There is growing interest in the role of structural variants (SVs) as drivers of local adaptation and speciation. From a biodiversity genomics perspective, the characterisation of genome-wide SVs provides an exciting opportunity to complement single nucleotide polymorphisms (SNPs). However, little is known about the impacts of SV discovery and genotyping strategies on the characterisation of genome-wide SV diversity within and among populations. Here, we explore a near whole-species resequence dataset, and long-read sequence data for a subset of highly represented individuals in the critically endangered kākāpō (Strigops habroptilus). We demonstrate that even when using a highly contiguous reference genome, different discovery and genotyping strategies can significantly impact the type, size and location of SVs characterised genome-wide. Further, we found that the mean number of SVs in each of two kākāpō lineages differed both within and across generations. These combined results suggest that genome-wide characterisation of SVs remains challenging at the population-scale. We are optimistic that increased accessibility to long-read sequencing and advancements in bioinformatic approaches including multi-reference approaches like genome graphs will alleviate at least some of the challenges associated with resolving SV characteristics below the species level. In the meantime, we address caveats, highlight considerations, and provide recommendations for the characterization of genome-wide SVs in biodiversity genomic research.

The production of high-quality recombinant proteins is critical to maintaining a continuous supply of biopharmaceuticals, such as therapeutic antibodies. Engineering mammalian cell factories presents a number of limitations typically associated with proteotoxic stress induced upon aberrant accumulation of off-pathway protein folding intermediates, which eventually culminate with the induction of apoptosis. Recent progress in mammalian synthetic biology provides unique opportunities to endow cells with programmable, user-defined behaviors, thereby addressing some of the challenges of current methods. In this review, we will discuss advances in synthetic biology to design efficient strategies for biomanufacturing.

Editorial accompanying ‘Implantation of a leadless pacemaker in young adults’

A document by Katherynn Zhang. Click on the document to view its contents.

● Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. ● Implementation of testing into routine practice across a healthcare system requires consideration of the evidence, clinical utility, cost-effectiveness, and operational requirements. ● A national approach to providing pharmacogenomic test recommendations and centralised commissioning will reduce inequity and duplication, but must be transparent and evidence based

A document by Muhammad Rafay Shahzad Cheema. Click on the document to view its contents.

Background: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins 4/13, key and central drivers of type 2 inflammation. The LIBERTY ASTHMA TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who had participated in a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Methods: This analysis includes patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose inhaled corticosteroids (ICS) at parent study baseline (PSBL) and enrolled in TRAVERSE. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (pre-BD) FEV 1 (L), asthma control (5-item asthma control questionnaire), and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. Results: Of patients with type 2 asthma (n=1,666) in this analysis, 891 (53.5%) were receiving high‑dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab vs placebo were 0.517 vs. 1.883 (phase 2b) and 0.571 vs. 1.300 (QUEST) over 52 weeks of the parent study, and remained low throughout TRAVERSE (0.313–0.494). Improvements in pre-BD FEV 1 from PSBL were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. Conclusions: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

No report exists on the role of Mastoparan B (MP-B) as an RND efflux pump inhibitor in multi-drug resistant (MDR) Acinetobacter baumannii. Here, we performed a series of in-silico experiments to predict the inhibition of the AdeB efflux pump by MP-B as a drug target agent. For this reason, an MDR strain of A. baumannii was subjected to minimum inhibitory concentration (MIC) against 12 antibiotics as well as MP-B. Expression of the a deB gene in the absence and presence of sub-MIC of MP-B was studied by qRT-PCR. It was found that MP-B had potent antimicrobial activity (MIC=1 µg/ml) associated with a 20-fold decrease in its expression at sub-MIC of MP-B. The stereochemical analysis using several automated servers confirmed that the AdeB is an inner membrane of the RND tripartite complex system with helix-turn-helix conformation and a pore rich in Phe, Ala, and Lys residue. The best model that showed high accuracy (Z=1.2, C=1.41, TM=0.99, and RMSD=4.4) was selected for docking purposes using the Site Map tool, and the correct protein-peptide complexes were simulated in the BioLiP platform. The molecular docking via AutoDock/Vina suggested that MP-B form H-bound with amino acid residues of the AdeB helix-5 and caused a shift in the dihedral angle by distances of 9.0 Å, 9.3 Å, and 9.6 Å, respectively. This shift was detected by the AlphaFold 2 tool and influenced the overall druggability of the protein. From the results, we concluded that, MP-B can be a good candidate for inhibition of bacterial efflux pump.

Introduction Lung biopsy is infrequently utilized in the population of infants with severe bronchopulmonary dysplasia (BPD). Yet, its presentation may overlap with other infant diffuse lung diseases, including those within the spectrum of childhood interstitial lung diseases (chILD). Lung biopsy might differentiate between these entities, or discern those with an extremely poor prognosis. Both might alter the clinical management of a subset of infants diagnosed with BPD. Methods In this tertiary referral center, we drew on a retrospective cohort of 306 preterm infants with severe BPD. Of these, nine underwent lung biopsy between 2012 and 2017. Our aim was to assess the indication of lung biopsy, the prior clinical history, safety of the procedure, and describe the biopsy findings. Finally, we considered management decisions in relation to the biopsy results in these patients. Results The average gestational age and birth weight of the 9 patients were 30±3 (range 27-34) weeks and 1421±571 (range 611-2140) grams. All infants had serial echocardiograms to assess for pulmonary hypertension, genetic testing, and computed tomography angiography (CTA) prior to biopsy. All patients showed moderate to severe alveolar simplification and 8 had some degree of pulmonary interstitial glycogenosis (PIG) ranging from focal to diffuse. Following biopsy, 2 infants with findings of PIG received high dose systemic steroids and 2 separate infants had care redirected. Conclusion In our cohort, lung biopsy was safe and well tolerated. Findings from lung biopsy may aid decision making in selected patients when used as a part of a step-wise diagnostic algorithm.

Introduction: Preterm children with bronchopulmonary dysplasia (BPD) frequently require supplemental oxygen in the outpatient setting. In this study, we sought to determine patient characteristics and demographics associated with need for supplemental oxygen at initial hospital discharge, timing to supplemental oxygen liberation, and associations between level of supplemental oxygen and likelihood of respiratory symptoms and acute care usage in the outpatient setting. Methods: A retrospective analysis of subjects with BPD on supplemental oxygen (O 2) was performed. Subjects were recruited from outpatient clinics at Johns Hopkins University and the Children’s Hospital of Philadelphia between 2008 and 2021. Data were obtained by chart review and caregiver questionnaires. Results: Children with BPD receiving > 1 liter of O 2 were more likely to have severe BPD, pulmonary hypertension and be older at initial hospital discharge. Children discharged on higher levels of supplemental O 2 were slower to wean to room air compared to lower O 2 groups (p<0.001). Additionally, weaning off supplemental O 2 in the outpatient setting was delayed in children with gastrostomy tubes and those prescribed inhaled corticosteroids, on public insurance or with lower estimated household incomes. Level of supplemental O 2 at discharge did not influence outpatient acute care usage or respiratory symptoms. Conclusion: BPD severity and level of supplemental oxygen use at discharge did not correlate with subsequent acute care usage or respiratory symptoms in children with BPD. Weaning of O 2 however was significantly associated with socioeconomic status and respiratory medication use, contributing to the variability in O 2 weaning in the outpatient setting.

A 37-year-old woman with chronic progressive myelopathy and syringomyelia and scoliosis presented with difficulty in walking at presentation. Dorsal CVJ CSF collection and adhesive arachnoiditis, compressing cerebellum, brainstem and upper cervical spinal cord with holocord syrinx was detected in neuroimaging beside thoracic scoliosis.

Most animals undergo ontogenetic niche shifts during their life. Yet, standard ecological theory builds on models that ignore this complexity. Here, we study how complex life cycles, where juvenile and adult individuals each feed on different sets of resources, affect community richness. Two different modes of community assembly are considered: gradual adaptive evolution and immigration of new species with randomly selected phenotypes. We find that under gradual evolution complex life cycles can lead to both higher and lower species richness when compared to a model of species with simple life cycles that lack an ontogenetic niche shift. Thus, complex life cycles do not per se increase the scope for gradual adaptive diversification. However, complex life cycles can lead to significantly higher species richness when communities are assembled trough immigration, as immigrants can occupy isolated peaks of the dynamic fitness landscape that are not accessible via gradual evolution.

Ageing is accompanied by numerous changes within the sensory and motor component of the muscle spindle pathway. To further document these age-related changes, this study compared the characteristics of the Hoffmann (H) reflex and M wave, evoked with several pulse durations, between young and old adults. The H-reflex and M-wave recruitment curves were analysed from recordings performed at rest in the flexor carpi radialis of 12 young (21-36 yrs) and 12 old adults (62-80 yrs). For each pulse duration (0.05-ms, 0.2-ms, and 1-ms), the maximal H-reflex amplitude (HMAX), the associated M wave (MHmax), and the H-reflex amplitude for a stimulus intensity evoking an M-wave of 5% MMAX (HM5%) were measured. The strength-duration time constant and response threshold were estimated from the charge/stimulus-duration relation for H reflex and M wave. The main results indicate that varying pulse duration mainly induces similar effect on H-reflex and M-wave recruitment curves between young and old adults. However, regardless of pulse duration, old adults had lesser HMAX (p = 0.029) but greater HM5% (p<0.001) and MHmax (p<0.001). The strength-duration time constant was lesser in old than young adults for the H reflex (p=0.048) but not the M wave (p=0.21). The H-reflex and M-wave response thresholds were greater in old than young adults (p=0.003). These results suggest greater age-related changes in the sensory than motor component of the H-reflex pathway, which may be indicative of a greater loss of sensory than motor axons or alterations of synapses between Ia afferents and motor neurones.

Trophic networks describe interactions between species at a given location and time. Due to environmental changes, anthropogenic perturbations or sampling effects, trophic networks may vary in space and time. The collection of network time series or networks in different sites thus constitutes a metanetwork. A crucial step toward the understanding of those metanetworks is to build appropriate tools to handle and represent them. We present here the R package metanetwork, which will ease the exploration and the analysis of trophic metanetwork datasets that are increasingly available. Our main methodological advance consists in suitable layout algorithm for trophic networks, which is based on trophic levels and dimension reduction of a graph diffusion kernel. In particular, it highlights relevant features of trophic networks (trophic levels, energetic channels). In addition, we developed graphical tools to handle, compare and aggregate those networks. Static and dynamic visualisation functions have been developed to represent large networks. We apply our package workflow to several trophic network data sets.

In organisms reproducing sexually, speciation occurs when increasing divergence results in pre- or post-zygotic reproductive isolation between lineages. Studies focusing on reproductive isolation origin in early stages of speciation are common. Many rely on indirect measures of introgression providing limited information on the genomic architecture of reproductive isolation maintenance in the long term. This study focuses on direct measures of introgression between two species in a late stage of speciation. We used ddRADseq genotyping in a natural hybrid zone between Podarcis bocagei and P. carbonelli to examine admixture extent, estimate effective selection, analyse hybrid zone stability, and assess variation in selection against introgression across the genome. Hybridization was confirmed the narrow and bimodal hybrid zone demonstrating the existence of strong mechanisms of reproductive isolation. Simulations suggested that simple premating barriers were not enough to explain the observed distribution of admixture classes, pointing out the role of post-mating isolation. A geographic cline approach confirmed strong reproductive isolation and high effective selection preventing extensive introgression outside of the contact zone; and detected a signal of hybrid zone movement towards P. bocagei distribution. Genomic cline analysis revealed heterogeneous patterns of introgression among loci within the syntopy zone, but most of the loci do not introgress more or less than the genomic average maintaining a strong association with the genomic background of origin. However, genomic clines can be driven by confounding effects resulting in incongruences between both cline approaches. Importantly, overall patterns of introgression seem to result from strong intrinsic barriers across the genome, without clear “islands of differentiation”. Last, an important role of the Z chromosome in reproductive isolation is suggested.

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon immunologic disorder associated with high rates of morbidity and mortality characterized by systemic inflammation and multiorgan dysfunction. The standard of care for primary treatment of HLH is chemotherapy (i.e. etoposide), but consideration of alternative therapies is warranted to support treatment goals for critically ill pediatric patients. We present the case of a 7-year-old male with trisomy 21, acute multiorgan failure secondary to infection, and subsequent HLH who was successfully treated with ruxolitinib. This represents the first use of ruxolitinib as a first-line agent for secondary HLH in a critically ill child with trisomy 21.

Background: V enetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more robust data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. Procedure: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco (UCSF) Benioff Children’s Hospitals from 2016 to 2022. Results: We identified 13 patients (AML , n= 8, B-ALL, n= 3, MDS, n= 2) aged 4 months to 27 years. A median of 3 prior lines of therapy were given (range 0 to 5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved a complete remission (CR); 2 (15%) achieved a partial remission (PR); 3 (23%) had stable disease (SD), and 5 (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5 to 52 months), and 3 months (range 2 weeks to 7.5 months), respectively. Five patients (38%) developed life-threatening infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, encephalitis with bacterial brain abscesses. Conclusions: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but was frequently associated with severe atypical infections, particularly in combination with cytotoxic chemotherapy.

Very high throughput satellite systems have recently been developed to offer high-speed connectivity, especially in remote areas, planes and ships. The high data rates can be achieved by using a multibeam approach with an aggressive reuse of the available frequency resources. Due to the high number of user beams, the system must support a large aggregated bandwidth. Multiple-gateway architectures are a necessary solution to sustain the immense bandwidth requirements. Multiple-input multiple-output (MIMO) feeder links have been proposed to address the ground segment design challenges of multiple-gateway architectures. The deployment costs and the link availability performance can in particular benefit from this approach. However, to coordinate the operation of multiple gateways, high precision time and phase synchronization is necessary. In this paper, the effect of time and phase misalignment in NxN MIMO feeder links is studied. The performance limitation due to imperfect time and phase distribution is analyzed. Synchronization via optical fiber is considered in this study. The accuracy of time distribution was verified through laboratory measurements. The impact of the residual timing error on the achievable system bandwidth was assessed. Results showed that several GHz of bandwidth can be supported. On the other hand, a recently proposed phase synchronization approach is considered as a promising candidate for MIMO feeder links. Its phase stability performance is assessed and it is emphasized that requirements in terms of link outage are fulfilled.