Loss Of Terminals Research Articles

WTP 19aalnxx: Discovery of a Bright Mid-infrared Transient in the Emerging Class of Low-luminosity Supernovae Revealed by Delayed Circumstellar Interaction

While core-collapse supernovae (SNe) often show early and consistent signs of circumstellar medium (CSM) interaction, some exhibit delayed signatures due to interaction with distant material around the progenitor star. Here we present the discovery in NEOWISE data of WTP 19aalnxx, a luminous mid-infrared (MIR) transient in the outskirts of the galaxy KUG 0022-007 at ≈190 Mpc. First detected in 2018, WTP 19aalnxx reaches a peak absolute (Vega) magnitude of ≈−22 at 4.6 μm in ≈3 yr, comparable to the most luminous interacting SNe. Archival data reveal a ≳5× fainter optical counterpart detected since 2015, while follow-up near-infrared observations in 2022 reveal an extremely red (Ks − W2 ≈ 3.7 mag) active transient. Deep optical spectroscopy confirm strong CSM interaction signatures via intermediate-width Balmer emission lines and coronal metal lines. Modeling the broadband spectral energy distribution, we estimate the presence of ≳10−2 M ⊙ of warm dust, likely formed in the cold dense shell. Together with the lack of nebular Fe emission, we suggest that WTP 19aalnxx is a missed, low (optical) luminosity SN in an emerging family of core-collapse SNe distinguished by their CSM-interaction-powered MIR emission that outshines the optical bands. Investigating the Zwicky Transient Facility sample of SNe with NEOWISE data, we find 16 core-collapse SNe (≳3% in a volume-limited sample) without early signs of CSM interaction that exhibit delayed IR brightening, suggestive of dense CSM shells at ≲1017 cm. We suggest that synoptic IR surveys offer a new route to revealing late-time CSM interaction and the prevalence of intense terminal mass loss in massive stars.

Association of Hemispheric Asymmetry of Dopamine-Transporter Binding with Risk of Parkinsonian Depression.

Depression is the most common psychiatric disorder diagnosed in patients with Parkinson's disease (PD). A direct role in PD depression for loss of dopaminergic terminals and dopamine-transporter (DAT) expression in the striatum is revealed by many studies. The objective was to discern the relationship between DAT neuroimaging and risk of depression in PD. One hundred and ninety-eight PD patients (101 with depression, 97 without depression) were evaluated using an extensive protocol from 2015 to 2023. DAT availability at striatal terminals was assessed with single-photon emission computed tomography with 123I-Ioflupane. Specific binding ratio (SBR) of 123I-Ioflupane and the whole striatum asymmetry index (SASI) were calculated. Data were analyzed with univariate/multivariate models as well as receiver operating characteristic (ROC) curves. A logistic regression model adjusting for confounding risk factors of depression indicates that SASI and PD duration are associated with the odds of having parkinsonian depression. SASI is the strongest predictor of risk of parkinsonian depression. Following ROC analysis, SASI is found to be an accurate factor for detecting parkinsonian depression because a cutoff value of 3.4895 of SASI shows good accuracy (0.813), sensitivity (81.1%), and specificity (80%). Higher SASI is also linked to more disease-related limitations in activities of daily living. The whole SASI is the strongest predictor of risk of parkinsonian depression. The findings could be valuable in evaluating depression in PD patients.

Increased intrinsic membrane excitability is associated with olivary hypertrophy in spinocerebellar ataxia type 1.

One of the characteristic regions of brainstem degeneration across multiple spinocerebellar ataxias (SCAs) is the inferior olive (IO), a medullary nucleus that plays a key role in motor learning. The vulnerability of IO neurons remains a poorly-understood area of SCA pathology. In this work, we address this by evaluating IO disease in SCA1, a prototypic inherited olivopontocerebellar atrophy, using the genetically-precise SCA1 knock-in (SCA1-KI) mouse. We find that these mice exhibit olivary hypertrophy, a phenotype reminiscent of a degenerative disorder known as hypertrophic olivary degeneration (HOD). Similar to early stages of HOD, SCA1-KI IO neurons display early dendritic lengthening and later somatic expansion without frank cell loss. Though HOD is known to be caused by brainstem lesions that disrupt IO inhibitory innervation, we observe no loss of inhibitory terminals in the SCA1-KI IO. Additionally, we find that a separate mouse model of SCA1 in which mutant ATXN1 is expressed solely in cerebellar Purkinje cells shows no evidence of olivary hypertrophy. Patch-clamp recordings from brainstem slices indicate that SCA1-KI IO neurons are hyperexcitable, generating spike trains in response to membrane depolarization. Transcriptome analysis further reveals reduced medullary expression of ion channels responsible for IO neuron spike afterhyperpolarization (AHP)-a result that appears to have a functional consequence, as SCA1-KI IO neuron spikes exhibit a diminished AHP. These findings suggest that expression of mutant ATXN1 in IO neurons results in an HOD-like olivary hypertrophy, in association with increased intrinsic membrane excitability and ion channel transcriptional dysregulation.

12405 A Severe Case Of Virilization Of Premenopausal Woman Secondary To A Rare Testosterone Producing Sertoli Cell Tumor

Abstract Disclosure: S. Waheed: None. N.J. Vernetti: None. S. Nakhle: None. Introduction: We present a case of a premenopausal woman with elevated testosterone who was diagnosed with an aggressive Sertoli cell tumor of the ovary. Case Description: A 49-year-old multiparous female presented to the clinic with hirsutism and markedly elevated testosterone levels. Her symptoms started a year before the presentation with diffuse alopecia, acne, and increased muscle mass. Last menstrual periods were 3 years, prior to the presentation.Denies any exposure to testosterone herself or indirectly through family. On physical exam, blood pressure 170/122 coarse features, oily skin, and muscular build. She had terminal hair loss and increased hair growth on face and arms. Laboratory data revealed testosterone levels of 9280 ng/dl (reference range premenopausal 18-55 ng/dl), free testosterone > 50 ng/dl (premenopausal0-4.2 ng/dl), LH <0.3 mIU/mL (2.4-12.6 mIU/mL), FSH <0.3 mIU/mL (3.6-12.5 mIU/mL), 17-OHP 2270 ng/dl (15-70 ng/dl), DHEA-S 71 ug/dl (<229 ug/dl), LDL 128 mg/dl, Creatinine 1.29 and hematocrit 56% (34-44.6%). CT abdomen/pelvis showed 10 cm ovarian mass. She underwent Total Abdominal Hysterectomy-Bilateral Salpingo Oophorectomy (TAH-BSO). After the surgery, her testosterone levels normalized and features of hyperandrogenism resolved. Pathology report revealed sex cord stromal tumor Not otherwise specified (NOS) with cellular atypia and possible aggressive behavior. Discussion: Androgen-producing tumors in women are rare neoplasms that can cause secondary virilizing characteristics. Of patients presenting with symptoms of hyperandrogenism, these tumors are found in ∼0.2% of cases. Androgen-producing tumors can arise from the ovary or the adrenal gland. Those arising from the ovary are rare, accounting for <5% of all ovarian tumors. Few cases of steroid cell tumors, not otherwise specified, have been reported in the literature.Testosterone elevation of more than 2 times upper normal limit increases the suspicion for cancer. In our patient, testosterone was 180 times above the normal range for women and 15 times above the normal range for men. With rapid virilization and significant elevation in testosterone, an androgen producing ovarian tumors should be considered. Presentation: 6/2/2024

Genomic Balancing Act: deciphering DNA rearrangements in the complex chromosomal aberration involving 5p15.2, 2q31.1, and 18q21.32.

Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and aterminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses enabled by long-read genome sequencing unveiled the presence of four distinct junctions in the father, who is acarrier of a balanced CCR. The proband inherited from the father both the abnormal chromosome 5 resulting in segmental aneusomies of chr5 (loss) and chr18 (gain) and a der(2) homologue. Evidences suggest a chromoplexy mechanism for this CCR derivation, involving double-strand breaks (DSBs) repaired by non-homologous end joining (NHEJ) or alternative end joining (alt-EJ). The complexity of the CCR and the segregation of homologues elucidate the genetic model for this family. This study demonstrates the importance of combining multiple genomic technologies to uncover genetic causes of complex neurodevelopmental syndromes and to better understand genetic disease mechanisms.

Neurophysiological markers of motor compensatory mechanisms in early Parkinson's disease.

Compensatory mechanisms in Parkinson's disease are defined as the changes that the brain uses to adapt to neurodegeneration and progressive dopamine reduction. Motor compensation in early Parkinson's disease could, in part, be responsible for a unilateral onset of clinical motor signs despite the presence of bilateral nigrostriatal degeneration. Although several mechanisms have been proposed for compensatory adaptations in Parkinson's disease, the underlying pathophysiology is unclear. Here, we investigate motor compensation in Parkinson's disease by investigating the relationship between clinical signs, dopamine transporter imaging data and neurophysiological measures of the primary motor cortex (M1), using transcranial magnetic stimulation in presymptomatic and symptomatic hemispheres of patients. In this cross-sectional, multicentre study, we screened 82 individuals with Parkinson's disease. Patients were evaluated clinically in their medication OFF state using standardized scales. Sixteen Parkinson's disease patients with bilateral dopamine transporter deficit in the putamina but unilateral symptoms were included. Twenty-eight sex- and age-matched healthy controls were also investigated. In all participants, we tested cortical excitability using single- and paired-pulse techniques, interhemispheric inhibition and cortical plasticity with paired associative stimulation. Data were analysed with ANOVAs, multiple linear regression and logistic regression models. Individual coefficients of motor compensation were defined in patients based on clinical and imaging data, i.e. the motor compensation coefficient. The motor compensation coefficient includes an asymmetry score to balance motor and dopamine transporter data between the two hemispheres, in addition to a hemispheric ratio accounting for the relative mismatch between the magnitude of motor signs and dopaminergic deficit. In patients, corticospinal excitability and plasticity were higher in the presymptomatic compared with the symptomatic M1. Also, interhemispheric inhibition from the presymptomatic to the symptomatic M1 was reduced. Lower putamen binding was associated with higher plasticity and reduced interhemispheric inhibition in the presymptomatic hemisphere. The motor compensation coefficient distinguished the presymptomatic from the symptomatic hemisphere. Finally, in the presymptomatic hemisphere, a higher motor compensation coefficient was associated with lower corticospinal excitability and interhemispheric inhibition and with higher plasticity. In conclusion, the present study suggests that motor compensation involves M1-striatal networks and intercortical connections becoming more effective with progressive loss of dopaminergic terminals in the putamen. The balance between these motor networks seems to be driven by cortical plasticity.

Monoaminergic degeneration, cognition, and autonomic symptom trajectory in early Parkinson's disease

IntroductionParkinson's disease (PD) encompasses a range of non-motor symptoms attributed to deficits in various neurotransmitter systems. This study aimed to investigate the associations between cognitive and autonomic symptoms and the degeneration of brainstem monoaminergic nuclei, particularly the serotonergic and noradrenergic nuclei, in a prospective cohort of early PD patients. MethodsTwenty-eight early PD patients (with an average disease duration of approximately three years) underwent baseline [18F]FP-CIT positron emission tomography (PET) scans, Montreal Cognitive Assessment (MoCA), and Composite Autonomic Symptom Scale-31 (COMPASS-31) evaluations, followed by repeat MoCA and COMPASS-31 assessments three years later. Regression models were utilized to analyze both cross-sectional and longitudinal changes in non-motor symptoms relative to baseline degeneration of the noradrenergic locus coeruleus (LC) and serotonergic raphe, normalized by striatal dopaminergic terminal loss. ResultsBaseline LC and raphe degeneration in early PD was cross-sectionally associated with poorer MoCA performances. Over the three-year follow-up, gastrointestinal symptoms exhibited progression, while cognitive scores remained stable. Profound baseline degeneration of the LC and raphe, relative to nigrostriatal terminal loss, were predictive of subsequent accelerated deterioration in gastrointestinal symptoms. ConclusionBrainstem non-dopaminergic dysfunction in early PD is linked to cognitive dysfunction and predicts progression in gastrointestinal symptoms, offering potential indicators for worsening non-motor trajectories.

Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities

Although most cases of Parkinson’s disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.

Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.

Putaminal dopamine modulates movement motivation in Parkinson's disease.

The relative inability to produce effortful movements is the most specific motor sign of Parkinson's disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson's disease. A total of 21 early-stage, unmedicated patients with Parkinson's disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed. Our results demonstrate that patients with Parkinson's disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor. Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson's disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.

Age-related upregulation of dense core vesicles in the central inferior colliculus.

Presbycusis is one of the most prevalent disabilities in aged populations of industrialized countries. As we age less excitation reaches the central auditory system from the periphery. To compensate, the central auditory system [e.g., the inferior colliculus (IC)], downregulates GABAergic inhibition to maintain homeostatic balance. However, the continued downregulation of GABA in the IC causes a disruption in temporal precision related to presbycusis. Many studies of age-related changes to neurotransmission in the IC have therefore focused on GABAergic systems. However, we have discovered that dense core vesicles (DCVs) are significantly upregulated with age in the IC. DCVs can carry neuropeptides, co-transmitters, neurotrophic factors, and proteins destined for the presynaptic zone to participate in synaptogenesis. We used immuno transmission electron microscopy across four age groups (3-month; 19-month; 24-month; and 28-month) of Fisher Brown Norway rats to examine the ultrastructure of DCVs in the IC. Tissue was stained post-embedding for GABA immunoreactivity. DCVs were characterized by diameter and by the neurochemical profile (GABAergic/non-GABAergic) of their location (bouton, axon, soma, and dendrite). Our data was collected across the dorsolateral to ventromedial axis of the central IC. After quantification, we had three primary findings. First, the age-related increase of DCVs occurred most robustly in non-GABAergic dendrites in the middle and low frequency regions of the central IC during middle age. Second, the likelihood of a bouton having more than one DCV increased with age. Lastly, although there was an age-related loss of terminals throughout the IC, the proportion of terminals that contained at least one DCV did not decline. We interpret this finding to mean that terminals carrying proteins packaged in DCVs are spared with age. Several recent studies have demonstrated a role for neuropeptides in the IC in defining cell types and regulating inhibitory and excitatory neurotransmission. Given the age-related increase of DCVs in the IC, it will be critical that future studies determine whether (1) specific neuropeptides are altered with age in the IC and (2) if these neuropeptides contribute to the loss of inhibition and/or increase of excitability that occurs during presbycusis and tinnitus.

Adenosine A2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson's Disease.

Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.

Pathogenesis of Alopecia Areata and Vitiligo: Commonalities and Differences.

Both alopecia areata (AA) and vitiligo are distinct, heterogenous, and complex disease entities, characterized by nonscarring scalp terminal hair loss and skin pigment loss, respectively. In AA, inflammatory cell infiltrates are in the deep reticular dermis close to the hair bulb (swarm of bees), whereas in vitiligo the inflammatory infiltrates are in the epidermis and papillary dermis. Immune privilege collapse has been extensively investigated in AA pathogenesis, including the suppression of immunomodulatory factors (e.g., transforming growth factor-β (TGF-β), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), and macrophage migration inhibitory factor (MIF)) and enhanced expression of the major histocompatibility complex (MHC) throughout hair follicles. However, immune privilege collapse in vitiligo remains less explored. Both AA and vitiligo are autoimmune diseases that share commonalities in pathogenesis, including the involvement of plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) and cytotoxic CD8+ T lymphocytes (and activated IFN-γ signaling pathways). Blood chemokine C-X-C motif ligand 9 (CXCL9) and CXCL10 are elevated in both diseases. Common factors that contribute to AA and vitiligo include oxidative stress, autophagy, type 2 cytokines, and the Wnt/β-catenin pathway (e.g., dickkopf 1 (DKK1)). Here, we summarize the commonalities and differences between AA and vitiligo, focusing on their pathogenesis.

Increased glutamatergic neurotransmission between the retinohypothalamic tract and the suprachiasmatic nucleus of old mice.

Circadian rhythms synchronize to light through the retinohypothalamic tract (RHT), which is a bundle of axons coming from melanopsin retinal ganglion cells, whose synaptic terminals release glutamate to the ventral suprachiasmatic nucleus (SCN). Activation of AMPA-kainate and NMDA postsynaptic receptors elicits the increase in intracellular calcium required for triggering the signaling cascade that ends in phase shifts. During aging, there is a decline in the synchronization of circadian rhythms to light. With electrophysiological (whole-cell patch-clamp) and immunohistochemical assays, in this work, we studied pre- and postsynaptic properties between the RHT and ventral SCN neurons in young adult (P90-120) and old (P540-650) C57BL/6J mice. Incremental stimulation intensities (applied on the optic chiasm) induced much lesser AMPA-kainate postsynaptic responses in old animals, implying a lower recruitment of RHT fibers. Conversely, a higher proportion of old SCN neurons exhibited synaptic facilitation,and variance-mean analysis indicated an increase in the probability of release in RHT terminals. Moreover, both spontaneous and miniature postsynaptic events displayed larger amplitudes in neurons from aged mice, whereas analysis of the NMDA and AMPA-kainate components (evoked by RHT electrical stimulation) disclosed no difference between the two ages studied. Immunohistochemistry revealed a bigger size in the puncta of vGluT2, GluN2B, and GluN2A of elderly animals, and the number of immunopositive particles was increased, but that of PSD-95 was reduced. All these synaptic adaptations could be part of compensatory mechanisms in the glutamatergic signaling to ameliorate the loss of RHT terminals in old animals.

Celecoxib to improve scar quality following acute burn injury: Lessons learned after premature termination of a randomised trial

BackgroundPre-clinical studies suggest that non-steroidal anti-inflammatory therapy may reduce acute inflammation and modulate scar formation after burn injury. The objective of this trial was to determine if celecoxib administered soon after acute burn improved scar quality. MethodsA single centre, parallel group, placebo-controlled, randomised, superiority trial. Adults with non-major acute burn injury were eligible for recruitment. Participants within 48 h of admission for acute burn injury received either six weeks of celecoxib 200 mg twice daily or identically packaged placebo capsules. The primary outcome was participant-reported Patient Observer Scar Assessment Scale (POSAS) at day 42 following burn injury. The best possible score using this assessment is 7 and the worst 70. Key safety outcomes included study drug side effects. ResultsRestrictions imposed during the COVID-19 pandemic resulted in slow recruitment and early termination after 59 of the 150 planned participants were enrolled. The primary outcome was available for 21/30 (70 %) participants in the celecoxib arm and for 23/29 (79 %) who received placebo. There was no significant difference in the primary outcome between treatment groups with a mean POSAS of 33.4 (standard deviation 12.7) in the celecoxib arm and 36.9 (13.7) in the control arm giving a difference of −3.49 (95 % CI [-11.57, 4.59], p =.39). Gastrointestinal symptoms occurred in 3/30 (10 %) allocated celecoxib and in none allocated placebo. Secondary outcomes including graft loss and delayed healing were similar between groups. ConclusionsAnti-inflammatory therapy did not improve scar quality. Due to early trial termination and significant loss to follow up these findings should be interpreted cautiously. To improve generalisability and to attain recruitment targets, future trials should apply different approaches to improve participant retention as well as including patients with larger burn injuries and an older population.Trial registration: ACTRN12618000732280.

Interferon-β deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV

Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function.

Dopaminergic neuron loss in mice due to increased levels of wild-type human α-Synuclein only takes place under conditions of accelerated aging

Understanding the intricate pathogenic mechanisms behind Parkinson's disease (PD) and its multifactorial nature presents a significant challenge in disease modeling. To address this, we explore genetic models that better capture the disease's complexity. Given that aging is the primary risk factor for PD, this study investigates the impact of aging in conjunction with overexpression of wild-type human α-synuclein (α-Syn) in the dopaminergic system. This is achieved by introducing a novel transgenic mouse strain overexpressing α-Syn under the TH-promoter within the senescence-accelerated SAMP8 (P8) genetic background. Behavioral assessments, conducted at both 10 and 16 months of age, unveil motor impairments exclusive to P8 α-SynTg mice, a phenomenon conspicuously absent in α-SynTg mice. These findings suggest a synergistic interplay between heightened α-Syn levels and the aging process, resulting in motor deficits. These motor disturbances correlate with reduced dopamine (DA) levels, increased DA turnover, synaptic terminal loss, and notably, the depletion of dopaminergic neurons in the substantia nigra and noradrenergic neurons in the locus coeruleus. Furthermore, P8 α-SynTg mice exhibit alterations in gut transit time, mirroring early PD symptoms. In summary, P8 α-SynTg mice effectively replicate parkinsonian phenotypes by combining α-Syn transgene expression with accelerated aging. This model offers valuable insights into the understanding of PD and serves as a valuable platform for further research.

HIV-1 Capsid Uncoating Is a Multistep Process That Proceeds through Defect Formation Followed by Disassembly of the Capsid Lattice.

The HIV-1 core consists of a cone-shaped capsid shell made of capsid protein (CA) hexamers and pentamers encapsulating the viral genome. HIV-1 capsid disassembly, referred to as uncoating, is important for productive infection; however, the location, timing, and regulation of uncoating remain controversial. Here, we employ amber codon suppression to directly label CA. In addition, a fluid phase fluorescent probe is incorporated into the viral core to detect small defects in the capsid lattice. This double-labeling strategy enables the visualization of uncoating of single cores in vitro and in living cells, which we found to always proceed through at least two distinct steps─the formation of a defect in the capsid lattice that initiates gradual loss of CA below a detectable level. Importantly, intact cores containing the fluid phase and CA fluorescent markers enter and uncoat in the nucleus, as evidenced by a sequential loss of both markers, prior to establishing productive infection. This two-step uncoating process is observed in different cells, including a macrophage line. Notably, the lag between the release of fluid phase marker and terminal loss of CA appears to be independent of the cell type or reverse transcription and is much longer (>5-fold) for nuclear capsids compared to cell-free cores or cores in the cytosol, suggesting that the capsid lattice is stabilized by capsid-binding nuclear factors. Our results imply that intact HIV-1 cores enter the cell nucleus and that uncoating is initiated through a localized defect in the capsid lattice prior to a global loss of CA.

Serotonin transporter density in isolated rapid eye movement sleep behavioral disorder.

The serotoninergic nervous system is known to play a role in the maintenance of rapid eye movement (REM) sleep. Serotoninergic projections are known to be vulnerable in synucleinopathies. To date, positron emission tomography (PET) studies using serotonin-specific tracers have not been reported in isolated REM sleep behavior disorder (iRBD). We conducted a cross-sectional imaging study using serotonin transporter (SERT) 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) PET to identify differences in serotonin system integrity between 11 participants with iRBD and 16 older healthy controls. Participants with iRBD showed lower DASB distribution volume ratios (DVRs) in the total neocortical mantle [1.13 (SD: 0.07) vs. 1.19 (SD: 0.06); t = 2.33, p = 0.028)], putamen [2.07 (SD: 0.19) vs. 2.25 (SD: 0.18); t = 2.55, p = 0.017], and insula [1.26 (SD: 0.11) vs. 1.39 (SD: 0.09); t = 3.58, p = 0.001]. Paradoxical increases relative to controls were seen in cerebellar hemispheres [0.98 (SD: 0.04) vs. 0.95 (SD: 0.02); t = 2.93, p = 0.007)]. No intergroup differences were seen in caudate, substantia nigra, or other brainstem regions with the exception of the dorsal mesencephalic raphe [3.08 (SD: 0.53) vs. 3.47 (SD: 0.48); t = 2.00, p = 0.056] that showed a non-significant trend toward lower values in iRBD. Insular, neocortical, and striatal serotoninergic terminal loss may be common in prodromal synucleinopathies before the onset of parkinsonism or dementia. Given our small sample size, these results should be interpreted as hypothesis-generating/exploratory in nature.

Red solid line: Patterns of terminal loss of cerebrovascular reactivity at the bedside

IntroductionContinuous monitoring of the pressure reactivity index (PRx) provides an estimation of dynamic cerebral autoregulation (CA) at the bedside in traumatic brain injury (TBI) patients. Visualising the time-trend of PRx with a risk bar chart in ICM + software at the bedside allows for better real-time interpretability of the autoregulation status. When PRx>0.3 is sustained for long periods, typically of at least half an hour, the bar shows a pattern called “red solid line” (RSL). RSL was previously described to precede refractory intracranial hypertension and brain death. Research questionWe aimed to describe pathophysiological changes in measured signals/parameters during RSL. Material and methodsObservation of time-trends of PRx, intracranial pressure, cerebral perfusion pressure, brain oxygenation and compensatory reserve of TBI patients with RSL. ResultsThree pathophysiological patterns were identified: RSL precedes intracranial hypertension, RSL is preceded by intracranial hypertension, or RSL is preceded by brain hypoperfusion. In all cases, RSL was followed by death and the RSL onset was between 1 h and 1 day before the terminal event. Discussion and conclusionRSL precedes death in intensive care and could represent a marker for terminal clinical deterioration in TBI patients. These findings warrant further investigations in larger cohorts to characterise pathophysiological mechanisms underlying the RSL pattern and whether RSL has a significant relationship with outcome after TBI.