patient global impression of change (PGIC) response rate at week 12. Analyses were by intention to treat. The trial was registered with ClinicalTrials.gov, NCT05243511 (now fully closed). FINDINGS: Between Feb 8, 2022, and Feb 2, 2023, 590 individuals were screened, of whom 275 (257 women and 18 men) were randomly assigned to the digital ACT group (n=140) and the active control group (n=135). At 12 weeks, 99 (71%) of 140 ACT participants reported improvement on PGIC versus 30 (22%) of 135 active control participants, corresponding to a difference in proportions of 48·4% (95% CI 37·9-58·9; p<0·0001). No device-related safety events were reported. INTERPRETATION: Digital ACT was safe and efficacious compared with digital symptom tracking in managing fibromyalgia in adult patients. FUNDING: Swing Therapeutics.

Fine-Tuning Low-Dose Total Skin Electron Therapy for Optimal Management of Cutaneous T-Cell Lymphoma: A Comparative Analysis of Regimens.

Purpose: Low-dose total skin electron beam therapy (TSEBT) is a proven treatment for managing cutaneous T-cell lymphoma (CTCL) and Sezary syndrome with skin burden. We performed a retrospective comparison of response rates and time to progression for patients receiving low-dose TSEBT based on dose per fractionation, total dose, and stage. Methods and Materials: One hundred and ten patients with CTCL and Sezary syndrome were treated with 135 courses of low-dose (400-1500 cGy) TSEBT or subtotal skin electron therapy at multiple centers of a single institution between August 2003 and June 2023. Patients were stratified according to total dose, dose per fraction, and stage. Results: The median follow-up was 301 days (IQR, 141, 767). The median age at treatment was 69.9 years (range, 29.7-96.5). T-stage distribution was as follows: 3 (2.7%) T1, 74 (67.3%) T2, 16 (14.5%) T3, and 17 (15.5%) T4. American Joint Committee on Cancer eighth edition stage distribution was as follows: 3 (2.7%) IA, 53 (48.2%) IB, 3 (2.7%) IIA, 16 (14.5%) IIB, 8 (7.3%) IIIA, 19 (17.3%) IVA, and 8 (7.3%) IVB. There was no significant difference in disease distribution between patients treated with different fractionation schemes. The overall response rate was 89.6%. Forty-four courses (32.6%), 34 courses (25.2%), and 43 (31.9%) resulted in a complete, near-complete, and partial response, respectively. Fourteen courses (10.4%) resulted in no clinical response. For all patients, the median time to response was 43.0 days (IQR, 23.0-70). The median time to skin progression for all patients was 107.5 days (IQR, 67.8-233.5). Conclusions: This analysis demonstrated that CTCL patients treated with low-dose radiation therapy delivered over various fractionation schemes had similar overall response rates and median time to progression.

What is the cognitive footprint of insular glioma?

Cognitive impairment has a profound deleterious impact on long-term outcomes of glioma surgery. The human insula, a deep cortical structure covered by the operculum, plays a role in a wide range of cognitive functions including interceptive thoughts and salience processing. Both low-grade (LGG) and high-grade gliomas (HGG) involve the insula, representing up to 25% of LGG and 10% of HGG. Surgical series from the past 30 years support the role of primary cytoreductive surgery for insular glioma patients; however, reported cognitive outcomes are often limited to speech and language function. The breath of recent neuroscience literature demonstrates that the insula plays a broader role in cognition including interoceptive thoughts and salience processing. This article summarizes the vast functional role of the healthy human insula highlighting how this knowledge can be leveraged to improve the care of patients with insular gliomas.

Pangenome comparison of Bacteroides fragilis genomospecies unveils genetic diversity and ecological insights.

Bacteroides fragilis is a Gram-negative commensal bacterium commonly found in the human colon, which differentiates into two genomospecies termed divisions I and II. Through a comprehensive collection of 694 B. fragilis whole genome sequences, we identify novel features distinguishing these divisions. Our study reveals a distinct geographic distribution with division I strains predominantly found in North America and division II strains in Asia. Additionally, division II strains are more frequently associated with bloodstream infections, suggesting a distinct pathogenic potential. We report differences between the two divisions in gene abundance related to metabolism, virulence, stress response, and colonization strategies. Notably, division II strains harbor more antimicrobial resistance (AMR) genes than division I strains. These findings offer new insights into the functional roles of division I and II strains, indicating specialized niches within the intestine and potential pathogenic roles in extraintestinal sites. IMPORTANCE: Understanding the distinct functions of microbial species in the gut microbiome is crucial for deciphering their impact on human health. Classifying division II strains as Bacteroides fragilis can lead to erroneous associations, as researchers may mistakenly attribute characteristics observed in division II strains to the more extensively studied division I B. fragilis. Our findings underscore the necessity of recognizing these divisions as separate species with distinct functions. We unveil new findings of differential gene prevalence between division I and II strains in genes associated with intestinal colonization and survival strategies, potentially influencing their role as gut commensals and their pathogenicity in extraintestinal sites. Despite the significant niche overlap and colonization patterns between these groups, our study highlights the complex dynamics that govern strain distribution and behavior, emphasizing the need for a nuanced understanding of these microorganisms.

Injury patterns in motor vehicle collision-youth pedestrian deaths.

OBJECTIVE: The objective of this study was to describe fatal pedestrian injury patterns in youth aged 15 to 24 years old and correlate them with motor vehicle collision (MVC) dynamics and pedestrian kinematics using data from medicolegal death investigations of MVCs occurring in the current Canadian motor vehicle (MV) fleet. METHODS: Based on a systematic literature review, MVC-pedestrian injuries were collated in an injury data collection form (IDCF). The IDCF was coded using the Abbreviated Injury Scale (AIS) 2015 revision. The AIS of the most frequent severe injury was noted for individual body regions. The Maximum AIS (MAIS) was used to define the most severe injury to the body overall and by body regions (MAISBR). This study focused on serious to maximal injuries (AIS 3-6) that had an increasing likelihood of causing death. The IDCF was used to extract collision and injury data from the Office of the Chief Coroner for Ontario (OCCO) database of postmortem examinations done at the Provincial Forensic Pathology Unit (PFPU) in Toronto, Canada, and other provincial facilities between 2013 and 2019. Injury data were correlated with data about the MVs and MV dynamics and pedestrian kinematics.The study was approved by the Western University Health Science Research Ethics Board (Project ID: 113440; Lawson Health Research Institute Approval No. R-19-066). RESULTS: There were 88 youth, including 54 (61.4%) males and 34 (38.6%) females. Youth pedestrians comprised 13.1% (88/670) of all autopsied pedestrians. Cars (n = 25/88, 28.4%) were the most frequent type of vehicle in single-vehicle impacts, but collectively vehicles with high hood edges (i.e., greater distance between the ground and hood edge) were in the majority. Forward projection (n = 34/88, 38.6%) was the most frequent type of pedestrian kinematics. Regardless of the type of vehicle, there was a tendency in most cases for the median MAISBR ≥ 3 to involve the head and thorax. A similar trend was seen in most of the pedestrian kinematics involving the various frontal impacts. Of the 88 cases, at least 63 (71.6%) were known to be engaged in risk-taking behaviors (e.g., activity on roadway). At least 12 deaths were nonaccidental (8 suicides and 4 homicides). Some activities may have been impairment related, because 26/63 (41.3%) pedestrians undertaking risk-taking behavior on the roadway were impaired. Toxicological analyses revealed that over half of the cases (47/88, 53.4%) tested positive for a drug that could have affected behavior. Ethanol was the most common. Thirty-one had positive blood results. CONCLUSION: A fatal dyad of head and thorax trauma was observed for pedestrians struck by cars. For those pedestrians hit by vehicles with high hood edges, which were involved in the majority of cases, a fatal triad of injuries to the head, thorax, and abdomen/retroperitoneum was observed. Most deaths occurred from frontal collisions and at speeds more than 35 km/h.

Atomic order of rare earth ions in a complex oxide: a path to magnetotaxial anisotropy.

Complex oxides offer rich magnetic and electronic behavior intimately tied to the composition and arrangement of cations within the structure. Rare earth iron garnet films exhibit an anisotropy along the growth direction which has long been theorized to originate from the ordering of different cations on the same crystallographic site. Here, we directly demonstrate the three-dimensional ordering of rare earth ions in pulsed laser deposited (EuxTm1-x)3Fe5O12 garnet thin films using both atomically-resolved elemental mapping to visualize cation ordering and X-ray diffraction to detect the resulting order superlattice reflection. We quantify the resulting ordering-induced 'magnetotaxial' anisotropy as a function of Eu:Tm ratio using transport measurements, showing an overwhelmingly dominant contribution from magnetotaxial anisotropy that reaches 30 kJ m-3 for garnets with x = 0.5. Control of cation ordering on inequivalent sites provides a strategy to control matter on the atomic level and to engineer the magnetic properties of complex oxides.

Effect of Different Isolation Methods on Bioaerosol Distribution: An In Vitro Study.

Purpose: The purposes of this in vitro study were to evaluate the effect of three isolation methods to mitigate bioaerosols during stainless steel crown (SSC) preparations and assess the distribution of Streptococcus mutans by aerosolization in closed-room operatories. Methods: Melamine teeth coated in laboratory-grown S. mutans biofilm were prepared for SSCs using three different isolation methods. Agar plates were placed in five locations throughout the operatory and opened during each preparation as well as for 10 minutes immediately following to collect aerosolized S. mutans. Bacterial colonies were counted after incubating plates for 48 hours. Data were analyzed for differences between the isolation method and plate locations. Results: Bacterial colony counts for teeth prepared using high-volume evacuation suction (HVE) with dental dam (DD) isolation were statistically significantly higher than for those prepared using HVE with a DryShield®(DS) and HVE with no isolation at the assistant (A) (P<0.001), operator face shield (FS) (P<0.001), and patient (Pt) (P=0.002) locations. No significant differences were found among isolation methods for parent (Pa) or rear delivery (RD) locations. The location that produced the most bacterial colony counts using HVE with DD isolation was FS (P<0.001), followed by A (P=0.04), Pt (P<0.001), and RD and Pa (P<0.001). Counts produced from teeth prepared with DS isolation were significantly higher at the Pt location than the A (P<0.001), FS (P=0.002), RD (P<0.001), and Pa (P=0.008) locations. Conclusion: The use of dental dam with high-volume evacuation suction during stainless steel crown preparations increased bioaerosols near the procedure, while dental evacuation systems (DryShield®) may effectively limit their spread.

Longitudinal Follow-up Comparing Future Care of Primary Teeth Treated with Silver Diammine Fluoride: A Private Dental Claims Review.

Purpose: The purpose of this study was to longitudinally evaluate follow-up treatment on primary teeth initially treated with silver diammine fluoride (SDF). Methods: This retrospective cohort evaluated private insurance (not Medicaid) claims data from 2018 to 2019 for children no older than 12 years with at least one primary tooth initially treated with SDF. Additional treatment per tooth was recorded over a follow-up of at least 24 months. Results: The mean and standard deviation (±SD) age of 46,884 patients was 5.7±2.3 and for SDF-treated teeth per patient was 2.6±2.1. Forty percent (95 percent confidence interval [95% CI] equals 39 to 40.7 percent) of teeth initially treated with SDF received additional treatment. The odds of SDF-treated teeth receiving future treatment significantly decreased with patient age by 22 percent per year (odds ratio equals 0.78; 95% CI equals 0.077 to 0.79; P<0.001). Pediatric dentists had only slightly lower odds than general dentists for providing additional treatment (0.91, P<0.001). Posterior teeth and teeth expected to exfoliate in two or more years had significantly higher odds of receiving additional treatment (2.47 and 1.27, respectively, P<0.001). Conclusions: Beginning at age four, patient age at placement of silver diammine fluoride was inversely proportional to future treatment provided. Posterior teeth and teeth expected to exfoliate in two or more years were more likely to receive additional treatment.

Central autonomic network dysfunction and plasma Alzheimer's disease biomarkers in older adults.

BACKGROUND: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults. METHODS: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aß42, Aß40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed. RESULTS: All autonomic networks were positively associated with Aß42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected. CONCLUSION: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aß42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.

Exploring cotton SFR2's conundrum in response to cold stress.

Cotton is an important agricultural crop to many regions across the globe but is sensitive to low-temperature exposure. The activity of the enzyme SENSITIVE TO FREEZING 2 (SFR2) improves cold tolerance of plants and produces trigalactosylsyldiacylglycerol (TGDG), but its role in cold sensitive plants, such as cotton remains unknown. Recently, it was reported that cotton SFR2 produced very little TGDG under normal and cold conditions. Here, we investigate cotton SFR2 activation and TGDG production. Using multiple approaches in the native system and transformation into Arabidopsis thaliana, as well as heterologous yeast expression, we provide evidence that cotton SFR2 activates differently than previously found among other plant species. We conclude with the hypothesis that SFR2 in cotton is not activated in a similar manner regarding acidification or freezing like Arabidopsis and that other regions of SFR2 protein are critical for activation of the enzyme than previously reported.

Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma.

The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

Sex differences in basal motivated behavior, chronic ethanol drinking, and amygdala activity in female and male mice.

Alcohol use disorder (AUD) is a major public health concern that despite its prevalence, lacks a widely-effective treatment due to the complexity of AUD pathology. AUD is highly comorbid with other psychiatric conditions including anxiety and mood disorders, however it is unclear how these disorders influence each other. The underlying etiology of these comorbidities is difficult to decipher and factors including sex, stress, and the environment further complicate both diagnosis and treatment strategies. To understand more about this bidirectional relationship between AUD and comorbid psychiatric disorders, we ran male and female C57Bl/6j mice through baseline behavioral testing followed by intermittent access-two bottle choice (IA-2BC) drinking. We found no sex differences in basal anxiety-like or depressive-like behavior, however females displayed enhanced motivated feeding behavior. Females consumed more ethanol than males, at both 1hr and 24hr timepoints. Basal affective state did not predict subsequent ethanol intake in either sex, however exploratory behavior was positively correlated with drinking in males but not females. We then re-assessed negative affect behavior following chronic ethanol drinking to determine if drinking impacted subsequent affective behavior and found no relationship between ethanol intake and affective state in males or females. We also examined how chronic ethanol drinking affected central amygdala (CeA) and basolateral amygdala (BLA) neuronal activity in males and females. Ethanol-drinking females had a decrease in CeA neuronal activity, driven by reduced activity in the lateral (CeAl) sub-region, while in males there was no significant difference in CeA activity compared to water controls. Neither males or females had a significant change in BLA neuronal activity following chronic ethanol drinking. Collectively, these results demonstrate sex differences in basal motivated behavior, drinking behavior, and subregion-specific amygdala neuronal activity following chronic ethanol drinking which may inform the sex differences seen in patients diagnosed with AUD and comorbid conditions.