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There is an ongoing debate about the ethics of research on lifespan extension: roughly, using medical technologies to extend biological human lives beyond the current "natural" limit of about 120 years. At the same time, there is an exploding interest in the use of artificial intelligence (AI) to create "digital twins" of persons, for example by fine-tuning large language models on data specific to particular individuals. In this paper, we consider whether digital twins (or digital doppelgängers, as we refer to them) could be a path toward a kind of life extension-or more precisely, a kind of person extension-that does not rely on biological continuity. We discuss relevant accounts of consciousness and personal identity and argue that digital doppelgängers may at least help us achieve some of the aims or ostensible goods of person-span extension, even if they may not count as literal extensions of our personhood on dominant philosophical accounts. We also consider relational accounts of personhood and discuss how digital doppelgängers may be able to extend personhood in a relational sense, or at least secure some of the goods associated with relevant relationships. We conclude by suggesting that a research program to investigate such issues is relevant to ongoing debates about the ethics of extending the human lifespan.

Participation in research is supposed to be voluntary and informed. Yet it is difficult to ensure people are adequately informed about the potential uses of their biological materials when they donate samples for future research. We propose a novel consent framework which we call "demonstrated consent" that leverages blockchain technology and generative AI to address this problem. In a demonstrated consent model, each donated sample is associated with a unique non-fungible token (NFT) on a blockchain, which records in its metadata information about the planned and past uses of the sample in research, and is updated with each use of the sample. This information is accessible to a large language model (LLM) customized to present this information in an understandable and interactive manner. Thus, our model uses blockchain and generative AI technologies to track, make available, and explain information regarding planned and past uses of donated samples.

The rapidly advancing field of brain-computer (BCI) and brain-to-brain interfaces (BBI) is stimulating interest across various sectors including medicine, entertainment, research, and military. The developers of large-scale brain-computer networks, sometimes dubbed 'Mindplexes' or 'Cloudminds', aim to enhance cognitive functions by distributing them across expansive networks. A key technical challenge is the efficient transmission and storage of information. One proposed solution is employing blockchain technology over Web 3.0 to create decentralised cognitive entities. This paper explores the potential of a decentralised web for coordinating large brain-computer constellations, and its associated benefits, focusing in particular on the conceptual and ethical challenges this innovation may pose pertaining to (1) Identity, (2) Sovereignty (encompassing Autonomy, Authenticity, and Ownership), (3) Responsibility and Accountability, and (4) Privacy, Safety, and Security. We suggest that while a decentralised web can address some concerns and mitigate certain risks, underlying ethical issues persist. Fundamental questions about entity definition within these networks, the distinctions between individuals and collectives, and responsibility distribution within and between networks, demand further exploration., (© 2024. The Author(s).)

With the advent of robust and high-throughput mass spectrometric technologies and bioinformatics tools to analyze large data sets, proteomics has penetrated broadly into basic and translational life sciences research. More than 95% of FDA-approved drugs currently target proteins, and most diagnostic tests are protein-based. The introduction of proteomics to the clinic, for instance to guide patient stratification and treatment, is already ongoing. Importantly, ethical challenges come with this success, which must also be adequately addressed by the proteomics and medical communities. Consortium members of the H2020 European Union-funded proteomics initiative: European Proteomics Infrastructure Consortium-providing access (EPIC-XS) met at the Core Technologies for Life Sciences (CTLS) conference to discuss the emerging role and implementation of proteomics in the clinic. The discussion, involving leaders in the field, focused on the current status, related challenges, and future efforts required to make proteomics a more mainstream technology for translational and clinical research. Here we report on that discussion and provide an expert update concerning the feasibility of clinical proteomics, the ethical implications of generating and analyzing large-scale proteomics clinical data, and recommendations to ensure both ethical and effective implementation in real-world applications., Competing Interests: Competing interests: M. M. is an indirect investor in Evosep Biosystems. All other authors declare no competing interests., (Copyright: © 2023 Mundt F et al.)

Recent advances in mass spectrometry (MS)-based proteomics have vastly increased the quality and scope of biological information that can be derived from human samples. These advances have rendered current workflows increasingly applicable in biomedical and clinical contexts. As proteomics is poised to take an important role in the clinic, associated ethical responsibilities increase in tandem with impacts on the health, privacy, and wellbeing of individuals. We conducted and here report a systematic literature review of ethical issues in clinical proteomics. We add our perspectives from a background of bioethics, the results of our accompanying paper extracting individual-sensitive results from patient samples, and the literature addressing similar issues in genomics. The spectrum of potential issues ranges from patient re-identification to incidental findings of clinical significance. The latter can be divided into actionable and unactionable findings. Some of these have the potential to be employed in discriminatory or privacy-infringing ways. However, incidental findings may also have great positive potential. A plasma proteome profile, for instance, could inform on the general health or disease status of an individual regardless of the narrow diagnostic question that prompted it. We suggest that early discussion of ethical issues in clinical proteomics can ensure that eventual healthcare practices and regulations reflect the considered judgment of the community and anticipate opportunities and problems that may arise as the technology matures., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The goal of clinical proteomics is to identify, quantify, and characterize proteins in body fluids or tissue to assist diagnosis, prognosis, and treatment of patients. In this way, it is similar to more mature omics technologies, such as genomics, that are increasingly applied in biomedicine. We argue that, similar to those fields, proteomics also faces ethical issues related to the kinds of information that is inherently obtained through sample measurement, although their acquisition was not the primary purpose. Specifically, we demonstrate the potential to identify individuals both by their characteristic, individual-specific protein levels and by variant peptides reporting on coding single nucleotide polymorphisms. Furthermore, it is in the nature of blood plasma proteomics profiling that it broadly reports on the health status of an individual-beyond the disease under investigation. Finally, we show that private and potentially sensitive information, such as ethnicity and pregnancy status, can increasingly be derived from proteomics data. Although this is potentially valuable not only to the individual, but also for biomedical research, it raises ethical questions similar to the incidental findings obtained through other omics technologies. We here introduce the necessity of-and argue for the desirability for-ethical and human-rights-related issues to be discussed within the proteomics community. Those thoughts are more fully developed in our accompanying manuscript. Appreciation and discussion of ethical aspects of proteomic research will allow for deeper, better-informed, more diverse, and, most importantly, wiser guidelines for clinical proteomics., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article, (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Chimeras have been an important part of animal research for decades. Yet crossing the species barrier has always been seen as potentially morally problematic. In recent years, advances in chimeric research and the attendant possibilities-organ xenotransplantation, cognitive enhancement, and others-have given rise to further ethical concern. This contribution surveys the main ethical questions that have been discussed in the literature. We examine two arguments-from the order of nature and from human dignity-which aim to show that chimerization is inherently wrong. Finding the first untenable and the second largely inapplicable, we then turn to two unconvincing arguments designed to show that chimerization must necessarily lead to negative outcomes. Having thus found that no blanket statements can be made on the ethics of chimerization, we examine two important parameters relevant to the ethical evaluation of proposed chimeric research: the argument from moral status and from risk.

Physical activity and alternate-day fasting/caloric restriction may both ameliorate aspects of the metabolic syndrome, such as insulin resistance, visceral fat mass accumulation, and cognitive impairment by overlapping mechanisms. The purpose of this study was to test the hypothesis that alternate-day caloric restriction (ADCR) with overall energy balance would reduce insulin resistance and accumulation of visceral fat, in addition to improving cognitive functions, after 8 consecutive days in bed. Healthy, lean men (n = 20) were randomized to 1) 8 days of bed rest with three daily isoenergetic meals (control group, n = 10); and 2) 8 days of bed rest with 25% of total energy requirements every other day and 175% of total energy requirements every other day (ADCR group). Oral glucose tolerance testing, dual-energy X-ray absorptiometry (DXA) scans, magnetic resonance imaging of the abdomen and brain, V̇o 2max , and tests for cognitive function were performed before and after bed rest. In addition, daily fasting blood samples and 24-h glucose profiles by continuous glucose monitoring system were assessed during the 8 days of bed rest period. Bed rest induced insulin resistance, visceral fat accumulation, and worsening of mood. No positive effects emerged from ADCR on these negative health outcomes. Compared with the control group, ADCR was associated with improved and steadier glycemic control on fasting days and higher glycemic fluctuation and indexes of insulin resistance on overeating days. In contrast to our hypothesis, the metabolic impairment induced by 8 days of bed rest was not counteracted by ADCR with overall energy balance., New & Noteworthy: Alternate-day caloric restriction without overall energy reduction does not ameliorate the metabolic impairment induced in lean men by 8 days of bed rest., (Copyright © 2017 the American Physiological Society.)

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone's efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisone-treated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression.

Herbal preparations are widely available and generally regarded by the public as harmless remedies for a variety of medical ailments. We report the first case in Australia of acute hepatitis associated with the Chinese herbal medicine Shou-Wu-Pian, prepared from Polygonum multiflorum. Cholestatic hepatitis developed in a Chinese woman taking this preparation for the greying of her hair, and liver biopsy was consistent with a toxic reaction. Clinical and biochemical resolution occurred following cessation of the drug.

The aim of this study was to review the clinical, serological and histopathological features of 20 patients who underwent orthotopic liver transplantation for hepatitis B virus (HBV) related liver disease in an attempt to identify factors which predict recurrence of HBV infection, pattern of disease and disease severity. Hepatitis B recurrence occurred in 11 patients (55%). Positive immunoperoxidase staining for HBsAg and HBcAg of the hepatectomy specimen were shown to have a sensitivity (82% and 64% respectively) and specificity (55% and 66%) in predicting recurrence. This was comparable to serological markers such as HBV DNA (36% sensitivity and 89% specificity). The staining for HBcAg in some cases was weak, focal and had a reticular pattern. Therefore, examination of multiple blocks with a high magnification was necessary to detect HBcAg staining. Negative staining of multiple sections for HBsAg and HBcAg were shown to have a good correlation with clearing of HBV infection (5 out of 6 patients). If recurrence occurred, the range of histological and clinical patterns of HBV recurrence was varied, with severe disease occurring in 5 patients. Neither pre-transplant serology nor hepatectomy immunoperoxidase staining characteristics were shown to be of value in predicting the pattern or the severity of disease once HBV recurrence had occurred. This study indicates that lack of staining for HBV antigens on multiple sections of the native liver may predict a subgroup of HBsAg positive transplant patients who will not suffer from recurrent disease. Once disease did occur however, markers for severity of recurrence were not identified.

Recombinant plasmid pM25 containing the celE gene of Clostridium thermocellum, which codes for an enzymatically active endoglucanase, was transformed into Lactobacillus plantarum by electroporation. Strains harboring pM25 expressed thermostable endoglucanase, which was found predominantly in the culture medium. Two other plasmids, pGK12 and pSA3, were transformed into L. plantarum, and the stability of each plasmid was evaluated.

Dopamine concentrations were estimated in different regions of the infundibular-pituitary system of the rat. The highest values were found in the pituitary stalk where they are comparable to the concentrations in the striatum, and higher than in the median eminence. In the anterior lobe the dopamine (DA) concentrations of the upper pole (10% of the lobe tissue) were 2-5 times higher than in the rest of the lobe. Anterior lobe DA was significantly higher in rats about 6 months old than in rats about 3 months old. After inhibition of MAO, the DA concentrations in the isolated neural lobe (NL) were more than doubled. In contrast there was no increase in the DA concentrations of the intermediate lobe, an observation which is in agreement with our previous finding that DA synthesis in the intermediate lobe after electrical stimulation of the pituitary stalk is much slower than in the neural lobe. Pargyline treatment caused an increase in the DA concentrations in the anterior lobe by about 150%. This rise (together with a DA increase in the stalk-infundibulum) may be related to the decrease in circulating prolactin which occurs in pargyline treated rats.

The combined neural and intermediate lobes (N.I.L.) of the pituitary glands of Brattleboro rats contained significantly more noradrenaline (NA) than those of normal controls of the same age. In addition, in 4 and 6 months old rats the N.I.L. of the homozygotes (Di-rats) contained about twice as much NA as those of the heterozygotes (non-Di-rats). In the enlarged and hyperaemic neural lobes of the Di-rats enlarged blood vessels could be seen. They were surrounded by a rich network of nerve fibres which displayed catecholamine fluorescence. The NA concentrations in the medial basal hypothalamus (M.B.H.) of 4, 6, and 9 months old Di-rats were significantly higher than those of the non-Di-rats and of controls of the same age. This may contribute to the diminished ACTH secretion in Brattleboro rats. The total amount of DA contained in the N.I.L. of 9 months old Di-rats was 20% lower than in the non-Di-rats of the same age. The concentrations of homovanillic acid (HVA) in the corpora striata of 4 months old Di- and non-Di-rats was significantly higher than in older Brattleboro rats and in control rats of various strains and ages. At 9 months it was nearly twice as high in the Di-rats as in the non-Di-rats. The concentrations of dihydroxyphenylacetic acid in the striata of 4--6 months old Di- and non-Di-rats were higher than those of Long Evans rats of the same age.

Duct ligation was found to cause a decrease in the weights of submaxillary and parotid glands examined 3 weeks postoperatively. Choline acetyltransferase activity in ligated glands was compared with that in unligated contralateral glands. The enzyme activity was also measured in the glands from both sides of unoperated control animals. Interference in the assay of choline acetyltransferase by other acetylated compounds was avoided by introducing suitable control incubations. Ligated submaxillary glands showed a small decrease in the activity of choline acetyltransferase both when compared with contralateral glands and with glands of control rats. In parotid glands the enzyme activity was found to be lower only when ligated and contralateral glands were compared. Structural changes in the nerves and reduced traffic of impulses in them may have to be considered as explanations for the reduction in enzyme activity in duct-ligated glands.

The activity of tyrosine hydroxylase (TH) in the corpus striatum of haloperidol treated and control rats has been examined. The activation of TH by haloperidol caused a decrease in the Km for tetrahydrobiopterin but no change in the Vmax. This effect was totally abolished when homogenates were prepared at high values of pH. A similar activation could be produced in vitro by preincubating with S-adenosylmethionine; conversely, enzyme activity was reduced by preincubating with S-adenosylhomocysteine. ATP and cyclic AMP activated the enzyme when incubated together with TH in vitro but the activity was reduced when the enzyme was preincubated with these substances. A possible role for carboxymethylation in controlling tyrosine hydroxylase activity is discussed.

1. Early weaning in piglets is associated with changes in dopamine metabolism in the caudate nucleus. In particular, a decrease in the amount of the enzyme tyrosine hydroxylase was observed. 2. An analysis of the kinetic properties of tyrosine hydroxylase from the caudate nucleus of early-weaned piglets shows that there is a relative increase in the activity of the enzyme which may indicate a mechanism compensating for the decreased amount of enzyme. 3. The increase in activity is mediated through a decrease in the Km for tetrahydrobiopterin and is reversed, in vitro, when the tissue is homogenized at pH values greater than 8.0.

In the urinary bladder of the rat, partially denervated by unilateral removal of the pelvic ganglion 3 days in advance, the activity of the acetylcholine-forming enzyme, choline acetyltransferase, measured by a radiolabelling method, was reduced to 58% of the control. A gain in enzyme activity of 28% was found to have occurred when the bladders were examined 25 days postoperatively; the main part of this increase took place during the period 3 to 6 days after the operation and beyond 25 days no further gain in enzyme activity was found. The present findings are compared with previous observations of a transient supersensitivity and an increased motor response to electrical stimulation of the intact pelvic nerve of such a partially denervated bladder.

The distribution of glycerylphosphorylcholine diesterase in the rat brain has been examined. The enzyme was evenly distributed throughout the brain but was localized in the synaptosome (nerve ending) fraction which was prepared by ultracentrifugation.

Labelled free choline injected into the peritoneum failed to enter the brain but preferentially entered the liver. Subsequently labelled phospholipid was found in the plasma with a concurrent increase in the brain. This labelled plasma injected by cardiac puncture caused a rapid incorporation of the choline labelled phospholipid into the brain.