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Female mating with multiple males in a single reproductive period, or polyandry, is a common phenomenon in animals. In this study we investigated variation in female mating behavior and its fitness consequences among three genetic strains of the red flour beetle, Tribolium castaneum. We found that the extent of polyandry and its fitness consequences varied significantly among the strains. In the first strain PRUZ, females mated multiply but incurred costs of polyandry in the form of reduced offspring production. Females of the second strain, NDG11, mated readily with multiple partners and benefited because polyandry led to higher offspring quality. Finally, TIW1 females were resistant to multiple mating and polyandry resulted in lower offspring production but improved offspring quality. Thus, in the first population we observed only costs of polyandry, in the second strain only benefits of polyandry whereas in the third we detected both costs and benefits of polyandry. Possible explanations for such a pattern are discussed. © 2007 Springer Science+Business Media, Inc.

Using a Nier-type electron impact ion source in combination with a double focusing two sector field mass spectrometer, partial cross sections for electron impact ionization of acetylene are measured for electron energies up to 1000 eV. Discrimination factors for ions are determined using the deflection field method in combination with a three-dimensional ion trajectory simulation of ions produced in the ion source. Analysis of the ion yield curves obtained by scanning the deflectors allows the assignment of ions with the same mass-to-charge ratio to specific production channels on the basis of their different kinetic energy distributions. This analysis also allows to determine, besides kinetic energy distributions of fragment ions, partial cross sections differential in kinetic energy. Moreover a charge separation reaction, the Coulomb explosion of the doubly charged parent ions C2H2++ into the fragment ions C2H+ and H+, is investigated and its mean kinetic energy release (=3.88 eV) is deduced. [ABSTRACT FROM AUTHOR]

The partial ionization cross section for the formation of SF3+ fragment ions following electron impact on SF6 is known to have a pronounced structure in the cross section curve slightly above 40 eV. We used the mass-analyzed ion kinetic energy (MIKE) scan technique to demonstrate the presence of a channel contributing to the SF3+ partial ionization cross section that we attribute to the Coulomb explosion of doubly charged metastable SF42+ ions into two singly charged ions SF3+ and F+, with a threshold energy of about 45.5 eV. Thus the observed unusual shape of the SF3+ partial ionization cross section is the result of two contributions, (i) the direct formation of SF3+ fragment ions via dissociative ionization of SF6 with a threshold energy of 22 eV and (ii) the Coulomb explosion of metastable SF42+ ions with a threshold energy of about 45.5 eV. A detailed analysis of the MIKE spectrum reveals an average kinetic energy release of about 5 eV in the Coulomb explosion of the SF42+ ions with evidence of a second channel corresponding to an average kinetic energy release of about 1.1 eV. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Room-temperature rate coefficients and product distributions are used for studying the reactions of ozone with the cations and dications of the alkaline-earth metals Ca, Sr, and Ba. The analysis has shown the metal/ozone cluster ions as large as [Sr.sup.2+][([O.sub.3]).sub.5] and [Ba.sup.2+][([O.sub.3]).sub.4].

The dissociation energies of singly and multiply charged Sc3@C78 and Sc3N@C80 towards loss of C2 are detailed using finite heat bath theory. The complexation energies are for a given charge state and within the experimental uncertainty, and are identical for n=76, 78, and 80

DIAM (Dispositif d'Irradiation d'Agrégats Moléculaires) is a new experimental setup devoted to investigate processes induced by irradiation at the nanoscale. The DIAM apparatus is based on a combination of techniques including a particle beam from high-energy physics, a cluster source from molecular and cluster physics, and mass spectrometry form analytical sciences. In this paper, we will describe the first part of the DIAM apparatus that consists of an ExB double spectrometer connected to a cluster ion source based on a continuous supersonic expansion in the presence of ionizing electrons. This setup produces high intensities of energy-and-mass selected molecular cluster ion beams (1000 s of counts s-1). The performance of the instrument will be shown through measurements of 6-8 keV beams of protonated water clusters, (H2O)nH+ (n = 0-21) and mixed protonated (or deprotonated) water-pyridine cluster ions: PyrH+(H2O)n (n = 0-15), Pyr2H+ (H2O)n (n = 0-9), and (Pyr-H)+ (H2O). [ABSTRACT FROM AUTHOR]

In this prospective study, we present the short-term clinical results of a novel endoscopic surgical technique for patients suffering from chronic painful mid-portion Achilles tendinopathy. Eight consecutive patients (seven men and one woman, mean age 52 years) diagnosed with chronic painful mid-portion Achilles tendinopathy were included in this study and were treated with endoscopic debridement of the ventral neovascularized area, the peritendineum and the Achilles tendon. Patients recorded the function of the Achilles tendon and the severity of Achilles tendon pain during tendon loading activity, pre and postoperatively in a visual analogue scale. Patient global satisfaction was also assessed in a similar manner. Patients were followed-up for 6 months. All patients experienced immediate postoperative pain relief. In terms of Achilles tendon pain, the median visual analogue score (VAS) increased from 40 (10-60) (preoperatively) to 97.5 (85-100) (last follow-up examination). In terms of Achilles tendon function, the median VAS increased from 22.5 (0-30) (preoperatively) to 90 (80-95) (last follow-up examination). In terms of global satisfaction, the median VAS in the last follow-up examination was 85 (70-95). No postoperative complications were recorded. In conclusion, the short-term clinical results were satisfactory. [ABSTRACT FROM AUTHOR]

p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs). Upon SMC-specific inactivation of mdm2, and not of mdm4, mice rapidly became ill and died. Necropsy showed small intestinal dilation, and histological analyses indicated a severe reduction in the number of intestinal SMCs. Increased p53 levels and activity were detected in the remaining SMCs, and the phenotype was completely rescued on a p53-null background. Interestingly, intestinal SMCs are caspase-3-negative and therefore did not undergo caspase-3-dependent apoptotic cell death. Together, Mdm2, but not Mdm4, prevents accumulation of active p53 in quiescent SMCs and thereby the induction of p53-mediated caspase-3-independent cell death.Cell Death and Differentiation (2006) 13, 2089–2098. doi:10.1038/sj.cdd.4401973; published online 26 May 2006 [ABSTRACT FROM AUTHOR]

Abstract: Neutral helium clusters, formed in a supersonic beam, are subjected to electron impact ionization. We report resolved size distributions of cations of size n ≤300. The distributions show the well established anomalies at n = 10 and 14, but none for larger sizes. MIKE scans of the cluster ions confirm the anomalies at n = 10 and 14, and another one at n = 7. Surprisingly broad distributions of fragment ions are observed for parent sizes 15≤ n ≤30. These findings are attributed to radiative heating. The kinetic energy released upon loss of one helium atom (KER) has been measured. The values drop below 1meV for n > 20. Neither the metastable fragment distribution nor the KER data provide evidence for the release of large, quantized energies that one would expect for relaxation of any long-lived vibronic states of the ionic core. [Copyright &y& Elsevier]

Abstract: We have measured the kinetic energy release distributions for unimolecular C2 loss from singly and multiply charged endohedral La@C80 z+ and La@C80 z+ ions for charge states z =1–3. Using finite heat bath theory, we deduce the dissociation energies for loss of C2. The charge state z has no statistically significant effect on the dissociation energies. The dissociation energies of endohedral fullerene ions are larger than those of the corresponding empty fullerene ions by a few tenths of an electron volt, but the differences are barely statistically significant. The small differences also imply that the complexation energies of La@C n z+ and La@C n −2 z+ are identical within the experimental errors, for n =80 and 82 and all charge states. [Copyright &y& Elsevier]

This paper presents results on fullerene formation during the processing of different graphite powders in an RF thermal plasma reactor. Graphite powders of different particle size and purity were fed into the reactor (Aldrich, KS4). Optical emission spectroscopy of atomic and molecular species is used as a diagnostic tool of the RF plasma flame. It was found that rotational and vibrational temperatures of C2 radicals depend on the feed rate of the precursor used. The volumes of RF plasma flame during processing of graphite powders have been calculated. By analysing scanning electron microscopy micrographs of soot, the evaporation rate of the precursors used has been evaluated as well. Based on the obtained values of volumes of plasma flame and evaporation rate of starting powders, the concentration of C2 radicals has been calculated. [ABSTRACT FROM AUTHOR]

Abstract: Nitric oxide (NO) modulates a variety of processes in the mammalian brain, but the mechanisms of neuronal NO signaling are poorly understood. In the periphery, many effects of NO are mediated via the generation of the second messenger cyclic guanosine-3′,5′-monophosphate (cGMP) and activation of the cGMP-dependent protein kinase type I (cGKI). However, previous studies suggested that the expression of cGKI in the nervous system is rather restricted, thus, questioning the functional significance of the cGMP/cGKI pathway as a mediator of NO signaling in the brain. Here we have performed a detailed immunohistochemical study to elucidate the distribution of cGKI in the CNS and eye of the mouse. Expression of cGKI protein was detected not only in the previously described areas (cerebellum, hippocampus, dorsomedial hypothalamus) but also in a number of additional regions, such as medulla, subcommissural organ, cerebral cortex, amygdala, habenulae, various hypothalamic regions, olfactory bulb, pituitary gland, and retina. Immunoblotting with isoform-specific antibodies indicated that the cGKIα isoform is prominent in the cerebellum and medulla, whereas the cGKIβ isoform is predominant in the cortex, hippocampus, hypothalamus, and olfactory bulb. Similar levels of the isoforms were detected in the pituitary gland and eye. Thus, it appears that distinct brain regions express distinct cGKI isoforms that signal via distinct pathways. Together, these results improve our understanding of the cellular and molecular mechanisms of NO/cGMP/cGKI signaling and indicate that the distribution and functional relevance of this pathway in the mammalian brain is broader than previously thought. [Copyright &y& Elsevier]

Abstract: Doubly charged ions produced by electron impact ionization of toluene undergo metastable decomposition. We have determined decay channels for and the average kinetic energy release (KER) by applying the MIKE scan technique. We observe several reactions that have not been reported previously, including H2 elimination from . The KER distribution for H2 loss shows no evidence for a reverse barrier. The average KER is <0.1 eV; it exhibits a distinct time dependence and isotope effect. On the other hand, some charge separation reactions reported previously in the literature are likely due to isotopic interference. [Copyright &y& Elsevier]

Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage- and Ca2+-activated K+ channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK-/-) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK-/- mice showed a dramatic reduction in spontaneous activity of the BK-/- cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown rotes of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Fully three-dimensional (3-D) ion trajectory simulations of a Nier-type ion source were performed for mono-energetic ions with a spatial resolution of the potential array of 0.1 mm. Experimentally determined ion beam profiles were fitted with a superposition of simulated ion beam profiles in an effort to determine the initial ion kinetic energy distribution and the extraction efficiency from the ion source for a given product ion. This method allows the analysis of ion beam profiles of highly energetic fragment ions that are affected by a reduced ion extraction efficiency. As an example, ion beam profiles of product ions formed by electron impact ionization of acetylene (C2H2) at an electron energy of 100 eV were analyzed with the present method as well as with a method developed by Poll et al. [Int. J. Mass Spectrom. Ion Process. 112 (1992) 1], which is based essentially on a simplified two-dimensional (2-D) ion trajectory analysis. For highly energetic fragment ions, the results obtained by the two methods differ by as much as 84%. [Copyright &y& Elsevier]

Abstract Background Up to date, no information exists about the intra-articular temperature changes of the knee related to activity and ambient temperature. Methods In 6 healthy males, a probe for intra-articular measurement was inserted into the notch of the right knee. Each subject was jogging on a treadmill in a closed room at 19°C room temperature and skiing in a ski resort at -3°C outside temperature for 60 minutes. In both conditions, temperatures were measured every fifteen minutes intra-articulary and at the skin surface of the knee. A possible influence on joint function and laxity was evaluated before and after activity. Statistical analysis of intra-articular and skin temperatures was done using nonparametric Wilcoxon's sign rank sum test and Mann-Whitney's-U-Test. Results Median intra-articular temperatures increased from 31.4°C before activity by 2.1°C, 4°C, 5.8°C and 6.1°C after 15, 30, 45 and 60 min of jogging (all p ≤ 0.05). Median intra-articular temperatures dropped from 32.2°C before activity by 0.5°C, 1.9°C, 3.6°C and 1.1°C after 15, 30, 45 and 60 min of skiing (all n.s.). After 60 minutes of skiing (jogging), the median intra-articular temperature was 19.6% (8.7%) higher than the skin surface temperature at the knee. Joint function and laxity appeared not to be different before and after activity within both groups. Conclusion This study demonstrates different changes of intra-articular and skin temperatures during sports in jogging and alpine skiing and suggests that changes are related to activity and ambient temperature.

Background: Up to date, no information exists about the intra-articular temperature changes of the knee related to activity and ambient temperature.Methods: In 6 healthy males, a probe for intra-articular measurement was inserted into the notch of the right knee. Each subject was jogging on a treadmill in a closed room at 19 degrees C room temperature and skiing in a ski resort at -3 degrees C outside temperature for 60 minutes. In both conditions, temperatures were measured every fifteen minutes intra-articulary and at the skin surface of the knee. A possible influence on joint function and laxity was evaluated before and after activity. Statistical analysis of intra-articular and skin temperatures was done using nonparametric Wilcoxon's sign rank sum test and Mann-Whitney's-U-Test.Results: Median intra-articular temperatures increased from 31.4 degrees C before activity by 2.1 degrees C, 4 degrees C, 5.8 degrees C and 6.1 degrees C after 15, 30, 45 and 60 min of jogging (all p < or = 0.05). Median intra-articular temperatures dropped from 32.2 degrees C before activity by 0.5 degrees C, 1.9 degrees C, 3.6 degrees C and 1.1 degrees C after 15, 30, 45 and 60 min of skiing (all n.s.). After 60 minutes of skiing (jogging), the median intra-articular temperature was 19.6% (8.7%) higher than the skin surface temperature at the knee. Joint function and laxity appeared not to be different before and after activity within both groups.Conclusion: This study demonstrates different changes of intra-articular and skin temperatures during sports in jogging and alpine skiing and suggests that changes are related to activity and ambient temperature. [ABSTRACT FROM AUTHOR]

Abstract: Vapor jets of DNA and RNA bases (adenine, cytosine, thymine, and uracil) from an oven with a capillary exit have been studied in the intermediate regime between molecular and viscous flow corresponding to Knudsen numbers in the range 0.1< Kn <10. The temperature control method ensured stationary flow. Assuming the Knudsen hypothesis, the pressure of sublimated molecules in the oven was determined as a function of temperature and the transmission probability of the capillary (Clausing factor). Thus it was possible to relate the oven temperature and pressure to the total flux through the capillary, determined by measuring the total mass of DNA/RNA base molecules condensed on a cold surface intersecting the jet. The angular distribution of molecules in the jet has been also studied experimentally using an optical interference method. The measured profiles are in good agreement with Troïtskii’s [Sov. Phys. JETP 7 (1962) 353] analytical law for (cos θ)3/2 angular dependence in the intermediate regime with error functions associated with the mean free path between intermolecular collisions. [Copyright &y& Elsevier]

Background: Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform PDE10A might be a target for analgesic therapy., Methods: In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors., Results: PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD; 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (Two-way ANOVA, group, F(1, 18) = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund's adjuvant (F(1, 14) = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920., Conclusion: Collectively, our data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs., Competing Interests: Conflicts of Interest: The authors declare no competing interests., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Recent clinical trials of drugs enhancing cyclic guanosine monophosphate (cGMP) signaling for cardiovascular diseases have renewed interest in cGMP biology within the kidney. However, the role of cGMP signaling in glomerular endothelial cells (GECs) and podocytes remains largely unexplored. Using acute kidney slices from mice expressing the FRET-based cGMP biosensor cGi500 in endothelial cells or podocytes enabled real-time visualization of cGMP. Stimulation with atrial natriuretic peptide (ANP) or SNAP (NO donor) and various phosphodiesterase (PDE) inhibitors elevated intracellular cGMP in both cell types. GECs showed a transient cGMP response upon particulate or soluble guanylyl cyclase activation, while the cGMP response in podocytes reached a plateau following ANP administration. Co-stimulation (ANP + SNAP) led to an additive response in GECs. The administration of PDE inhibitors revealed a broader basal PDE activity in GECs dominated by PDE2a. In podocytes, basal PDE activity was mainly restricted to PDE3 and PDE5 activity. Our data demonstrate the existence of both guanylyl cyclase pathways in GECs and podocytes with cell-specific differences in cGMP synthesis and degradation, potentially suggesting new therapeutic options for kidney diseases., (© 2024. The Author(s).)

Background: Cardiac hypertrophy is characterized by remodeling of the myocardium, which involves alterations in the ECM (extracellular matrix) and cardiomyocyte structure. These alterations critically contribute to impaired contractility and relaxation, ultimately leading to heart failure. Emerging evidence implicates that extracellular signaling molecules are critically involved in the pathogenesis of cardiac hypertrophy and remodeling. The immunophilin CyPA (cyclophilin A) has been identified as a potential culprit. In this study, we aimed to unravel the interplay between eCyPA (extracellular CyPA) and myocardial dysfunction and evaluate the therapeutic potential of inhibiting its extracellular accumulation to improve heart function., Methods: Employing a multidisciplinary approach encompassing in silico, in vitro, in vivo, and ex vivo experiments we studied a mouse model of cardiac hypertrophy and human heart specimen to decipher the interaction of CyPA and the cardiac microenvironment in highly relevant pre-/clinical settings. Myocardial expression of CyPA (immunohistology) and the inflammatory transcriptome (NanoString) was analyzed in human cardiac tissue derived from patients with nonischemic, noninflammatory congestive heart failure (n=187). These analyses were paralleled by a mouse model of Ang (angiotensin) II-induced heart failure, which was assessed by functional (echocardiography), structural (immunohistology, atomic force microscopy), and biomolecular (Raman spectroscopy) analyses. The effect of inhibiting eCyPA in the cardiac microenvironment was evaluated using a newly developed neutralizing anti-eCyPA monoclonal antibody., Results: We observed a significant accumulation of eCyPA in both human and murine-failing hearts. Importantly, higher eCyPA expression was associated with poor clinical outcomes in patients ( P =0.043) and contractile dysfunction in mice (Pearson correlation coefficient, -0.73). Further, myocardial expression of eCyPA was critically associated with an increase in myocardial hypertrophy, inflammation, fibrosis, stiffness, and cardiac dysfunction in vivo. Antibody-based inhibition of eCyPA prevented (Ang II)-induced myocardial remodeling and dysfunction in mice., Conclusions: Our study provides strong evidence of the pathogenic role of eCyPA in remodeling, myocardial stiffening, and dysfunction in heart failure. The findings suggest that antibody-based inhibition of eCyPA may offer a novel therapeutic strategy for nonischemic heart failure. Further research is needed to evaluate the translational potential of these interventions in human patients with cardiac hypertrophy., Competing Interests: None.

The contribution of splicing variants to molecular diagnostics of inherited diseases is reported to be less than 10%. This figure is likely an underestimation due to several factors including difficulty in predicting the effect of such variants, the need for functional assays, and the inability to detect them (depending on their locations and the sequencing technology used). The aim of this study was to assess the utility of Nanopore sequencing in characterizing and quantifying aberrant splicing events. For this purpose, we selected 19 candidate splicing variants that were identified in patients affected by inherited retinal dystrophies. Several in silico tools were deployed to predict the nature and estimate the magnitude of variant-induced aberrant splicing events. Minigene assay or whole blood-derived cDNA was used to functionally characterize the variants. PCR amplification of minigene-specific cDNA or the target gene in blood cDNA, combined with Nanopore sequencing, was used to identify the resulting transcripts. Thirteen out of nineteen variants caused aberrant splicing events, including cryptic splice site activation, exon skipping, pseudoexon inclusion, or a combination of these. Nanopore sequencing allowed for the identification of full-length transcripts and their precise quantification, which were often in accord with in silico predictions. The method detected reliably low-abundant transcripts, which would not be detected by conventional strategies, such as RT-PCR followed by Sanger sequencing.

Cyclic guanosine monophosphate (cGMP) is a second messenger produced by the NO-sensitive guanylyl cyclase (NO-GC). The NO-GC/cGMP pathway in platelets has been extensively studied. However, its role in regulating the biomechanical properties of platelets has not yet been addressed and remains unknown. We therefore investigated the stiffness of living platelets after treatment with the NO-GC stimulator riociguat or the NO-GC activator cinaciguat using scanning ion conductance microscopy (SICM). Stimulation of human and murine platelets with cGMP-modulating drugs decreased cellular stiffness and downregulated P-selectin, a marker for platelet activation. We also quantified changes in platelet shape using deep learning-based platelet morphometry, finding that platelets become more circular upon treatment with cGMP-modulating drugs. To test for clinical applicability of NO-GC stimulators in the context of increased thrombogenicity risk, we investigated the effect of riociguat on platelets from human immunodeficiency virus (HIV)-positive patients taking abacavir sulfate (ABC)-containing regimens. Our results corroborate a functional role of the NO-GC/cGMP pathway in platelet biomechanics, indicating that biomechanical properties such as stiffness or shape could be used as novel biomarkers in clinical research.

Purpose: To evaluate mid- to long-term clinical outcomes after arthroscopic bucket-handle meniscal tear (BHMT) repair and to assess the impact of concurrent anterior cruciate ligament reconstruction (ACLR)., Methods: A comparative retrospective case series with blinded outcome assessment was conducted. All consecutive patients treated with arthroscopic BHMT repair with or without concurrent ACLR between 2001 and 2021 were eligible for inclusion. Fifty-five patients with an average follow-up of 7.3 ± 3.4 years were included in the analysis. Outcome measures comprised post-operative IKDC Subjective Knee Form, Lysholm Score, Tegner Activity Scale, KOOS, and visual analogue scale (VAS) for satisfaction. Additionally, failure and reoperation rates were assessed., Results: The failure rate was 9%. Medial BHMT repair showed superior post-operative IKDC scores compared to lateral meniscus repair ( p  = 0.038). Concurrent ACLR did not demonstrate any impact on post-operative KOOS, IKDC, Tegner or patient satisfaction. The mean IKDC score at final follow-up across both groups was 80.4 ± 17.8. The mean Lysholm score was 86.9 ± 16.7. Mean KOOS scores were (i) symptoms: 83.6 ± 18.3, (ii) pain: 90.2 ± 14.4, (iii) activities of daily living: 93.6 ± 15.1, (iv) sports: 78.3 ± 26.0 and (v) quality of life: 70.5 ± 24.5. Mean patient satisfaction (VAS) was 7.9 ± 2.5. The mean Tegner score was 4.9 ± 1.9. A consistent positive correlation between the number of sutures used and post-operative outcome measures was observed but did not reach statistical significance for most items., Conclusion: Arthroscopic BHMT repair achieved good clinical outcomes and an acceptable failure rate of 9% at a mean follow-up of 7 years, supporting the clinical value of meniscal repair, including large BHMTs. Concurrent ACLR showed no impact on clinical outcomes., Level of Evidence: Level IV (retrospective case series)., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

The proneural transcription factor atonal basic helix-loop-helix transcription factor 7 ( ATOH7 ) is expressed in early progenitors in the developing neuroretina. In vertebrates, this is crucial for the development of retinal ganglion cells (RGCs), as mutant animals show an almost complete absence of RGCs, underdeveloped optic nerves, and aberrations in retinal vessel development. Human mutations are rare and result in autosomal recessive optic nerve hypoplasia (ONH) or severe vascular changes, diagnosed as autosomal recessive persistent hyperplasia of the primary vitreous (PHPVAR). To better understand the role of ATOH7 in neuroretinal development, we created ATOH7 knockout and eGFP-expressing ATOH7 reporter human induced pluripotent stem cells (hiPSCs), which were differentiated into early-stage retinal organoids. Target loci regulated by ATOH7 were identified by Cleavage Under Targets and Release Using Nuclease with sequencing (CUT&RUN-seq) and differential expression by RNA sequencing (RNA-seq) of wildtype and mutant organoid-derived reporter cells. Additionally, single-cell RNA sequencing (scRNA-seq) was performed on whole organoids to identify cell type-specific genes. Mutant organoids displayed substantial deficiency in axon sprouting, reduction in RGCs, and an increase in other cell types. We identified 469 differentially expressed target genes, with an overrepresentation of genes belonging to axon development/guidance and Notch signaling. Taken together, we consolidate the function of human ATOH7 in guiding progenitor competence by inducing RGC-specific genes while inhibiting other cell fates. Furthermore, we highlight candidate genes responsible for ATOH7 -associated optic nerve and retinovascular anomalies, which sheds light to potential future therapy targets for related disorders.

The purpose of this study was to assess the added diagnostic value of whole genome sequencing (WGS) for patients with inherited retinal diseases (IRDs) who remained undiagnosed after whole exome sequencing (WES). WGS was performed for index patients in 66 families. The datasets were analyzed according to GATK's guidelines. Additionally, DeepVariant was complemented by GATK's workflow, and a novel structural variant pipeline was developed. Overall, a molecular diagnosis was established in 19/66 (28.8%) index patients. Pathogenic deletions and one deep-intronic variant contributed to the diagnostic yield in 4/19 and 1/19 index patients, respectively. The remaining diagnoses (14/19) were attributed to exonic variants that were missed during WES analysis due to bioinformatic limitations, newly described loci, or unclear pathogenicity. The added diagnostic value of WGS equals 5/66 (9.6%) for our cohort, which is comparable to previous studies. This figure would decrease further to 1/66 (1.5%) with a standardized and reliable copy number variant workflow during WES analysis. Given the higher costs and limited added value, the implementation of WGS as a first-tier assay for inherited eye disorders in a diagnostic laboratory remains untimely. Instead, progress in bioinformatic tools and communication between diagnostic and clinical teams have the potential to ameliorate diagnostic yields.

Background: The current management of patients with stroke with intravenous thrombolysis and endovascular thrombectomy is effective only when it is timely performed on an appropriately selected but minor fraction of patients. The development of novel adjunctive therapy is highly desired to reduce morbidity and mortality with stroke. Since endothelial dysfunction is implicated in the pathogenesis of stroke and is featured with suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency, restoring endothelial nitric oxide represents a promising approach to treating stroke injury., Methods: This is a preclinical proof-of-concept study to determine the therapeutic effect of transcranial treatment with a low-power near-infrared laser in a mouse model of ischemic stroke. The laser treatment was performed before the middle cerebral artery occlusion with a filament. To determine the involvement of eNOS phosphorylation, unphosphorylatable eNOS S1176A knock-in mice were used. Each measurement was analyzed by a 2-way ANOVA to assess the effect of the treatment on cerebral blood flow with laser Doppler flowmetry, eNOS phosphorylation by immunoblot analysis, and stroke outcomes by infarct volumes and neurological deficits., Results: Pretreatment with a 1064-nm laser at an irradiance of 50 mW/cm 2 improved cerebral blood flow, eNOS phosphorylation, and stroke outcomes., Conclusions: Near-infrared II photobiomodulation could offer a noninvasive and low-risk adjunctive therapy for stroke injury. This new modality using a physical parameter merits further consideration to develop innovative therapies to prevent and treat a wide array of cardiovascular diseases., Competing Interests: Disclosures None.