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The management of patients with diffuse liver metastases remains a significant clinical challenge. In many cancer patients, metastatic disease may be isolated to the liver or the liver may be the dominant site of progressive metastatic cancer. In this setting, progression of disease in the liver generally is the most significant cause of morbidity and mortality., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Since a significant proportion of plant matter is consumed by herbivores, a necessary adaptation for many phyllosphere microbes could be to survive through the guts of herbivores. While many studies explore the gut microbiome of herbivores by surveying the microbiome in their frass, few studies compare the phyllosphere microbiome to the gut microbiome of herbivores. High-throughput metabarcode sequencing was used to track the fungal community from milkweed (Asclepias spp.) leaves to monarch caterpillar frass. The most commonly identified fungal taxa that dominated the caterpillar frass after the consumption of leaves were yeasts, mostly belonging to the Basidiomycota phylum. While most fungal communities underwent significant bottlenecks and some yeast taxa increased in relative abundance, a consistent directional change in community structure was not identified from leaf to caterpillar frass. These results suggest that some phyllosphere fungi, especially diverse yeasts, can survive herbivory, but whether herbivory is a key stage of their life cycle remains uncertain. For exploring phyllosphere fungi and the potential coprophilous lifestyles of endophytic and epiphytic fungi, methods that target yeast and Basidiomycota fungi are recommended., (© 2024 The Authors. Environmental Microbiology Reports published by Applied Microbiology International and John Wiley & Sons Ltd.)

Microglia and neuroinflammation play an important role in the development and progression of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD., (© 2023. The Author(s).)

SORL1 is implicated in the pathogenesis of Alzheimer's disease (AD) through genetic studies. To interrogate the roles of SORL1 in human brain cells, SORL1-null induced pluripotent stem cells (iPSCs) were differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) and altered lipid profiles. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in postmortem brain. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1-null neurons but does not rescue APOE levels. Pathway analyses implicate transforming growth factor β (TGF-β)/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Taken together, these data provide a mechanistic link between strong genetic risk factors for AD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) manifests along a spectrum of cognitive deficits and levels of neuropathology. Genetic studies support a heterogeneous disease mechanism, with around 70 associated loci to date, implicating several biological processes that mediate risk for AD. Despite this heterogeneity, most experimental systems for testing new therapeutics are not designed to capture the genetically complex drivers of AD risk. In this review, we first provide an overview of those aspects of AD that are largely stereotyped and those that are heterogeneous, and we review the evidence supporting the concept that different subtypes of AD are important to consider in the design of agents for the prevention and treatment of the disease. We then dive into the multifaceted biological domains implicated to date in AD risk, highlighting studies of the diverse genetic drivers of disease. Finally, we explore recent efforts to identify biological subtypes of AD, with an emphasis on the experimental systems and data sets available to support progress in this area., Competing Interests: Declaration of interests D.J.S. is a director and consultant to Prothena Biosciences and an ad hoc advisor to Eisai and Roche. T.L.Y-P. is a member of the AMP-AD consortium and collaborates with industry partners within the context of AMP-AD., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1 G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration., Competing Interests: Declaration of interests I.M.C. receives sponsored research support from Abbvie/Allergan Pharmaceuticals and is on the SAB for GSK and LIMM therapeutics. J.L. is a cofounder and SAB member of Ventus Therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Loss-of-function mutations in the depalmitoylating enzyme palmitoyl protein thioesterase 1 (PPT1) cause neuronal ceroid lipofuscinosis (NCL), a devastating neurodegenerative disease. The substrates of PPT1 are largely undescribed, posing a limitation on molecular dissection of disease mechanisms and therapeutic development. Here, we provide a resource identifying >100 novel PPT1 substrates. We utilized Acyl Resin-Assisted Capture (Acyl RAC) and mass spectrometry to identify proteins with increased in vivo palmitoylation in PPT1 knockout (KO) mouse brains. We then validated putative substrates through direct depalmitoylation with recombinant PPT1. This stringent screen elucidated diverse PPT1 substrates at the synapse, including channels and transporters, G-protein-associated molecules, endo/exocytic components, synaptic adhesion molecules, and mitochondrial proteins. Cysteine depalmitoylation sites in transmembrane PPT1 substrates frequently participate in disulfide bonds in the mature protein. We confirmed that depalmitoylation plays a role in disulfide bond formation in a tertiary screen analyzing posttranslational modifications (PTMs). Collectively, these data highlight the role of PPT1 in mediating synapse functions, implicate molecular pathways in the etiology of NCL and other neurodegenerative diseases, and advance our basic understanding of the purpose of depalmitoylation., Competing Interests: The authors have declared that no competing interests exist.

The convergence of internal path integration and external sensory landmarks generates a cognitive spatial map in the hippocampus. We studied how localized odor cues are recognized as landmarks by recording the activity of neurons in CA1 during a virtual navigation task. We found that odor cues enriched place cell representations, dramatically improving navigation. Presentation of the same odor at different locations generated distinct place cell representations. An odor cue at a proximal location enhanced the local place cell density and also led to the formation of place cells beyond the cue. This resulted in the recognition of a second, more distal odor cue as a distinct landmark, suggesting an iterative mechanism for extending spatial representations into unknown territory. Our results establish that odors can serve as landmarks, motivating a model in which path integration and odor landmarks interact sequentially and iteratively to generate cognitive spatial maps over long distances., Competing Interests: Declaration of interests M.J.S. is a scientific co-founder of Inscopix, which produces the miniature fluorescence microscope used in this study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aβ and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD., Competing Interests: Declaration of interests D.J.S. is a director and consultant for Prothena Biosciences., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The management of patients with diffuse liver metastases remains a significant clinical challenge. In many cancer patients, metastatic disease may be isolated to the liver or the liver may be the dominant site of progressive metastatic cancer. In this setting, progression of disease in the liver generally is the most significant cause of morbidity and mortality., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Satisfaction with a contraceptive method constitutes an important factor in its acceptance and long-term use. The objective of this study was to assess the relationship between user satisfaction with the 20-μg/day levonorgestrel-releasing intrauterine system (LNG-IUS) and the bleeding patterns reported at two different time-points during follow-up., Methods: A total of 251 LNG-IUS users aged 18-45 years were invited to answer a questionnaire on their return to the clinic for a routine follow-up visit and again 1 year later. Data were collected face-to-face., Results: Twenty women discontinued prematurely; therefore, the analysis was performed on 231 women. Most users were either highly satisfied (66.6% and 66.2% at the first and second interviews, respectively) or satisfied (26.4% and 26.4% at the first and second interviews, respectively) with the LNG-IUS. Satisfaction was related to amenorrhea (P < 0.001) and duration of use (P < 0.001). Prolonged bleeding and spotting were the main causes of dissatisfaction with the device., Conclusion: Most LNG-IUS users in this sample were satisfied with the device. The only two factors associated with satisfaction were amenorrhea and duration of use, while prolonged bleeding and spotting were the main causes of dissatisfaction. These findings could be useful for health-care professionals and policy-makers when developing information material for women. The study provides insight into the profile of satisfied LNG-IUS users; however, this information is not suitable for counseling women who are considering using an LNG-IUS., (© 2017 Japan Society of Obstetrics and Gynecology.)

Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJ-depleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-κB and MYC were essential for survival of RBPJ-depleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notch-independent activation by alternate transcription factors that promote tumorigenesis., (© 2015 Kulic et al.)

Background: Between June-October 2012, 61 flight-medic-directed transfusions took place aboard U.S. Army Medical Evacuation (medevac) helicopters in Afghanistan. This represents the initial experience for pre-hospital blood product transfusion by U.S. Army flight medics., Methods: We performed a retrospective review of clinical records, operating guidelines, after-action reviews, decision and information briefs, bimonthly medical conferences, and medevac-related medical records., Results: A successful program was administered at 10 locations across Afghanistan. Adherence to protocol transfusion indications was 97%. There were 61 casualties who were transfused without any known instance of adverse reaction or local blood product wastage. Shock index (heart rate/systolic blood pressure) improved significantly en route, with a median shock index of 1.6 (IQR 1.2-2.0) pre-transfusion and 1.1 (IQR 1.0-1.5) post-transfusion (P < 0.0001). Blood resupply, training, and clinical procedures were standardized across each of the 10 areas of medevac operations., Discussion: Potential risks of medical complications, reverse propaganda, adherence to protocol, and diversion and/or wastage of limited resources were important considerations in the development of the pilot program. Aviation-specific risk mitigation strategies were important to ensure mission success in terms of wastage prevention, standardized operations at multiple locations, and prevention of adverse clinical outcomes. Consideration of aviation risk mitigation strategies may help enable other helicopter emergency medical systems to develop remote pre-hospital transfusion capability. This pilot program provides preliminary evidence that blood product administration by medevac is safe.

Balsam of Peru (BOP) is a well-known contact allergen that is one of the most prevalent in the United States. For some patients allergic to BOP, external avoidance of fragrance is not enough to eliminate their dermatitis. A BOP avoidance diet has been shown to help many of these patients. This article reviews BOP allergens found in food. A special patch test series of allergens found in BOP along with data regarding which foods contain specific BOP constituents makes it possible to design potential targeted, refined, and simplified diets for BOP systemic contact dermatitis.

The 5- and 12/15-lipoxygenase (LOX) isozymes have been implicated to contribute to disease development in CNS disorders such as Alzheimer's disease. These LOX isozymes are distinct in function, with differential effects on neuroinflammation, and the impact of the distinct isozymes in the pathogenesis of Parkinson's disease has not as yet been evaluated. To determine whether the isozymes contribute differently to nigrostriatal vulnerability, the effects of 5- and 12/15-LOX deficiency on dopaminergic tone under naïve and toxicant-challenged conditions were tested. In naïve mice deficient in 5-LOX expression, a modest but significant reduction (18.0% reduction vs. wildtype (WT)) in striatal dopamine (DA) was detected (n=6-8 per genotype). A concomitant decline in striatal tyrosine hydroxylase (TH) enzyme was also revealed in null 5-LOX vs. WT mice (26.2%); however, no changes in levels of DA or TH immunoreactivity were observed in null 12/15-LOX vs. WT mice. When challenged with the selective dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), WT mice showed a marked reduction in DA (31.9%) and robust astrocytic and microglial activation as compared to saline-treated animals. In contrast, null 5-LOX littermates demonstrated no significant striatal DA depletion or astrogliosis (as noted by Western blot analyses for glial acidic fibrillary protein (GFAP) immunoreactivity). In naïve null 12/15-LOX mice, no significant change in striatal DA values was observed compared to WT, and following MPTP treatment, the transgenics revealed striatal DA reduction similar to the challenged WT mice. Taken together, these data provide the first evidence that: (i) LOX isozymes are involved in the maintenance of normal dopaminergic function in the striatum and (ii) the 5- and 12/15-LOX isozymes contribute differentially to striatal vulnerability in response to neurotoxicant challenge., (Copyright © 2012 IBRO. All rights reserved.)

Allergic disorders and skin response to histamine have been noted to vary in different ethnicities. We investigated IgE-mediated allergic sensitization and skin response to histamine in Asian Pacific Americans (APAs), black and Hispanic Americans, and white adults. A retrospective questionnaire-based study was performed of 2222 adults presenting at a New York City allergy referral center from 1994 to 2003. Questionnaire data included sex, age, and ethnicity and personal and family history of atopic disorders. Skin-prick test (SPT) data included saline and histamine controls and response to a standardized panel of 10 aeroallergens. APA patients had a lower odds of asthma (adjusted odds ratio [aOR], 0.68; 95% confidence interval [CI], 0.52-0.89; p = 0.005) and/or animal allergies (aOR, 0.64; 95% CI, 0.50-0.82; p = 0.0003). Histamine response was not significantly different in APA (aOR, 0.90; 95% CI, 0.73-1.12; p = 0.36) or Hispanic Americans (aOR, 1.03; 95% CI, 0.85-1.24; p = 0.76), but was higher in black Americans (aOR, 2.32; 95% CI, 1.67-3.21; p < 0.0001). APA had higher odds of a positive SPT to trees (aOR, 1.49; 95% CI, 1.16-1.91; p = 0.002), grasses (aOR, 1.32; 95% CI, 1.05-1.43; p = 0.02), feathers (aOR, 1.65; 95% CI, 1.31-2.09; p < 0.0001), and cockroaches (aOR, 1.37; 95% CI, 1.10-1.62; p = 0.005). Moreover, APA had a higher total number of positive SPTs when compared with white patients (5.5 ± 3.2 versus 4.9 ± 3.3; aOR, 1.34; 95% CI, 1.10-1.62 p = 0.004). APA adults in our patient population had more IgE sensitizations but not an increased skin response to histamine. In contrast, black Americans had increased skin response to histamine.

Research with human oocytes, embryos, and additional embryonic stem cell lines is needed to address important scientific questions and to fulfill the promise of stem cell transplantation for degenerative diseases. Proponents need to develop guidelines for the appropriate conduct of embryonic stem cell research. Such guidelines will help build public trust and acceptance for this research. In this article, we offer recommendations for informed consent, discussing who should give consent, what the consent process should cover, when consent should be obtained, and who should obtain consent. Consent to use embryos for research should be obtained from oocyte and sperm donors as well as from the woman or couple undergoing infertility treatment. The consent discussion must cover information that donors need to know to make an informed decision about various types of research. Donations for research should be discussed at the initiation of advanced infertility treatment and reconfirmed if possible at the time of actual donation for research. Treating assisted reproduction technology physicians can help with the consent process, provided that they are not involved in the research.

The Samaritan community, which numbered more than a million in late Roman times and only 146 in 1917, numbers today about 640 people representing four large families. They are culturally different from both Jewish and non-Jewish populations in the Middle East and their origin remains a question of great interest. Genetic differences between the Samaritans and neighboring Jewish and non-Jewish populations are corroborated in the present study of 7,280 bp of nonrecombining Y-chromosome and 5,622 bp of coding and hypervariable segment I (HVS-I) mitochondrial DNA (mtDNA) sequences. Comparative sequence analysis was carried out on 12 Samaritan Y-chromosome, and mtDNA samples from nine male and seven female Samaritans separated by at least two generations. In addition, 18-20 male individuals were analyzed, each representing Ethiopian, Ashkenazi, Iraqi, Libyan, Moroccan, and Yemenite Jews, as well as Druze and Palestinians, all currently living in Israel. The four Samaritan families clustered to four distinct Y-chromosome haplogroups according to their patrilineal identity. Of the 16 Samaritan mtDNA samples, 14 carry either of two mitochondrial haplotypes that are rare or absent among other worldwide ethnic groups. Principal component analysis suggests a common ancestry of Samaritan and Jewish patrilineages. Most of the former may be traced back to a common ancestor in the paternally-inherited Jewish high priesthood (Cohanim) at the time of the Assyrian conquest of the kingdom of Israel., (Copyright 2004 Wiley-Liss, Inc.)

Context: Noninvasive prenatal diagnostic tests using free fetal DNA provide an alternative to invasive tests and their attendant risks; however, free fetal DNA exists in the maternal circulation at low percentages, which has hindered development of noninvasive tests., Objective: To test the hypothesis that using formaldehyde to reduce cell lysis could increase the relative percentage of free fetal DNA in samples of maternal blood., Design, Setting, and Patients: The first phase of the study was conducted from January through February 2002 at a single US clinical site; 2 samples of blood were collected from each of 10 pregnant women, and the percentage of free fetal DNA in formaldehyde-treated and untreated samples was determined. The second phase of the study was conducted from March 2002 through May 2003, and measured the percentage of free fetal DNA in 69 formaldehyde-treated samples of maternal blood obtained from a network of 27 US clinical sites in 16 states., Main Outcome Measure: Percentage of free fetal DNA in samples of maternal blood., Results: In the first phase of the study, the mean percentage of free fetal DNA in the untreated samples was 7.7% (range, 0.32%-40%), while the mean percentage of free fetal DNA in the formaldehyde-treated samples was 20.2% (range, 1.6%-40%) (P =.02 for difference). In the second phase, a median of 25% (range, 3.1% to >50%) free fetal DNA was obtained for the 69 formaldehyde-treated maternal blood samples. Approximately 59% of the samples in this study had 25% or greater fetal DNA, and only 16% of the samples had less than 10% fetal DNA. In addition, 27.5% of the samples in this study had 50% or greater fetal DNA., Conclusion: Addition of formaldehyde to maternal blood samples, coupled with careful processing protocols, increases the relative percentage of free fetal DNA, providing a foundation for development of noninvasive prenatal diagnostic tests to distinguish fetal DNA from maternal DNA in the maternal circulation.

As research with human embryos and embryonic stem cells proceeds, the authors of this Policy Forum argue that all donors of biological materials should give informed consent, including oocyte and sperm donors. Informed consent is particularly important because of the diverse opinions and strong emotions that surround such research. Some gamete donors who are willing to help women and couples bear children may object to the use of their genetic materials for certain types of research.