dataesr/scientific-paragraphs-categorization huggingface dataset:
Target prediction The entire sequence of SNORD90 was used to blast against the human genome allowing G-T wobble base pairing and one mismatch base pairing (Supplementary file 5). From this prediction, we identified 100 locations on the human genome (both within genes and gene desert regions) that has complementarity sequences to SNORD90. NRG3 was ranked as one of highest genes housing a complementarity sequence to SNORD90 without any mismatches. To increase our confidence in target selection, we also utilized the C/D box snoRNA target prediction algorithm PLEXY, using default parameters  (Kehr et al. , 2011). SNORD90 mature sequence was used as the input snoRNA and target sequence input was the entire human genome downloaded from the Ensembl genome browser database (Supplementary files 6-7).
Acknowledgements GT holds a Canada Research Chair (Tier 1) and is supported by grants from the  Canadian Institute of Health Research (CIHR)  ( FDN148374 ,  EGM141899 ,  ENP161427 ), and by the  Fonds de recherche du Québec -Santé (FRQS)  through the  Quebec Network on Suicide, Mood Disorders, and Related Disorders. CAN-BIND  is an  Integrated Discovery Program  carried out in partnership with, and financial support from, the  Ontario Brain Institute , an independent nonprofit corporation, funded partially by the  Ontario government. The opinions, results, and conclusions are those of the authors and no endorsement by the  Ontario Brain Institute  is intended or should be inferred. Additional funding is provided by the  Canadian Institutes of Health Research (CIHR). All study medications were independently purchased at wholesale market values.
Ethics statement All experiments reported in this manuscript conformed to policies set by the National Institutes of Health (USA) in the Guide for the Care and Use of Laboratory Animals and EU Directive 2010/63/EU for animal experiments. These experiments were performed on 44 male Sprague-Dawley rats (7-weekold, body weight 350 g, Janvier, Le Genest-Saint-Isle, France). We did not use female rats to avoid non-reproductible data due to hormonal cycle. Hormonal cycle change is linked to respiratory changes  (Behan and Kinkead, 2011). The animals were dual-housed in individually ventilated cages in a state-of-the-art animal care facility (2CARE animal facility, accreditation A78-322-3, France) with access to food and water ad libitum and a 12-hour light/dark cycle. These experiments were approved by the Ethics Committee of the University of Versailles Saint-Quentin-en-Yvelines and complied with French and European laws regarding animal experimentation (Apafis #2017111516297308, approval date August 9, 2021).
Whole-body plethysmography In total, 15 rats were used for whole-body plethysmography recordings. The rats were randomly divided into two groups: sham (n = 7) and 7 days postinjury (7 d PI, n = 8). Whole-body constant flow (2 L/min) plethysmography (EMKA, France) was used to assess global ventilatory function (e. g. , the tidal volume, minute ventilation, and breathing frequency) in our rats, as previously described  (Fayssoil et al. , 2021). The rats were weighed, and the plethysmography system was calibrated before the animals were placed in the chambers. After a 30-minute acclimation period, recording began under normoxic conditions (room air). The minute ventilation and tidal volume were reported according to the bodyweight (per 100 g) for each animal. Data obtained from one of the sham rats were corrupted and therefore could not be analyzed, meaning the number of plethysmography recordings used for this group is n = 6.
Echography data acquisition In total, 14 from the 15 rats used for whole-body plethysmography recordings were also used for ultrasound data acquisition. The rats were randomly divided into two different groups: sham (n = 7) and 7 d PI (n = 7). One of the rats from the 7 d PI group used for whole-body plethysmography recordings was not used for ultrasound recordings due to technical event. To evaluate diaphragm activity and cardiac function, a high-resolution ultrasound system (LOGIQ E9; GE, Solingen, Germany) and a high-frequency (18 MHz) linear L8-18i probe (GE) were used. Anesthesia was induced by isoflurane (5% at 500 mL/min in 100% O 2 ) in a closed chamber and maintained through a nose cone (isoflurane balanced at 1. 5-2% in 100% O 2 ). Each rat's anterior thorax and upper abdomen were shaved before exploration.
The electrode was gently placed on the crural part of each hemidiaphragm during spontaneous poïkilocapnic normoxic breathing as previously described  (Keomani et al. , 2014; Vinit et al. , 2016). The recorded signals were digitized by an 8-channel Powerlab data acquisition device (Acquisition rate: 100 k/s; AD Instruments, Dunedin) connected to a computer and analyzed using LabChart 8 Pro software (AD Instruments, Dunedin).
One-way repeated-measures analysis of variance was used to compare the MAP and heart rate analysis results obtained from the same animal over time (before injury, 20 s PI and 1 h PI). All data are presented as the mean ± SD, and values were considered significant when P < 0. 05. For scatter plot analysis, confidence ellipses were calculated using the Khi2 confidence interval (95%). SigmaPlot 12. 5 software (Systat Software, San Jose, CA, USA), and XLSTAT Premium 2016. 1. 1 (Addinsoft, Paris, France; https://www. xlstat. com) were used for all statistical analyses.
By measuring this relative change in blood volume, sudden changes in peripheral arterial tone that occur in response to respiratory events can be detected  (O'Donnell et al. , 2002). These pulse wave amplitude drops have been shown to be an important biomarker of cardiometabolic risk and outcomes  (Hirotsu et al. , 2020; Strassberger et al. , 2021; Solelhac et al. , 2023). Peripheral artery tonometry-based devices combine information on changes in arterial volume with oxygen saturation (SpO 2 ; both from the PPG signal) with data on peripheral arterial tone and heart rate  (Yalamanchali et al. , 2013; Massie et al. , 2018; Van Pee et al. , 2022; Lyne et al. , 2023). During recording, a respiratory event is typically detected by analyzing the co-occurrence of one or more of the following events: oxygen desaturation; vasoconstriction (decreased peripheral artery tonometry signal); and increased pulse rate.
, 2020; Roeder et al. , 2020; Lechat et al. , 2022). Furthermore, emerging evidence suggests that large nightto-night variability in sleep apnea severity (based on the AHI) is a predictor of uncontrolled hypertension  (Lechat et al. , 2023) , and that sleep data from a single night of recording performed worse than multi-night testing with respect to cardiovascular risk prediction  (Lechat et al. , 2023). For data from multiple nights of sleep testing (at least three nights in total, including one night on the weekend), some experts believe that it is probably best to use the highest AHI value recorded to provide guidance regarding treatment initiation, rather than the average AHI. However, studies are needed to validate this approach. In summary, the multi-night monitoring capability of peripheral artery tonometry devices allows patient sleep trajectories over time to be determined in an accessible and acceptable manner, providing a clearer understanding of sleep habits and allowing better shared decision-making and more personalized therapy  (Hrubos-Strøm et al.
Ambroxol is an inhibitory chaperone that mobilizes the sequestered mutant GCase from the ER, inducing a conformational change that facilitates transport to lysosomes and the recovery of GCase lysosomal function. In vitro and in vivo studies have confirmed that ambroxol can increase GCase activity and reduce α-synuclein levels  [37]. In a phase 2, open-label study (NCT02941822) involving 17 PD patients with and without GBA mutations, ambroxol (at an escalating oral dose to 1. 26 g per day) was able to both cross the blood-brain barrier (BBB) and to increase the GCase and α-synuclein concentrations in the cerebrospinal fluid (CSF)  [38]. Based on these promising results, two phase 2 clinical trials are ongoing (NCT05287503, NCT02914366). In particular, NCT02914366 is a 52-week, randomized, placebo-controlled, quadruple-masking trial that is testing the hypothesis that oral ambroxol (1050 mg/daily) may improve cognitive and motor symptoms in patients with PD dementia (PDD).
In addition, the multicenter, randomized, double-blind, placebo-controlled NCT05287503 trial (Ambitious study) is investigating whether the prolonged administration of high-dose oral ambroxol is able to change GCase activity and α-synuclein CNS levels and to reduce the progression of cognitive decline and motor disability in a cohort of 60 PD-GBA patients. Aside from ambroxol, other small-molecule chaperones (GC00188758, NCGC607, quetiapine, PGRN, HSP70, arimoclomol, LTI-291) have been investigated, but are so far supported by limited preclinical evidence  [27]. Gene therapy in GBA-PD patients relies on the delivery of a normal GBA gene using an adenoassociated virus (AAV) vector  [39]. The efficacy of this approach has been confirmed in different animal models of PD-GBA  [39] [40] [41] [42] , showing a significant reduction in both α-synuclein accumulation and CNS inflammation  [39].
Based on these premises, the first experimental gene therapy in PD-GBA patients has been recently developed  [39]. This investigational drug (PR001) is composed of a viral vector (adenoassociated virus serotype 9) containing a codon-optimized plasmid encoding a wild-type human GBA gene, proved to be able to increase GCase activity, decrease glycolipid substrate accumulation, and improve motor abnormalities in GBA-PD models in vivo  [27, 39]. This has led to the development of the J3Z-MC-OJAA study, a Phase 1/2a, multicenter, open-label, ascending-dose, first inhuman study that will evaluate the safety of intratecal LY3884961 administration in patients with moderate to severe PD with at least one pathogenic GBA mutation (NCT04127578). Two escalating dose cohorts (low-dose and high-dose) will be studied, and patients will be evaluated for the effect of LY3884961 on safety, tolerability, immunogenicity, biomarkers, and clinical efficacy measures with a 5-year follow-up.
Another therapeutic approach in GBA-PD is focused on the reduction of GL-1 accumulation  [25]. Venglustat is a potent, CNS-penetrant inhibitor of glucosylceramide synthase that can reduce the formation of GL-1  [33]. The efficacy of venglustat in GBA-PD patients was explored in the MOVES-PD trial, a randomized, double-blinded, placebo-controlled, dose-escalation study (NCT02906020). The first part of the study included 29 GBA-PD patients, and showed that venglustat had a favorable safety and tolerability profile  [33]. However, the second part of the MOVES-PD trial (NCT02906020), which included 273 early-PD patients, did not meet the study's primary objective, i. e. , the efficacy on motor symptoms (primary endpoints: MDS-UPDRS part II-III). In particular, a progressive deterioration in clinical outcomes was noticed over time in the treatment arm compared to the placebo, leading to a premature interruption of the study  [27].
Novel Therapeutic Approaches and Ongoing Clinical Trials The objective of the novel therapeutic approaches in LRRK2-PD is to reduce the pathological excessive kinase activity of the mutated gene. Table  3  summarizes the ongoing clinical trial in LRRK2-PD. The CNS-penetrant, selective, small-molecule LRRK2 kinase inhibitor DNL201 was able to inhibit LRRK2 kinase activity and improve lysosomal function in preclinical models  [49]. In one phase 1 and one phase 1b clinical trial, which included 122 healthy volunteers and 28 PD patients, DNL201 (at single and multiple doses) inhibited LRRK2, was well tolerated, and showed robust CSF penetrance  [49]. The safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of LRRK2 kinase inhibitor BIIB122/DNL151 were assessed in PD patients in a phase 1 study (NCT04056689) whose results are still pending.
This molecule is now under investigation in two other ongoing trials. The objective of the phase 2b, multicenter, randomized, double-blind, placebo-controlled study LUMA (NCT05348785) is to assess the safety of BIIB122 oral tablets (225 mg once daily) and the possible impact of the drug on disease progression. A total of 640 early-stage PD patients without mutations in the LRRK2 gene will be enrolled. In addition, the phase 3, multicenter, randomized, double-blind, placebo-controlled study LIGHTHOUSE (NCT05418673) will aim to determine the safety profile and the efficacy of BIIB122/DNL151 to slow the progression of disease in 400 LRRK2-PD patients. The use of antisense oligonucleotides (ASOs) for LRRK2 inhibition represents another therapeutic approach under investigation in LRRK2-PD patients.
This approach is supported by preclinical studies that showed that the administration of LRRK2 ASOs to the brain was able to reduce LRRK2 protein levels and fibril-induced α-synuclein inclusions  [50]. Furthermore, mice exposed to α-synuclein fibrils treated with LRRK2 ASOs showed more tyrosine hydroxylase (TH)-positive neurons compared to control mice, suggesting that LRRK2 ASOs treatment could be a potential therapeutic strategy for preventing PD-associated pathology  [50]. Based on these premises, the ongoing phase 1 single-and multiple-ascending-dose study REASON (NCT03976349) will assess the safety, tolerability, and pharmacokinetic profile of intrathecal injections of the LRRK2 ASO inhibitor BIIB094 in PD patients with and without LRRK2 mutations.
This approach includes other possible targets including the mammalian target of rapamycin (mTOR) signalling and the cellular homolog of ABL1 (c-Abl)  [10]. Indeed, α-synuclein overexpression inhibits autophagy by increasing mTOR activity, which can be modulated or inhibited by different substances or drugs, including rapamycin, curcumin, piperine, lithium (ongoing phase I clinical trial (NCT04273932), trehalose, corynoxine B, sodium valproate, and carbamazepine  [10]. Studies in PD animal models and brain specimens from PD patients have revealed increased levels and activity of c-Abl in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase  [61]. The inhibition of c-Abl kinase activity by drugs used in the treatment of human leukaemia has shown promising neuroprotective effects in cell and animal models of PD  [61].
This has led to the development of several ongoing phase 1 and phase 2 clinical trials testing the safety and efficacy of c-Abl inhibitors (i. e. , imatinib, nilotinib, bafetinib, IkT-148009) in PD patients. In particular, the results from two recent trials have been recently published. The single-center, phase 2, double-blind trial NCT02954978 included 75 patients randomized vs. placebo and oral nilotinib 150-mg or nilotinib 300-mg for 12 months followed by a 3-month washout period  [62]. This trial met its primary outcome (safety, tolerability, and detection in CSF), and is expected to guide a future phase 3 study to evaluate oral nilotinib as a disease-modifying medication for PD  [62]. Nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid, and exploratory biomarkers were altered in response to it  [62].
Different results came from a 6-month, multicenter, double-blind trial (NCT03205488) that included 76 PD patients randomized to placebo vs. 150-mg nilotinib or 300-mg nilotinib once daily orally for 6 months, followed by a 2-month off-drug evaluation  [63]. Unfortunately, nilotinib at 150 mg and 300 mg worsened on-medication PD motor scores (MDS-UPDRS-3) compared with placebo, with no differences in the change in off-medication MDS-UPDRS-3 scores  [63]. Furthermore, there was no evidence of a treatment-related alteration of dopamine metabolites in the CSF. The authors concluded that, due to the low CSF exposure, lack of biomarker effect, and lack of efficacy, nilotinib should not be further tested in PD  [63]. Furthermore, GCase may also decrease soluble α-synuclein in mice expressing mutant human A53T α-synuclein  [64].
Two non-inhibitory GCase modulators (NCGC00188758 and NCGC607) have been found to increase GCase activity and decrease α-synuclein accumulation and toxicity in human neurons derived from induced pluripotent stem cells (iPSCs)  [27]. Another different approach relies on the blockage of α-synuclein propagation between neurons. This approach is supported by preclinical studies, which showed that memantine, an antagonist of the NMDA (N-Methyl-D-Aspartate) subtype of glutamate receptor, may exert neuroprotective properties via the inhibition of cell-to-cell transmission of extracellular α-synuclein. A phase 3 trial (NCT03858270) is ongoing in order to evaluate the drug's clinical impact on PD patients. A further promising approach to target α-synuclein aggregates is based on passive immunization using antibodies against α-synuclein, which may promote its lysosomal clearance.
Antibodies against α-synuclein have already been tested in two recent RCTs, PRX002 (Roche) and BIIB054 (Biogen). Unfortunately, a randomized, double-blind, placebo-controlled study (SPARK) that evaluated the efficacy and safety of BIIB054 in PD patients did not meet both primary and secondary outcome measures for year one and also failed to meet secondary outcome measures  [65]. This has led to the discontinuation of the development of BIIB054 for PD, and the SPARK study has been closed. Even the phase 2 PASADENA trial (NCT03100149), evaluating the safety and efficacy of intravenous prasinezumab (PRX002) in early-stage PD, did not show promising results  [66]. This trial included 316 participants; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab  [66].
Treatment with prasinezumab had no meaningful effect on global or imaging measures of PD progression compared to the placebo and was associated with infusion reactions  [66]. However, another phase 2b, randomized, double-blind, placebo-controlled study with prasinezumab (NCT04777331), the PADOVA trial, is ongoing. As opposed to passive immunization, which involves administering anti-α-syn antibodies to the patient conferring temporary protection against the disease, active immunization involves stimulation of the immune system to produce antibodies against toxic α-syn conformations  [67]. In this contest, different phase 1 clinical trials (PD03A [SYMPATH grant agreement 602999], PD01A [NCT01568099], UB-312 [NCT04075318]) targeted against oligomeric α-synuclein have been completed and have shown promising results with a positive antibody response  [68, 69].
Background and Objectives: Pituitary abscess (PA) is a rare occurrence, representing less than 1% of pituitary lesions, and is defined by the presence of an infected purulent collection within the sella turcica. Pas can be classified as either primary, when the underlying pituitary is normal prior to infection, or secondary, when there is associated a pre-existing sellar pathology (i. e. , pituitary adenoma, Rathke's cleft cysts, or craniopharyngioma), with or without a recent history of surgery. Preoperative diagnosis, owing to both non-specific symptoms and imaging features, remains challenging. Treatment options include endonasal trans-sphenoidal pus evacuation, as well as culture and tailored antibiotic therapy. Methods: A retrospective multicenter study, conducted on a prospectively built database over a 20-year period, identified a large series of 84 patients harboring primary sellar abscess.
Patients and Methods We conducted a retrospective review of 84 cases of primary PAs extracted from a prospectively built database of patients undergoing pituitary surgery from 8 neurosurgical centers during a 20-year period (from January 1999 to December 2018). Inclusion criteria were: (1) detection of pus during the surgical procedure, and (2) germs isolated in bacteriological analysis and/or evidence of acute or chronic inflammation on histopathology. Patients' demographic, clinical, visual, and pituitary function, consisting of full neuro-ophthalmological examination and endocrinological laboratory testing, including standardized basal and dynamic stimulation tests, were assessed at admission, as well as at 3-, 6-, 12-, and 24-months follow-up for each case of PA preoperatively suspected and postoperatively confirmed.
Population A total of 84 patients harboring a primary PA were identified among 11,531 cases of trans-sphenoidal (microscopic/endoscopic) pituitary surgery, indicating that PAs represent 0. 7% of all sellar lesions from our database. The diagnosis was established perioperatively in all patients by: identification of ring-enhancement in post-contrast pituitary MRI scans; detection of frank pus at time of surgical evacuation; and laboratory confirmation through bacteriology analysis and/or histopathology assessment (see also Figure  1 ). Patient demographic and clinical characteristics are summarized in Table  1. Among the 84 patients included and followed up for a minimum of 24 months (range 24 to 54), 32 (38%) were men and 52 (62%) were women, with a mean age of 44 years (ranging from 14 to 71 years).
Study Limitation and Strength While the retrospective and non-randomized design of the present study represent its main limitations, this manuscript reports on the largest series of PAs ever described in the English literature. Such point of strength was achieved through the multi-centric set-up of the study, which exploited an accurate and robust, prospectively-built database, which will allow for the generation of new studies in the near future. Additionally, it should be mentioned that the current knowledge gap on this rare pathological entity should be covered by a systematic review of the over 200 cases now described in the literature; a protocol for such study is currently under submission to the PROSPERO database. data from the relevant literature, and has the potential to substantially help clinicians in their routine clinical practice (see also Figure  2 ).
Study Limitation and Strength While the retrospective and non-randomized design of the present study represent its main limitations, this manuscript reports on the largest series of PAs ever described in the English literature. Such point of strength was achieved through the multi-centric setup of the study, which exploited an accurate and robust, prospectively-built database, which will allow for the generation of new studies in the near future. Additionally, it should be mentioned that the current knowledge gap on this rare pathological entity should be covered by a systematic review of the over 200 cases now described in the literature; a protocol for such study is currently under submission to the PROSPERO database.
On the other hand, perceptual discrimination also depends on mechanisms operating during the processing of the target itself. A stimulus onset can induce a functional disinhibition of neurons in task-relevant cortical regions, reflected in the decrease of alpha-band power  (Jensen & Mazaheri, 2010; Klimesch et al. , 2011). For instance, detecting a target presented at the perceptual threshold is accompanied by posterior alpha-band power decreases  (Babiloni et al. , 2006) , supporting the idea that a decrease in alpha-band power reflects to some extent visual awareness  (Harris et al. , 2020). Overall, this means that temporal discrimination abilities in vision can be reflected in both pre-and post-target posterior alpha-band power decreases. In this cross-sectional study, EEG and eye-tracking data are used to evaluate whether preparatory processing, target processing, or both could explain the potential enhancement of temporal discrimination skills in VGPs.