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Nucleosomes containing the histone H3 variant CENP-A are the epigenetic mark of centromeres, the kinetochore assembly sites required for chromosome segregation. HJURP is the CENP-A chaperone, which associates with Mis18α, Mis18β, and M18BP1 to target centromeres and deposit new CENP-A. How these proteins interact to promote CENP-A deposition remains poorly understood. Here we show that two repeats in human HJURP proposed to be functionally distinct are in fact interchangeable and bind concomitantly to the 4:2:2 Mis18α:Mis18β:M18BP1 complex without dissociating it. HJURP binds CENP-A:H4 dimers, and therefore assembly of CENP-A:H4 tetramers must be performed by two Mis18αβ:M18BP1:HJURP complexes, or by the same complex in consecutive rounds. The Mis18α N-terminal tails blockade two identical HJURP-repeat binding sites near the Mis18αβ C-terminal helices. These were identified by photo-cross-linking experiments and mutated to separate Mis18 from HJURP centromere recruitment. Our results identify molecular underpinnings of eukaryotic chromosome inheritance and shed light on how centromeres license CENP-A deposition. The CENP-A chaperone HJURP associates with Mis18α, Mis18β, and M18BP1 to target centromeres and deposit new CENP-A. Here the authors provide evidence that two repeats in human HJURP previously proposed to be functionally distinct are interchangeable and bind concomitantly to the 4:2:2 Mis18α:Mis18β:M18BP1 complex without dissociating it.

Well balanced novelty seeking and exploration are fundamental behaviours for survival and are found to be dysfunctional in several psychiatric disorders. Recent studies suggest that the endocannabinoid (eCB) system is an important control system for investigatory drive. Pharmacological treatment of rodents with cannabinergic drugs results in altered social and object investigation. Interestingly, contradictory results have been obtained, depending on the treatment, drug concentration and experimental conditions. The cannabinoid type 1 (CB1) receptor, a central component of the eCB system, is predominantly found at the synapses of two opposing neuronal populations, i.e. on inhibitory GABAergic and excitatory glutamatergic neurons. In the present study, using different transgenic mouse lines, we aimed at investigating the impact of CB1 receptor inactivation in glutamatergic or GABAergic neurons on investigatory behaviour. We evaluated animate (interaction partner) and inanimate (object) exploratory behaviour in three different paradigms. We show that exploration was increased when CB1 receptor was deleted from cortical and striatal GABAergic neurons. No effect was observed when CB1 receptor was deleted specifically from dopamine receptor D1-expressing striatal GABAergic medium spiny neurons. In contrast, deletion of CB1 receptor from cortical glutamatergic neurons resulted in a decreased exploration. Thus, our results indicate that exploratory behaviour is accurately balanced in both, the social and non-social context, by the eCB system via CB1 receptor activation on cortical glutamatergic and GABAergic neurons. In addition, the results could explain the contradictory findings of previous pharmacological studies and could further suggest a possibility to readjust an imbalance in exploratory behaviour observed in psychiatric disorders.

Background Children often experience anxiety and pain during minor surgical procedures, prompting the search for effective pain management strategies beyond traditional pharmaceutical approaches. This study aims to evaluate the efficacy of virtual reality (VR) as a pain reduction method in pediatric outpatient surgical interventions compared to the standard use of nitrous oxide. The research questions explore pain reduction levels, patient preferences, enjoyment during VR use, and the time limit of the VR application. Methods The study employs a randomized controlled trial design, utilizing VR technology and nitrous oxide in separate groups in 100 children at the age from 6 to 15 undergoing minor surgical procedures. Outcomes are monitored directly after the intervention and two weeks following the procedure. The primary outcome measure is the pain level, assessed using visual face and visual analog scales. Secondary outcomes are the fun and/or fear experienced during the intervention, the willingness to undergo the same procedure again (if necessary), and whether there is a time limit with the VR application compared to nitrous oxide. The study also considers adverse events and safety measures. Discussion The study aims to address a significant research gap in pediatric pain management strategies, as it is the first randomized controlled trial designed to compare pain levels using VR versus a control group with nitrous oxide analgosedation in children undergoing minor surgical procedures. Preliminary evidence suggests VR may offer a viable alternative to traditional pain management methods, as VR technology could be an effective distraction and pain management tool for pediatric patients undergoing outpatient surgical procedures. Trial registration ClinicalTrials.gov NCT05510141. Registered on August 22, 2022. Virtual Reality Games in Pediatric Surgery—Full Text View—ClinicalTrials.gov. Trial sponsor The principal investigator, Cordula Scherer act as the Sponsor, Clinic for pediatric surgery, Inselspital, Bern University Hospital, CH 3010 Bern, Switzerland.

Marijuana and its main psychotropic ingredient Delta(9)-tetrahydrocannabinol (THC) exert a plethora of psychoactive effects through the activation of the neuronal cannabinoid receptor type 1 (CB1), which is expressed by different neuronal subpopulations in the central nervous system. The exact neuroanatomical substrates underlying each effect of THC are, however, not known. We tested locomotor, hypothermic, analgesic, and cataleptic effects of THC in conditional knockout mouse lines, which lack the expression of CB1 in different neuronal subpopulations, including principal brain neurons, GABAergic neurons (those that release gamma aminobutyric acid), cortical glutamatergic neurons, and neurons expressing the dopamine receptor D1, respectively. Surprisingly, mice lacking CB1 in GABAergic neurons responded to THC similarly as wild-type littermates did, whereas deletion of the receptor in all principal neurons abolished or strongly reduced the behavioural and autonomic responses to the drug. Moreover, locomotor and hypothermic effects of THC depend on cortical glutamatergic neurons, whereas the deletion of CB1 from the majority of striatal neurons and a subpopulation of cortical glutamatergic neurons blocked the cataleptic effect of the drug. These data show that several important pharmacological actions of THC do not depend on functional expression of CB1 on GABAergic interneurons, but on other neuronal populations, and pave the way to a refined interpretation of the pharmacological effects of cannabinoids on neuronal functions.

(1) Background: We aimed to evaluate the health-related quality of life (HRQoL) in children with fractures of the distal forearm and to assess if HRQoL was associated with fracture classification; (2) Methods: We followed up on 432 patients (185 girls, 247 boys) who sustained a fracture of the distal radius or forearm from 1/2007 to 6/2007, 1/2014 to 6/2014, and 11/2016 to 10/2017. Patients filled in the Quick-DASH (primary outcome) and the Peds-QL; (3) Results: The radius was fractured in 429 and the ulna in 175 cases. The most frequent injury of the radius was a buckle fracture (51%, mean age 8.5 years), followed by a complete metaphyseal fracture (22%, 9.5 years), Salter-Harris-2 fracture (14%, 11.4 years), greenstick fracture (10%, 9.3 years), Salter-Harris-1 fracture (1%, 12.6 years), and other rare injuries. The most common treatment was closed reduction and an above-elbow cast in 138 cases (32%), followed by a cast without reduction (30%), splint (28%), and K-wire fixation and cast (9%). Definite treatment was performed initially in 95.8%, a new cast or cast wedging was performed in 1.6%, and revision surgery was performed in 2.5%. There were no open reductions and no plate fixations. After a mean follow-up of 4.2 years, patients with buckle fractures had a mean Quick-DASH of 3.3 (scale of 0–100) (complete fracture: 1.5; greenstick: 1.5; SH-1: 0.9; SH-2: 4.1; others: 0.9). The mean function score of the PedsQL ranged from 93.0 for SH-2 fractures to 97.9 for complete fractures; (4) Conclusions: In this cohort of 432 children with fractures of the distal forearm, there was equally good mean mid- and long-term HRQoL when assessed by the Quick-DASH and the PedsQL. There was a trend for children with complete metaphyseal fractures reporting better HRQoL than patients with buckle fractures or patients with Salter-Harris II fractures, however, these differences were not statistically significant nor clinically relevant.

In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans.

IntroductionThe aim of this study was to report a long-term follow-up of patients treated with autologous matrix-induced chondrogenesis (AMIC) for full-thickness chondral and osteochondral defects of the femoral condyle or patella combined with the correction of lower limb malalignment or patellar tracking if indicated.MethodsThirty-three patients (thirty-four knees) were treated surgically for chondral and osteochondral cartilage defects of the knee joint. Regarding the origin of the lesion, patients were divided into three groups. Chondral lesions were observed in the patella (cP group) in fifteen patients, whereas eight patients demonstrated a femoral condylar location (cF group). Eleven patients presented with osteochondritis dissecans of the femur (ocF group). Associated procedures involving realignment of the patella, osteotomy around the knee, or cancellous bone grafting were performed when necessary. The mean size of the lesions was 2.8 ± 1.6 cm2, and the mean patient age was 37.1 ± 11.9 years. To evaluate the clinical outcomes, the Lysholm score and the VAS pain score were imposed, as well as the reoperation rate.ResultsAfter an average of 9.3 ± 1 years, follow-up was completed in 79% of the patients. Two patients from the cohort received a total knee prosthesis. The primary outcome measures (Lysolm and VAS pain) at 9-year follow-up were 85 ± 13 for the Lysholm score and 1.9 ± 1.6 for the VAS score in the entire analyzed population. Compared to the preoperative values (Lysholm 56 ± 19, VAS 5.8 ± 2.4) and the 2-year results (Lysholm 85 ± 16, VAS 2.0 ± 2.1), there was significant improvement in the first 2 years after intervention and a stable course in the long-term observation. The same was observed in the cP and ocF subgroups, whereas patients of the cF group showed even further improvement.ConclusionsAMIC showed durable results in aligned knees. The favorable outcome was maintained after an average of 9 years when malalignment of the lower limb and patellar maltracking were corrected. Such data are particularly encouraging for young adult patients who may benefit from a procedure that circumvents early arthroplasty.

Background The Ponseti method is the most frequent method for clubfoot treatment. It includes a six-year night-splinting period, which is difficult to comply with. The objective of this study is to evaluate the clinical outcomes, recurrence rates, and patient-reported health-related quality of life following a modified Ponseti method with reduced night splinting duration. Methods We analyzed 107 children (77 boys, 30 girls, 152 clubfeet) who were treated for idiopathic clubfoot from January 1994 to January 2015. The initial treatment started at a mean age of 9.2 days. Long-leg Soft Casts TM3 were applied until the desired position of the foot was achieved. At a mean age of 3.2 months, the residual deformity was corrected surgically. We assessed the clinical outcome by chart review and the functional outcome by a questionnaire that included the disease specific instrument (DSI) and the health-related quality of life assessed by the pediatric quality of life inventory (PedsQL™).  Results In 101 patients (92.7%) and 142 feet (93.4%), we had a clinical follow-up at a mean age of 7.39±4.9 years. A Denise Brown splint or a unilateral orthosis was applied for a mean period of 7.8±4.8 months over the whole day and an additional 17.3 ±16.3) nights only. At a mean follow-up of 10.0±SD 6.2 years, 82.2% of patients returned the questionnaires. The mean DSI was 74.8±17.5. The mean overall PedsQL™ was 87.8±12.6. The PedsQL™ functional component score showed a mean of 89.4±5.6, and the PedsQL™ social component score a mean of 86.9±13.5. Ten (9.3%) patients had a bilateral, and 18 (16.8%) patients had a unilateral relapse. Conclusions Achilles tendon lengthening (ATL) and limited posterior release, followed by a reduced period of splinting of 2.1 years, provide similar results compared to the original Ponseti method.

The cannabinoid type 1 receptor ( Cnr1 , CB1R) mediates a plethora of physiological functions in the central nervous system as a presynaptic modulator of neurotransmitter release. The recently identified cannabinoid receptor-interacting protein 1a ( Cnrip1a , CRIP1a) binds to the C-terminal domain of CB1R, a region known to be important for receptor desensitization and internalization. Evidence that CRIP1a and CB1R interact in vivo has been reported, but the neuroanatomical distribution of CRIP1a is unknown. Moreover, while alterations of hippocampal CRIP1a levels following limbic seizures indicate a role in controlling excessive neuronal activity, the physiological function of CRIP1a in vivo has not been investigated. In this study, we analyzed the spatial distribution of CRIP1a in the hippocampus and examined CRIP1a as a potential modulator of CB1R signaling. We found that Cnrip1a mRNA is co-expressed with Cnr1 mRNA in pyramidal neurons and interneurons of the hippocampal formation. CRIP1a protein profiles were largely segregated from CB1R profiles in mossy cell terminals but not in hippocampal CA1 region. CB1R activation induced relocalization to close proximity with CRIP1a. Adeno-associated virus-mediated overexpression of CRIP1a specifically in the hippocampus revealed that CRIP1a modulates CB1R activity by enhancing cannabinoid-induced G protein activation. CRIP1a overexpression extended the depression of excitatory currents by cannabinoids in pyramidal neurons of the hippocampus and diminished the severity of chemically induced acute epileptiform seizures. Collectively, our data indicate that CRIP1a enhances hippocampal CB1R signaling in vivo.