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ABSTRACT Protein-protein interactions are either through direct contacts between two binding partners or mediated by structural waters. Both direct contacts and water-mediated interactions are crucial to the formation of a protein-protein complex. During the recent CAPRI rounds, a novel parallel searching strategy for predicting water-mediated interactions is introduced into our protein-protein docking method, MDockPP. Briefly, a FFT-based docking algorithm is employed in generating putative binding modes, and an iteratively derived statistical potential-based scoring function, ITScorePP, in conjunction with biological information is used to assess and rank the binding modes. Up to 10 binding modes are selected as the initial protein-protein complex structures for MD simulations in explicit solvent. Water molecules near the interface are clustered based on the snapshots extracted from independent equilibrated trajectories. Then, protein-ligand docking is employed for a parallel search for water molecules near the protein-protein interface. The water molecules generated by ligand docking and the clustered water molecules generated by MD simulations are merged, referred to as the predicted structural water molecules. Here, we report the performance of this protocol for CAPRI rounds 28-29 and 31-35 containing 20 valid docking targets and 11 scoring targets. In the docking experiments, we predicted correct binding modes for nine targets, including one high-accuracy, two medium-accuracy, and six acceptable predictions. Regarding the two targets for the prediction of water-mediated interactions, we achieved models ranked as 'excellent' in accordance with the CAPRI evaluation criteria; one of these two targets is considered as a difficult target for structural water prediction. Proteins 2017; 85:424-434. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Venom proteins act in the immunological interactions between parasitoids and their host insects. The effect of venom proteins on host immunity is not fully understood in pupal parasitoids. We identified the functions of a venom protein, calreticulin (PvCRT), in the pupal ectoparasitoid Pachycrepoideus vindemiae. Here, we report that PvCRT features a signal peptide and two conserved "calreticulin" domains. Multiple sequence alignments show that PvCRT shares 83.54% amino acid identity with CRT from both Pteromalus puparum and Nasonia vitripennis, which infers a close relationship among these three species. Using qPCR analysis, we found a lower expression level of PvCRT (0.27-fold) in the venom apparatus compared to the corresponding carcass. Immunohistochemical localization revealed that PvCRT was ubiquitously expressed in venom gland. The expression of the PvCRT gene in Drosophila transgenic lines via the UAS/Gal4 binary expression system reduced the self-encapsulation phenotype of tu(1)Sz1 mutants. Additionally, studies on humoral immunity indicate that PvCRT does not affect the antimicrobial immune responses of the host. This work on an ectoparasitoid will increase our understanding of venom–mediated host-parasitoid interactions. [ABSTRACT FROM AUTHOR]

Identifying relatively low permeability areas (RLPA) is significant for site selection and parameter design for implementing enhanced gas mining measures (e.g. hydraulic fracturing, hydraulic perforation, etc.) in coal and gas outburst seams. The P-wave velocity of coal is sensitive to the variation of porosity. This paper researched the P-wave velocity change of coal with respect to confining pressure and gas pressure, the mathematical relationship model between P-wave velocity with porosity and permeability, and the relative permeability identification index. The research found that the P-wave velocity response to gas pressure varies non-monotonically. When the gas pressure is <2 MPa, the confining pressure is the main control factor leading to P-wave velocity variation. The mathematical model of P-wave velocity versus porosity and permeability was derived based on the linear relationship between wave velocity and porosity in dense rocks and the Seidle permeability model for porous media. Then the wave velocity anomaly coefficient (A n) is used as the identification index for the relative permeability of the coal seam. That is, when the anomaly coefficient of coal seam wave velocity A n < -8%, the coal seam is a relatively high permeability area (RHPA); when −8% < A n < 8%, the coal seam is relatively normal permeability area (RNPA); when A n > 8%, the coal seam is (RLPA). Based on the identification indexes studied, two RHPA (H1 and H2) and two RLPA (L1 and L2) were identified in the field engineering application. Comparing the drainage parameters in different relative permeability areas, the gas drainage volume fraction and flow in the RLPA are 56% and 90% lower than RHPA, respectively, validating the accuracy of identifying RLPA in the coal seam. • Relationship model between P-wave velocity and coal permeability was developed. • Established an identification index for the relative permeability of coal seams. • Proposed a method to identify the relative permeability of coal seams. [ABSTRACT FROM AUTHOR]

• HHT method can well process and analyze the EMR waveform signal of coal failure. • The EMR parameters extracted by HHT improve the identification of coal failure. • Compared with STFT and WT, HHT has more advantages in processing EMR waveform. Electromagnetic radiation (EMR) waveforms contain rich information on coal fracture law, which is of great value to the refined study of their characteristics. In this paper, the Hilbert-Huang transform (HHT) method is used to analyze and process EMR waveform of coal failure process. The results show that HHT method can adapt well to the nonstationary and nonlinear characteristics of EMR waveform. It adaptively decomposes EMR waveforms by empirical mode decomposition (EMD), extracts the intrinsic mode function (IMF) characteristics of EMR waveforms, and obtains the law of instantaneous energy changes of EMR waveforms. At the same time, EMR waveform energy is quantitatively expressed on the three-dimensional Hilbert energy spectrum (time–frequency-energy distribution), and the refined features of EMR waveform signal are effectively extracted. The instantaneous energy of EMR and the three-dimensional Hilbert energy spectrum processed by HHT method more easily describe the fracture law of coal body. Compared with conventional characteristic parameters, such as EMR amplitude and dominant frequency, the identification degree of the precursor characteristics of coal body instability is greatly improved. Among the short-term Fourier transform (STFT), wavelet transform (WT) and HHT nonstationary signal processing methods, HHT method has an improved adaptability and superiority and can reveal the characteristics of coal deformation and failure more carefully and accurately, which provides a new means for better using and improving EMR method to monitor coal instability and failure. [ABSTRACT FROM AUTHOR]

Coal rock friction generally exists in various geological movements, and it is of great significance to effectively monitor the friction process. In this paper, the commonly used methods of coal rock friction are systematically summarized, and the double shear friction experimental method suitable for coal friction electromagnetic radiation monitoring is preferentially selected. A coal friction device with controllable lateral pressure was independently developed, coal friction experiments were carried out under different lateral pressure, and the time-frequency evolution law and generation mechanism of electromagnetic radiation in coal friction were studied. The results show that coal friction can generate abundant EMR signals. With increasing coal friction lateral pressure, the EMR signal develops from sparse to abundant, and the signal energy, amplitude, and dominant frequency gradually increase. The EMR signal of the coal friction process shows clear stage characteristics. At the stable sliding stage, the EMR signal is weak and energy is low. At the stick slip stage, the EMR signal is generated intermittently along with the load drop cycle, with more signals and strong intensity. The main mechanisms of coal friction EMR are the frictional slip electrification of the micro-convex body on the coal surface, charge separation, and the variable-speed movement of the charged particles formed by crack propagation of the micro-convex body. These results clarify the mechanical behavior of coal friction sliding instability and the time-frequency evolution law of the EMR of coal friction, which further improves the accuracy of EMR monitoring and early warning of coal rock dynamic disasters. • The methods of coal rock friction are systematically summarized. • The friction process of coal can generate abundant EMR. • The EMR signal of the coal friction process shows clear stage characteristics. • Time-frequency evolution law of EMR in coal friction process is obtained. • The EMR mechanism of coal friction micro convex bodies slip fracture is revealed. [ABSTRACT FROM AUTHOR]

• A three-axis antenna is made to measure the near-field generated by rock fracture. • The three-axis antenna is relatively advantageous in response to lower frequency band. • Signals of same fracture received at the same location vary in different directions. In general, the generation of electromagnetic radiation initiates with the evolution of the crack in a rockmass. Theoretical observations depict that the low-frequency electromagnetic field excited by a dipole on cracks are directional in the near-field range. Therefore, in this paper, to achieve the measurement of low-frequency near-field, an electromagnetic antenna capabale of simultaneously measuring in directions of three axes is designed. After calibration of the standard alternating field, the antenna is used to monitor electromagnetic signals generated during the uniaxial compression and the Brazilian test. For the same fracture, signals differ in directions at the same position, which are actually components in three coordinate directions. And the three-axis antenna is relatively advantageous in response to low-frequency signals compared with the wide-band loop antenna. The outcomes of this research can provide theoretical as well as a practical basis for characterizing electromagnetic radiations associated with rock fractures. [ABSTRACT FROM AUTHOR]

• Three rock burst mechanism in SIETCS and the factors influencing them are proposed. • Associated mechanical models and elastic deformation energy functions are developed. • Static and dynamic stresses are analyzed via theoretical analysis and MS monitoring. • A load-reduction and prying-reduction rock burst-prevention strategy is put forward. Rock bursts frequently occur in steeply inclined and extremely thick coal seams (SIETCS), posing severe challenges to safe mining. To reduce the risk of rock burst in SIETCS, this study investigated the mechanisms of the rock bursts occurrence in SIETCS and formulated the principles for its prevention. To this end, field investigation, geophysical monitoring, theoretical analyses, and numerical simulation were employed. Mechanical models have been developed for a "steeply inclined suspended roof structure" and a "steeply inclined suspended rock pillar structure", which are relevant to the rock burst mechanisms. The elastic deformation energy distribution functions for both models have been obtained, and the factors influencing the elastic deformation energy have been analyzed. The sources of microseismic (MS) events associated with rock bursts monitored in the typical SIETCS (with a dip angle of 87°) are mainly concentrated in the roof and interlayer rock pillar, making up 17.0% and 60% of the events recorded, respectively. The elastic deformation energy of the roof and rock pillar is mainly influenced by the dip angle of the coal seam, the lateral pressure coefficient, and the supporting force coefficient. The peak stress of the coal body at the compressive and prying area is 1.7 times of the horizontal tectonic stress. The minimum normal and tangential dynamic load stresses generated by the recorded rock bursts are 84.5 MPa and 48.6 MPa, respectively; such stress levels exert strong destructive forces when superimposed with static stress. The analytical results of the failure law of rock burst, MS monitoring, mechanical model, numerical simulation, and elastic deformation energy function of the typical SIETCS identify the main causes of rock burst as the high static stress of a coal body under the coupled action of compressive and prying effects of roof and rock pillar and the dynamic stress caused by breakage of the roof and rock pillar. The damage models and the damage process by which a rock burst is induced have been constructed. Three mechanisms by which a rock burst can occur in SIETCS are proposed. Finally, prevention principles of load-reduction and prying-reduction for rock burst in SIETCS have been developed. [ABSTRACT FROM AUTHOR]

Background: Prior studies suggest that patients with essential tremor (ET) have increased rates of healthcare utilization, but the reason for this increased use is unknown. The objective of this study was to evaluate the reasons for healthcare use among ET patients., Methods: This was a retrospective cross-sectional study of ET patients with an admission or emergency department (ED) visit at a tertiary health system from 2018-2023. Patients were matched on an encounter level with control patients based on propensity scores incorporating age, sex, race, and co-morbid conditions. The primary outcome was the odds of an encounter for each diagnostic category comparing ET patients with matched controls., Results: Only inpatient admissions for neurologic diagnoses were more likely for ET compared to control patients (odds ratio (OR) 3.73, 95% confidence interval (CI) 2.54 - 5.49, p < 0.001). Once admissions related to the surgical treatment of tremor were excluded, admissions for neurologic diagnoses were equally likely among ET and control patients (OR 0.96, 95% CI 0.59 - 1.57, p = 0.88)., Discussion: Surgical treatment of tremor appears to be a key driver of healthcare use among ET patients. Future investigations should examine the pattern of healthcare use of ET patients before and after surgery., Highlights: Prior studies have shown increased healthcare use among essential tremor (ET) patients. The objective of this study was to evaluate the reasons for healthcare use among ET patients compared to matched control patients. Surgical treatment of tremor was found to be a key driver of healthcare use among ET patients., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Background: The zona incerta (ZI) is a subcortical structure primarily investigated in rodents that is implicated in various behaviors, ranging from motor control to survival-associated activities, partly due to its integration in multiple neural circuits. In the current study, we used diffusion magnetic resonance imaging tractography to segment the ZI and gain insight into its connectivity in various circuits in humans., Methods: We performed probabilistic tractography in 7T diffusion MRI on 178 participants from the Human Connectome Project to validate the ZI's anatomical subdivisions and their respective tracts. K-means clustering segmented the ZI based on each voxel's connectivity profile. We further characterized the connections of each ZI subregion using probabilistic tractography with each subregion as a seed., Results: We identified 2 dominant clusters that delineated the whole ZI into rostral and caudal subregions. The caudal ZI primarily connected with motor regions, while the rostral ZI received a topographic distribution of projections from prefrontal areas, notably the anterior cingulate and medial prefrontal cortices. We generated a probabilistic ZI atlas that was registered to a patient-participant's magnetic resonance imaging scan for placement of stereoencephalographic leads for electrophysiology-guided deep brain stimulation to treat their obsessive-compulsive disorder. Rostral ZI stimulation improved the patient's core symptoms (mean improvement 21%)., Conclusions: We present a tractography-based atlas of the rostral and caudal ZI subregions constructed using high-resolution diffusion magnetic resonance imaging from 178 healthy participants. Our work provides an anatomical foundation to explore the rostral ZI as a novel target for deep brain stimulation to treat refractory obsessive-compulsive disorder and other disorders associated with dysfunctional reward circuitry., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: There are critical disparities in the neurosurgical care provided around the globe due to challenges in resource allocation, training, and infrastructure. Global neurosurgical collaborations have replaced classical mission trips to address these disparities. However, the development of these collaborations and the impact of research funding on their growth has not yet been systematically studied. In this article, we use a graph theoretical approach to investigate trends in funding and co-authorship between and among authors from high-income countries (HICs) and authors from low- and middle-income countries (LMICs)., Methods: A bibliometric search of the global neurosurgical literature returned 307 articles between 1985 and 2020. A connectivity analysis was conducted to compute the number of co-authorships between HIC-HIC, LMIC-HIC, and LMIC-LMIC authors. The number of connections, summarized as either a global sum of connections or an average number of connections per manuscript, were analyzed in the context of time and funding through parametric statistical tests., Results: An exponential increase in co-authorship collaboration was observed over time, especially after 2015. Notably, LMIC-LMIC collaborations appear to be rising at over twice the rate of other collaboration types. The presence of funding, in general, was associated with increased co-authorship of manuscripts by LMIC and HIC authors together (p = 0.033). A significant majority of the funding associated with LMIC-HIC co-authorships was supplied through charitable organizations and government grants (p = 0.034, p = 0.009, respectively). Most LMIC-LMIC co-authorships had no funding., Conclusion: This work shows significant and rapid growth in international neurosurgical partnerships, especially in HIC-LMIC and LMIC-LMIC collaborations. Also, a significant positive relationship exists between research funding and LMIC-HIC co-authorship trends. This work encourages us as a community to continue to expand our translational collaborations with LMIC neurosurgeons and establish funding mechanisms independent of HIC authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological derangements. Recent developments in advanced neuroimaging have led to a growing understanding of PWS as a neural circuit disorder, as well as subsequent interests in the application of neuromodulatory therapies. Various non-invasive and invasive device-based neuromodulation methods, including vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) have all been reported to be potentially promising treatments for addressing the major symptoms of PWS. In this systematic literature review, we summarize the recent literature that investigated these therapies, discuss the underlying circuits which may underpin symptom manifestations, and cover future directions of the field. Through our comprehensive search, there were a total of 47 patients who had undergone device-based neuromodulation therapy for PWS. Two articles described VNS, 4 tDCS, 1 rTMS and 2 DBS, targeting different symptoms of PWS, including aberrant behavior, hyperphagia and weight. Multi-center and multi-country efforts will be required to advance the field given the low prevalence of PWS. Finally, given the potentially vulnerable population, neuroethical considerations and dialogue should guide the field., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aysegul Gunduz reports a relationship with Medtronic Inc that includes: funding grants. Casey H. Halpern reports a relationship with Boston Scientific Corp that includes: consulting or advisory and speaking and lecture fees. Casey H. Halpern reports a relationship with Insightec that includes: consulting or advisory and speaking and lecture fees. Casey H. Halpern reports a relationship with SynchNeuro Inc that includes: board membership and equity or stocks. Michael S. Okun reports a relationship with Parkinson's Foundation that includes: consulting or advisory and funding grants. Michael S. Okun reports a relationship with National Institutes of Health that includes: funding grants. Michael S. Okun reports a relationship with Michael J. Fox Foundation, Parkinson Alliance, Smallwood Foundation, Bachmann-Strauss Foundation, Tourette Syndrome Association, UF Foundation that includes: funding grants. Casey H. Halpern has patent #USPTO serial number: 63/170,404 and 63/220,432 issued to Stanford University. Casey H. Halpern has patent #USPTO serial number: 63/210,472 pending to SynchNeuro. Michael S. Okun has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, Perseus, Robert Rose, Oxford and Cambridge (movement disorders books). M.S.O. is an associate editor for New England Journal of Medicine Journal Watch Neurology and JAMA Neurology. He has participated in CME and educational activities (past 12–24 months) on movement disorders sponsored by WebMD/Medscape, RMEI Medical Education, American Academy of Neurology, Movement Disorders Society, Mediflix and by Vanderbilt University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objectives: Nonhuman primates (NHPs) are important preclinical models for evaluating therapeutics because of their anatomophysiological similarities to humans, and can be especially useful for testing new delivery targets. With the growing promise of cell and gene therapies for the treatment of neurological diseases, it is important to ensure the accurate and safe delivery of these agents to target structures in the brain. However, a standard guideline or method has not been developed for stereotactic targeting in NHPs. In this article, we describe the safe use of a magnetic resonance imaging-guided frameless stereotactic system to target bilateral cerebellar dentate nuclei for accurate, real-time delivery of viral vector in NHPs., Methods: Seventeen rhesus macaques (Macaca mulatta) underwent stereotactic surgery under real-time MRI guidance using the ClearPoint® system. Bilateral cerebellar dentate nuclei were targeted through a single parietal entry point with a transtentorial approach. Fifty microliters of contrast-impregnated infusate was delivered to each dentate nucleus, and adjustments were made as necessary according to real-time MRI monitoring of delivery. Perioperative clinical outcomes and postoperative volumes of distribution were recorded., Results: All macaques underwent bilateral surgery successfully. Superficial pin site infection occurred in 4/17 (23.5%) subjects, which resolved with antibiotics. Two episodes of transient neurological deficit (anisocoria and unilateral weakness) were recorded, which did not require additional postoperative treatment and resolved over time. Volume of distribution of infusate achieved satisfactory coverage of target dentate nuclei, and only 1 incidence (2.9%) of cerebrospinal fluid penetration was recorded. Mean volume of distribution was 161.22 ± 39.61 mm3 (left, 173.65 ± 48.29; right, 148.80 ± 23.98)., Conclusion: MRI-guided frameless stereotactic injection of bilateral cerebellar dentate nuclei in NHPs is safe and feasible. The use of this technique enables real-time modification of the surgical plan to achieve adequate target coverage and can be readily translated to clinical use., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background: Occipital neuralgia (ON) is a debilitating headache disorder. Due to the rarity of this disorder and lack of high-level evidence, a clear framework for choosing the optimal surgical approach for medically refractory ON incorporating shared decision making with patients does not exist., Methods: A literature review of studies reporting pain outcomes of patients who underwent surgical treatment for ON was performed, as well as a retrospective chart review of patients who underwent surgery for ON within our institution., Results: Thirty-two articles met the inclusion criteria. A majority of the articles were retrospective case series (22/32). The mean number of patients across the studies was 34 (standard deviation (SD) 39). Among the 13 studies that reported change in pain score on 10-point scales, a study of 20 patients who had undergone C2 and/or C3 ganglionectomies reported the greatest reduction in pain intensity after surgery. The studies evaluating percutaneous ablative methods including radiofrequency ablation and cryoablation showed the smallest reduction in pain scores overall. At our institution from 2014 to 2023, 11 patients received surgical treatment for ON with a mean follow-up of 187 days (SD 426)., Conclusion: Based on these results, the first decision aid for selecting a surgical approach to medically refractory ON is presented. The algorithm prioritizes nerve sparing followed by non-nerve sparing techniques with the incorporation of patient preference. Shared decision making is critical in the treatment of ON given the lack of clear scientific evidence regarding the superiority of a particular surgical method., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Calcineurin inhibitor-related tremors occur in up to 50% of solid organ transplant recipients and are disabling in severe cases. We describe a bilateral lung transplant recipient with essential tremors that significantly worsened after tacrolimus initiation. She did not have improvement with the change to extended-release tacrolimus, the use of everolimus as a calcineurin inhibitor-sparing agent, or the addition of primidone, clonazepam, or propranolol. She underwent magnetic resonance-guided focused ultrasound thalamotomy with significant improvement in her tremor and activities of daily living., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Weight loss in Parkinson's disease (PD) is common and associated with increased mortality. The clinical significance of weight changes following deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is unclear., Objectives: To address (1) whether PD patients exhibit progressive weight loss, (2) whether staged DBS surgery is associated with weight changes, and (3) whether survival after DBS correlates with post-DBS weight., Methods: This is a single-center, longitudinal, retrospective cohort study of 1625 PD patients. We examined trends in weight over time and the relationship between weight and years survival after DBS using regression and mixed model analyses., Results: There was a decline in body weight predating motor symptom onset (n = 756, 0.70 ± 0.03% decrease per year, p < 0.001). Weight decline accelerated in the decade preceding death (n = 456, 2.18 ± 0.31% decrease per year, p < 0.001). DBS patients showed a weight increase of 2.0 ± 0.33% at 1 year following the first DBS lead implant (n = 455) and 2.68 ± 1.1% at 3 years if a contralateral DBS lead was placed (n = 249). The bilateral STN DBS group gained the most weight after surgery during 6 years of follow up (vs bilateral GPi, 3.03 ± 0.45% vs 1.89 ± 0.31%, p < 0.01). An analysis of the DBS cohort with date of death available (n = 72) revealed that post-DBS weight (0-12 months after the first or 0-36 months after the second surgery) was positively associated with survival (R 2  = 0.14, p < 0.001)., Discussion: Though PD is associated with significant weight loss, DBS patients gained weight following surgery. Higher post-operative weight was associated with increased survival. These results should be replicated in other cohorts., Competing Interests: Declaration of competing interest No conflict of interest, (Copyright © 2023. Published by Elsevier Ltd.)

Reliably scoring and ranking candidate models of protein complexes and assigning their oligomeric state from the structure of the crystal lattice represent outstanding challenges. A community-wide effort was launched to tackle these challenges. The latest resources on protein complexes and interfaces were exploited to derive a benchmark dataset consisting of 1677 homodimer protein crystal structures, including a balanced mix of physiological and non-physiological complexes. The non-physiological complexes in the benchmark were selected to bury a similar or larger interface area than their physiological counterparts, making it more difficult for scoring functions to differentiate between them. Next, 252 functions for scoring protein-protein interfaces previously developed by 13 groups were collected and evaluated for their ability to discriminate between physiological and non-physiological complexes. A simple consensus score generated using the best performing score of each of the 13 groups, and a cross-validated Random Forest (RF) classifier were created. Both approaches showed excellent performance, with an area under the Receiver Operating Characteristic (ROC) curve of 0.93 and 0.94, respectively, outperforming individual scores developed by different groups. Additionally, AlphaFold2 engines recalled the physiological dimers with significantly higher accuracy than the non-physiological set, lending support to the reliability of our benchmark dataset annotations. Optimizing the combined power of interface scoring functions and evaluating it on challenging benchmark datasets appears to be a promising strategy., (© 2023 Wiley-VCH GmbH.)

HIV-1 integrase (IN) is a key enzyme that is essential for mediating the insertion of retroviral DNA into the host chromosome. IN also exhibits additional functions which are not fully elucidated, including its ability to bind to viral genomic RNA. Lack of binding of IN to RNA within the virions has been shown to be associated with production of morphologically defective virus particles. However, the exact structure of HIV-1 IN bound to RNA is not known. Based on the studies that C-terminal domain (CTD) of IN binds to TAR RNA region and based on the observation that TAR and the host factor INI1 binding to IN-CTD are identical, we computationally modelled the IN-CTD/TAR complex structure. Computational modeling of nucleic acid binding to proteins is a valuable method to understand the macromolecular interaction when experimental methods of solving the complex structures are not feasible. The current model of the IN-CTD/TAR complex may facilitate further understanding of this interaction and may lead to therapeutic targeting of IN-CTD/RNA interactions to inhibit HIV-1 replication., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Here, we evaluate the evolution and growth of global neurosurgery publications over time, further focusing on the contributions and impact of authors in low- and middle-income countries (LMICs)., Methods: In this systematic bibliometric analysis, we conducted a two-stage blinded screening process of global neurosurgery publications from 5 databases from inception through July 2021. Articles involving multi-national/multi-institutional research collaborations, detailing any area of global neurosurgery collaboration, or influencing global neurosurgery practice were included. Statistical hypothesis testing was conducted to analyze trends and hypotheses of LMIC authorship contributions., Results: The number of global neurosurgery publications has soared in the last decade. Overall, authors from HIC countries were most commonly from the US (41.1%), Canada (4.0%), and the UK (3.9%), while authors from LMIC countries were most commonly from Uganda (4.2%), Tanzania (2.6%), Cameroon (1.8%), and India (1.8%). Over a quarter (28%) of publications had no LMIC authors, while only 11% had 3 or more LMIC authors. The proportion of LMIC authors (LMIC-R) was not correlated with the citation rate of individual articles or with the year of publication, and a positive trend emerged when the LMIC-R of top-publishing LMICs was individually examined and compared to the year of publication., Conclusions: Despite recent growth, the number of global neurosurgery publications arising from LMICs pales in comparison to those from HICs. Collaborative efforts between certain HICs and LMICs have likely contributed to the observed increase in LMIC author independence over time., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 domain and exhibits multifaceted role in HIV-1 replication. Determining the NMR structure of INI1-Rpt1 and modeling its interaction with the IN-C-terminal domain (IN-CTD) reveal that INI1-Rpt1/IN-CTD interface residues overlap with those required for IN/RNA interaction. Mutational analyses validate our model and indicate that the same IN residues are involved in both INI1 and RNA binding. INI1-Rpt1 and TAR RNA compete with each other for IN binding with similar IC 50 values. INI1-interaction-defective IN mutant viruses are impaired for incorporation of INI1 into virions and for particle morphogenesis. Computational modeling of IN-CTD/TAR complex indicates that the TAR interface phosphates overlap with negatively charged surface residues of INI1-Rpt1 in three-dimensional space, suggesting that INI1-Rpt1 domain structurally mimics TAR. This possible mimicry between INI1-Rpt1 and TAR explains the mechanism by which INI1/SMARCB1 influences HIV-1 late events and suggests additional strategies to inhibit HIV-1 replication.

Chronic subdural haemorrhage (CSDH) is a common neurosurgical entity with complex pathophysiological pathways. The generally favourable surgical outcome may be affected by its associated risks including recurrence rates. We performed a prospective randomized multi-center clinical trial comparing the addition of tranexamic acid (TXA) to standard neurosurgical procedures for patients with symptomatic CSDH. The primary endpoint was CSDH requiring repeat surgery within 6-month post-operatively. Secondary endpoints were comparison of post-operative volumes between the treatment arms and safety evaluation of the dosing regime. 90 patients were analyzed with 49 patients in the observation arm and 41 patients in the TXA arm. The observation arm had five (10.2%) recurrences compared to two (4.8%, p = 0.221) in the TXA arm. Patients in the TXA arm demonstrated a greater reduction of their CSDH volume at 6 weeks follow up (36.6%) compared to the observation arm (23.3%, p = 0.6648). There were no reportable serious adverse events recorded in the observation arm, compared to 4 (9.8%) patients in the TXA arm. The addition of TXA treatment to standard surgical drainage of CSH did not significantly reduce symptomatic post-operative recurrence. Patients in the TXA arm had a delay in the CSDH recurrence with a comparative reduction of residual hematoma volume at the 6-week follow up although the effect was unsustained. Larger randomized trials with dose adjustments should be considered to investigate subgroups of patients that may benefit from this medical adjunct., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rationale: Trimeric intracellular cation (TRIC)-A and B are distributed to endoplasmic reticulum/sarcoplasmic reticulum intracellular Ca 2+ stores. The crystal structure of TRIC has been determined, confirming the homotrimeric structure of a potassium channel. While the pore architectures of TRIC-A and TRIC-B are conserved, the carboxyl-terminal tail (CTT) domains of TRIC-A and TRIC-B are different from each other. Aside from its recognized role as a counterion channel that participates in excitation-contraction coupling of striated muscles, the physiological function of TRIC-A in heart physiology and disease has remained largely unexplored., Objective: In cardiomyocytes, spontaneous Ca 2+ waves, triggered by store overload-induced Ca 2+ release mediated by the RyR 2 (type 2 ryanodine receptor), develop extrasystolic contractions often associated with arrhythmic events. Here, we test the hypothesis that TRIC-A is a physiological component of RyR 2 -mediated Ca 2+ release machinery that directly modulates store overload-induced Ca 2+ release activity via CTT., Methods and Results: We show that cardiomyocytes derived from the TRIC-A -/- (TRIC-A knockout) mice display dysregulated Ca 2+ movement across sarcoplasmic reticulum. Biochemical studies demonstrate a direct interaction between CTT-A and RyR 2 . Modeling and docking studies reveal potential sites on RyR 2 that show differential interactions with CTT-A and CTT-B. In HEK293 (human embryonic kidney) cells with stable expression of RyR 2 , transient expression of TRIC-A, but not TRIC-B, leads to apparent suppression of spontaneous Ca 2+ oscillations. Ca 2+ measurements using the cytosolic indicator Fura-2 and the endoplasmic reticulum luminal store indicator D1ER suggest that TRIC-A enhances Ca 2+ leak across the endoplasmic reticulum by directly targeting RyR 2 to modulate store overload-induced Ca 2+ release. Moreover, synthetic CTT-A peptide facilitates RyR 2 activity in lipid bilayer reconstitution system, enhances Ca 2+ sparks in permeabilized TRIC-A -/- cardiomyocytes, and induces intracellular Ca 2+ release after microinjection into isolated cardiomyocytes, whereas such effects were not observed with the CTT-B peptide. In response to isoproterenol stimulation, the TRIC-A -/- mice display irregular ECG and develop more fibrosis than the WT (wild type) littermates., Conclusions: In addition to the ion-conducting function, TRIC-A functions as an accessory protein of RyR 2 to modulate sarcoplasmic reticulum Ca 2+ handling in cardiac muscle.

The use of anticoagulation and antiplatelet agents (ACAP) has steadily increased over recent years. However, the effects of ACAP on traumatic brain injuries (TBI) are not well investigated. The aim of this study was to investigate the effects of pre-injury ACAP use on clinical outcome and mortality in severe TBI. A retrospective case-control study was performed for all patients who presented with severe TBI (GCS < 8) to the National Neuroscience Institute, Singapore, between 2006 and 2009. Patients with pre-injury ACAP use were compared to matched controls. Outcome measures were mortality at 14 days and 6 months, and Glasgow Outcome Score (GOS) at 6 months using a sliding dichotomy approach. Univariate analysis was performed using Chi-square and student's t-test and logistic regression was used to model the effect of ACAP on mortality rate. Forty-five patients with pre-injury use of ACAP were compared with matched controls. The mortality at 14 days (OR = 0.5, 95% CI 0.2-1.4) and 6 months (OR = 0.7, 95% CI 0.2-1.9) were not significantly different between the 2 groups. Using the sliding dichotomy approach, there was no difference in the odds for unfavorable functional outcomes at 6 months (OR = 1.2, 95% CI 0.4-3.7). In this case-control study, the use of ACAP did not have a significant effect on mortality and adverse outcomes in patients with severe TBI. This would suggest that in severe TBI, ACAP use may not contribute significantly to the overall prognosis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Neurosurgery presents unique surgical challenges arising from delicate neural structures, limited accessibility, and the risk of CSF leakage that can lead to CNS infections. Sutures and staples may have limited applicability in the complex anatomical constraints of cranial and spinal surgeries, especially in trauma settings when time is of the essence. Surgical bioadhesives are emerging as attractive alternatives because they avoid traumatic application methods, provide a stress-distributed fixation, and provide good cosmesis and outcomes. This article presents the history of the development of surgical bioadhesives, and is also a review of current applications of commercial surgical bioadhesives within neurosurgical procedures and the unmet clinical needs that should be addressed in bioadhesives technologies., Methods: A PubMed literature search was performed using the terms "(glue OR bioadhesive OR fibrin OR tisseel OR evicel OR tachosil OR cyanoacrylate OR duraseal OR bioglue) AND (neurosurgery OR spine OR spinal OR dural OR microvascular decompression OR transsphenoidal OR endovascular)." Of 2433 records screened, 168 studies were identified that described the use of bioadhesives in neurosurgical procedures., Results: The greatest number of studies describing the use of bioadhesives in neurosurgery were identified for endovascular embolization, followed by dural closure and transsphenoidal surgeries. Other common areas of application were for microvascular decompression, skin closure, peripheral nerve repair, and other novel uses. Numerous case reports were also identified describing complications associated with bioadhesive use., Conclusions: Despite the paucity of approved indications, surgical bioadhesive use in neurosurgical procedures is prevalent. However, current bioadhesives still each have their own limitations and research is intense in the development of novel solutions.

Introduction: Spontaneous primary intracerebral hemorrhage (ICH) accounts for approximately 25% of all strokes in Singapore. Incidence of recurrent ICH is not well studied, and previous studies have reported inconsistent findings in the rate and risk factors associated with ICH recurrences. We aimed to study the incidence of recurrent ICHs in Singapore and to identify the associated risk factors as well as pattern of ICH recurrence., Methods: A retrospective review of all consecutive admissions for intracerebral hemorrhage at the National Neuroscience Institute between January 2006 and November 2013 was performed. Imaging and computerized clinical records were reviewed. The demographic, clinical, and radiological characteristics of index and recurrent ICH were compared. Univariate analysis was performed using chi-square and Student's t-test, and logistic regression was used to analyze the predictors of ICH recurrence., Results: In total, 1708 patients who survived the index ICH beyond 14 days were followed up for 6398 person-years. Sixty patients developed 68 recurrences of ICH, giving rise to an annual incidence rate of ICH recurrence of 1.1%. A history of previous ischemic stroke (P = .001) and index lobar location of ICH (P = .004) were significantly associated with the occurrence of ICH recurrences on multivariate analysis. The most common pattern on ICH recurrence was ganglionic-ganglionic (44.1%), followed by lobar-lobar (17.6%). Overall mortality of recurrent ICH was 17.6%., Conclusion: The average annual incidence rate of primary ICH recurrence in Singapore is 1.1%, and is associated with previous ischemic stroke and lobar location of index ICH., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The interaction of an amphiphilic, 40-amino acid beta-amyloid (Abeta) peptide with liposomal membranes as a function of sterol mole fraction (X(sterol)) was studied based on the fluorescence anisotropy of a site-specific membrane sterol probe, dehydroergosterol (DHE), and fluorescence resonance energy transfer (FRET) from the native Tyr-10 residue of Abeta to DHE. Without Abeta, peaks or kinks in the DHE anisotropy versus X(sterol) plot were detected at X(sterol) approximately 0.25, 0.33, and 0.53. Monomeric Abeta preserved these peaks/kinks, but oligomeric Abeta suppressed them and created a new DHE anisotropy peak at X(sterol) approximately 0.38. The above critical X(sterol) values coincide favorably with the superlattice compositions predicted by the cholesterol superlattice model, suggesting that membrane cholesterol tends to adopt a regular lateral arrangement, or domain formation, in the lipid bilayers. For FRET, a peak was also detected at X(sterol) approximately 0.38 for both monomeric and oligomeric Abeta, implying increased penetration of Abeta into the lipid bilayer at this sterol mole fraction. We conclude that the interaction of Abeta with membranes is affected by the lateral organization of cholesterol, and hypothesize that the formation of an oligomeric Abeta/cholesterol domain complex may be linked to the toxicity of Abeta in neuronal membranes.