ObjectiveFamilial neuropsychological deficits are well established in schizophrenia but remain less well characterized in other psychotic disorders. This study from the Bipolar-Schizophrenia Network ...on Intermediate Phenotypes (B-SNIP) consortium 1) compares cognitive impairment in schizophrenia and bipolar disorder with psychosis, 2) tests a continuum model of cognitive dysfunction in psychotic disorders, 3) reports familiality of cognitive impairments across psychotic disorders, and 4) evaluates cognitive impairment among nonpsychotic relatives with and without cluster A personality traits.MethodParticipants included probands with schizophrenia (N=293), psychotic bipolar disorder (N=227), schizoaffective disorder (manic, N=110; depressed, N=55), their first-degree relatives (N=316, N=259, N=133, and N=64, respectively), and healthy comparison subjects (N=295). All participants completed the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery.ResultsCognitive impairments among psychotic probands, compared to healthy comparison subjects, were progressively greater from bipolar disorder (z=–0.77) to schizoaffective disorder (manic z=–1.08; depressed z=–1.25) to schizophrenia (z=–1.42). Profiles across subtests of the BACS were similar across disorders. Familiality of deficits was significant and comparable in schizophrenia and bipolar disorder. Of particular interest were similar levels of neuropsychological deficits in relatives with elevated cluster A personality traits across proband diagnoses. Nonpsychotic relatives of schizophrenia probands without these personality traits exhibited significant cognitive impairments, while relatives of bipolar probands did not.ConclusionsRobust cognitive deficits are present and familial in schizophrenia and psychotic bipolar disorder. Severity of cognitive impairments across psychotic disorders was consistent with a continuum model, in which more prominent affective features and less enduring psychosis were associated with less cognitive impairment. Cognitive dysfunction in first-degree relatives is more closely related to psychosis-spectrum personality disorder traits in psychotic bipolar disorder than in schizophrenia.
Abstract Amongst the major types of archaeal filaments, several have been shown to closely resemble bacterial homologues of the Type IV pili (T4P). Within Sulfolobales , member species encode for ...three types of T4P, namely the archaellum, the UV-inducible pilus system (Ups) and the archaeal adhesive pilus (Aap). Whereas the archaellum functions primarily in swimming motility, and the Ups in UV-induced cell aggregation and DNA-exchange, the Aap plays an important role in adhesion and twitching motility. Here, we present a cryoEM structure of the Aap of the archaeal model organism Sulfolobus acidocaldarius . We identify the component subunit as AapB and find that while its structure follows the canonical T4P blueprint, it adopts three distinct conformations within the pilus. The tri-conformer Aap structure that we describe challenges our current understanding of pilus structure and sheds new light on the principles of twitching motility.
Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed ...on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells.
Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate ORR: complete and partial response (PR); secondary end points included clinical benefit ORR+stable disease (SD), progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile.
From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent.
Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials.
NCT01197885.
In-vivo foliar spectroscopy, also known as contact hyperspectral reflectance, enables rapid and non-destructive characterization of plant physiological status. This can be used to assess pathogen ...impact on plant condition both prior to and after visual symptoms appear. Challenging this capacity is the fact that dead tissue yields relatively consistent changes in leaf optical properties, negatively impacting our ability to distinguish causal pathogen identity. Here, we used in-situ spectroscopy to detect and differentiate Phytophthora infestans (late blight) and Alternaria solani (early blight) on potato foliage over the course of disease development and explored non-destructive characterization of contrasting disease physiology. Phytophthora infestans, a hemibiotrophic pathogen, undergoes an obligate latent period of two–seven days before disease symptoms appear. In contrast, A. solani, a necrotrophic pathogen, causes symptoms to appear almost immediately when environmental conditions are conducive. We found that respective patterns of spectral change can be related to these differences in underlying disease physiology and their contrasting pathogen lifestyles. Hyperspectral measurements could distinguish both P. infestans-infected and A. solani-infected plants with greater than 80% accuracy two–four days before visible symptoms appeared. Individual disease development stages for each pathogen could be differentiated from respective controls with 89–95% accuracy. Notably, we could distinguish latent P. infestans infection from both latent and symptomatic A. solani infection with greater than 75% accuracy. Spectral features important for late blight detection shifted over the course of infection, whereas spectral features important for early blight detection remained consistent, reflecting their different respective pathogen biologies. Shortwave infrared wavelengths were important for differentiation between healthy and diseased, and between pathogen infections, both pre- and post-symptomatically. This proof-of-concept work supports the use of spectroscopic systems as precision agriculture tools for rapid and early disease detection and differentiation tools, and highlights the importance of careful consideration of underlying pathogen biology and disease physiology for crop disease remote sensing.
Patients with schizophrenia (SZ) show deficits on tasks of rapid reinforcement learning, like probabilistic reversal learning (PRL), but the neural bases for those impairments are not known. Recent ...evidence of relatively intact sensitivity to negative outcomes in the ventral striatum (VS) in many SZ patients suggests that PRL deficits may be largely attributable to processes downstream from feedback processing, involving both the activation of executive control task regions and deactivation of default mode network (DMN) components. We analyzed data from 29 chronic SZ patients and 21 matched normal controls (NCs) performing a PRL task in an MRI scanner. Subjects were presented with eight pairs of fractal stimuli, for 50 trials each. For each pair, subjects learned to choose the more frequently-rewarded (better) stimulus. Each time a criterion was reached, the better stimulus became the worse one, and the worse became the better. Responses to feedback events were assessed through whole-brain and regions-of-interest (ROI) analyses in DMN. We also assessed correlations between BOLD signal contrasts and clinical measures in SZs. Relative to NCs, SZ patients showed comparable deactivation of VS in response to negative feedback, but reduced deactivation of DMN components including medial prefrontal cortex (mPFC). The magnitudes of patients' punishment-evoked deactivations in VS and ventromedial PFC correlated significantly with clinical ratings for avolition/anhedonia. These findings suggest that schizophrenia is associated with a reduced ability to deactivate components of default mode networks, following the presentation of informative feedback and that motivational deficits in SZ relate closely to feedback-evoked activity in reward circuit components. These results also confirm a role for ventrolateral and dorsomedial PFC in the execution of response-set shifts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Impairments in willingness to exert effort contribute to the motivational deficits characteristic of the negative symptoms of schizophrenia. The current study evaluated the psychometric properties of ...5 new or adapted paradigms to determine their suitability for use in clinical trials of schizophrenia. This study included 94 clinically stable participants with schizophrenia and 40 healthy controls. The effort-based decision-making battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 5 paradigms included 1 that assesses cognitive effort, 1 perceptual effort, and 3 that assess physical effort. Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure (ie, practice effects), and (4) tolerability. The 5 paradigms showed varying psychometric strengths and weaknesses. The Effort Expenditure for Rewards Task showed the best reliability and utility as a repeated measure, while the Grip Effort Task had significant patient-control group differences, and superior tolerability and administration duration. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting effort and motivation paradigms for use in clinical trials.
Pili are filamentous surface extensions that play roles in bacterial and archaeal cellular processes such as adhesion, biofilm formation, motility, cell-cell communication, DNA uptake and horizontal ...gene transfer. The model archaeaon Sulfolobus acidocaldarius assembles three filaments of the type-IV pilus superfamily (archaella, archaeal adhesion pili and UV-inducible pili), as well as a so-far uncharacterised fourth filament, named "thread". Here, we report on the cryo-EM structure of the archaeal thread. The filament is highly glycosylated and consists of subunits of the protein Saci_0406, arranged in a head-to-tail manner. Saci_0406 displays structural similarity, but low sequence homology, to bacterial type-I pilins. Thread subunits are interconnected via donor strand complementation, a feature reminiscent of bacterial chaperone-usher pili. However, despite these similarities in overall architecture, archaeal threads appear to have evolved independently and are likely assembled by a distinct mechanism.
Highlights • Paclitaxel-induced mechanical hypersensitivity is specific to the glabrous skin. • Paclitaxel-induced Ca2+ dysregulation is sensory neuron subpopulation-specific. • The largest ...paclitaxel-induced changes occur in glabrous skin putative nociceptors. • Mechanisms underlying these changes may suggest therapeutic targets for CIPN.
Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment ...strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically <1month post-injury and cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2–3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9–25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18–38%), astrocytes (GFAP, 13–16%), and oligodendrocytes (Olig2, 11–13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal tissue volume. Instead, we have found an overall increase in host hippocampal neuron survival in hNSC transplanted animals and demonstrate that a correlation exists between hippocampal neuron survival and cognitive performance. Together, these findings support the use of immunodeficient rodents in models of TBI that involve the transplantation of human cells, and suggest that hNSC transplantation may be a viable, long-term therapy to restore cognition after brain injury.
•Immunodeficient ATN rats demonstrate long-term hippocampal-dependent spatial memory deficits after cortical impact TBI.•Transplantation of human neural stem cells (hNSCs) rescues TBI-induced long-term memory impairment.•hNSC transplantation does not reduce lesion volume but does improve host hippocampal neuron survival.•Transplanted hNSCs survive long-term and differentiate into all three neural lineages.
Jail as injunction Gold, Russell M
The Georgetown law journal,
03/2019, Letnik:
107, Številka:
3
Journal Article
Recenzirano
Half a million people sit in jail every day in America who have not been convicted of a crime but stand merely accused. Detention can cost defendants their jobs, housing, or even custody of their ...children; detention makes defendants more likely to commit a crime and can harm them mentally and physically; it takes a toll on defendants’ families and communities too. Courts simply ignore these serious harms when deciding whether a defendant should lose her liberty because of a mere accusation of wrongdoing. Yet in striking contrast to criminal cases, where the government so often succeeds in obtaining before trial the relief that it ultimately seeks-incarceration of the defendant-civil plaintiffs attempting to obtain before judgment the relief that they ultimately seek-by way of a preliminary injunction-face quite a challenge. Civil plaintiffs cannot obtain such prejudgment relief unless they demonstrate likelihood of irreparable injury and that denying interim relief would be more harmful to them than granting such relief would be to the defendant. This disparity between criminal pretrial detention and civil preliminary injunctions is both troubling and illuminating. It is troubling that the law affords more protection to the property interests of civil defendants than to the liberty interests of criminal defendants who are purportedly presumed innocent. But in this historical moment where pretrial detention and bail systems are changing in many jurisdictions, the preliminary injunction comparison offers a valuable lens through which to reconceptualize pre-trial detention.
A more civil-like approach to pretrial detention would raise the threshold of government interest necessary to justify detaining an accused-not some minimal likelihood that the defendant might forget to appear in court or be accused of some minor crime such as jaywalking. As in the civil system, criminal courts should not simply ignore the immense costs to a defendant of ordering pretrial detention. Rather, courts should consider those costs to defendants, their loved ones, and the broader public and should detain defendants only when the benefits outweigh those substantial costs. Finally, to detain a defendant, courts should require that the government demonstrate likelihood of success on the merits through evidence subject to the defendant's refutation. Such additional process would increase costs on the front end but would potentially lower the pretrial process costs overall by reducing rates of pretrial detention, post-trial incarceration, and recidivism caused by criminogenic jails and prisons., Half a million people sit in jail every day in America who have not been convicted of a crime but stand merely accused. Detention can cost defendants their jobs, housing, or even custody of their children; detention makes defendants more likely to commit a crime and can harm them mentally and physically; it takes a toll on defendants' families and communities too. Courts simply ignore these serious harms when deciding whether a defendant should lose her liberty because of a mere accusation of wrongdoing. Yet in striking contrast to criminal cases, where the government so often succeeds in obtaining before trial the relief that it ultimately seeks-incarceration of the defendant-civil plaintiffs attempting to obtain before judgment the relief that they ultimately seek-by way of a preliminary injunction-face quite a challenge. Civil plaintiffs cannot obtain such prejudgment relief unless they demonstrate likelihood of irreparable injury and that denying interim relief would be more harmful to them than granting such relief would be to the defendant. This disparity between criminal pretrial detention and civil preliminary injunctions is both troubling and illuminating. It is troubling that the law affords more protection to the property interests of civil defendants than to the liberty interests of criminal defendants who are purportedly presumed innocent. But in this historical moment where pretrial detention and bail systems are changing in many jurisdictions, the preliminary injunction comparison offers a valuable lens through which to reconceptualize pre-trial detention.
A more civil-like approach to pretrial detention would raise the threshold of government interest necessary to justify detaining an accused-not some minimal likelihood that the defendant might forget to appear in court or be accused of some minor crime such as jaywalking. As in the civil system, criminal courts should not simply ignore the immense costs to a defendant of ordering pretrial detention. Rather, courts should consider those costs to defendants, their loved ones, and the broader public and should detain defendants only when the benefits outweigh those substantial costs. Finally, to detain a defendant, courts should require that the government demonstrate likelihood of success on the merits through evidence subject to the defendant's refutation. Such additional process would increase costs on the front end but would potentially lower the pretrial process costs overall by reducing rates of pretrial detention, post-trial incarceration, and recidivism caused by criminogenic jails and prisons.
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