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Abstract Population-based studies of human mitochondrial genetic diversity often require the classification of mitochondrial DNA (mtDNA) haplotypes into more than 5400 described haplogroups, and further grouping those into hierarchically higher haplogroups. Such secondary haplogroup groupings (e.g., “macro-haplogroups”) vary across studies, as they depend on the sample quality, technical factors of haplogroup calling, the aims of the study, and the researchers' understanding of the mtDNA haplogroup nomenclature. Retention of historical nomenclature coupled with a growing number of newly described mtDNA lineages results in increasingly complex and inconsistent nomenclature that does not reflect phylogeny well. This “clutter” leaves room for grouping errors and inconsistencies across scientific publications, especially when the haplogroup names are used as a proxy for secondary groupings, and represents a source for scientific misinterpretation. Here we explore the effects of phylogenetically insensitive secondary mtDNA haplogroup groupings, and the lack of standardized secondary haplogroup groupings on downstream analyses and interpretation of genetic data. We demonstrate that frequency-based analyses produce inconsistent results when different secondary mtDNA groupings are applied, and thus allow for vastly different interpretations of the same genetic data. The lack of guidelines and recommendations on how to choose appropriate secondary haplogroup groupings presents an issue for the interpretation of results, as well as their comparison and reproducibility across studies. To reduce biases originating from arbitrarily defined secondary nomenclature-based groupings, we suggest that future updates of mtDNA phylogenies aimed for the use in mtDNA haplogroup nomenclature should also provide well-defined and standardized sets of phylogenetically meaningful algorithm-based secondary haplogroup groupings such as “macro-haplogroups”, “meso-haplogroups”, and “micro-haplogroups”. Ideally, each of the secondary haplogroup grouping levels should be informative about different human population history events. Those phylogenetically informative levels of haplogroup groupings can be easily defined using TreeCluster, and then implemented into haplogroup callers such as HaploGrep3. This would foster reproducibility across studies, provide a grouping standard for population-based studies, and reduce errors associated with haplogroup nomenclatures in future studies.

Abstract Background Effective governance arrangements are central to the successful functioning of health systems. While the significance of governance as a concept is acknowledged within health systems research, its interplay with health system reform initiatives remains underexplored in the literature. This study focuses on the development of new regional health structures in Ireland in the period 2018–2023, one part of a broader health system reform programme aimed at greater universalism, in order to scrutinise how aspects of governance impact on the reform process, from policy design through to implementation. Methods This qualitative, multi-method study draws on document analysis of official documents relevant to the reform process, as well as twelve semi-structured interviews with key informants from across the health sector. Interviews were analysed according to thematic analysis methodology. Conceiving governance as comprising five domains (Transparency, Accountability, Participation, Integrity, Capacity) the research uses the TAPIC framework for health governance as a conceptual starting point and as initial, deductive analytic categories for data analysis. Results The analysis reveals important lessons for policymakers across the five TAPIC domains of governance. These include deficiencies in accountability arrangements, poor transparency within the system and vis-à-vis external stakeholders and the public, and periods during which a lack of clarity in terms of roles and responsibilities for various process and key decisions related to the reform were identified. Inadequate resourcing of implementation capacity, competing policy visions and changing decision-making arrangements, among others, were found to have originated in and continuously reproduced a lack of trust between key institutional actors. The findings highlight how these challenges can be addressed through strengthening governance arrangements and processes. Importantly, the research reveals the interwoven nature of the five TAPIC dimensions of governance and the need to engage with the complexity and relationality of health system reform processes. Conclusions Large scale health system reform is a complex process and its governance presents distinct challenges and opportunities for stakeholders. To understand and be able to address these, and to move beyond formulaic prescriptions, critical analysis of the historical context surrounding the policy reform and the institutional relationships at its core are needed.

Abstract The real‐life retrospective observational study CARMYN aimed at investigating the long‐term efficacy and safety of carfilzomib in combination with dexamethasone and lenalidomide (KRd, 159 patients). These patients (62% in first and 38% in second relapse, median age 62 yo) were treated between 02/2014 and 02/2017. Most had been pre‐exposed to bortezomib (98.2%) and to an IMID (75.4%). At the time of collection, 90% had permanently discontinued carfilzomib. Data collection was conducted from January to July 2021 in 27 participating sites, after a median of 39 months follow‐up. For patients treated with KRd, an overall response rate of 78.4% translated in a median progression free survival (PFS) of 24.0 months (95% CI 18.8–27.6) and a median overall survival (OS) of 51.1 months (95% CI 41.3–not reached). Results were poorer but difficult to interpret in the small cohort of Kd recipients. The study is one of the longest real‐life studies of carfilzomib treatment in patients in first or second relapse. CARMYN confirmed the real‐life long‐term efficacy of carfilzomib in combination with lenalidomide and dexamethasone with results similar to those of clinical trials. The KRd regimen is thus an option to consider for late relapses in the current context of MM management.

Clinical and preclinical studies suggest that some of the behavioral alterations observed in schizophrenia (SZ) may be mechanistically linked to synaptic dysfunction of glutamatergic signaling. Recent genetic and proteomic studies suggest alterations of cortical glutamate receptors of the AMPA-type (AMPARs), which are the predominant ligand-gated ionic channels of fast transmission at excitatory synapses. The impact of gene and protein alterations on the electrophysiological activity of AMPARs is not known in SZ. In this proof of principle work, using human postmortem brain synaptic membranes isolated from the dorsolateral prefrontal cortex (DLPFC), we combined electrophysiological analysis from microtransplanted synaptic membranes (MSM) with transcriptomic (RNA-Seq) and label-free proteomics data in 10 control and 10 subjects diagnosed with SZ. We observed in SZ a reduction in the amplitude of AMPARs currents elicited by kainate, an agonist of AMPARs that blocks the desensitization of the receptor. This reduction was not associated with protein abundance but with a reduction in kainates potency to activate AMPARs. Electrophysiologically-anchored dataset analysis (EDA) was used to identify synaptosomal proteins that linearly correlate with the amplitude of the AMPARs responses, gene ontology functional annotations were then used to determine protein-protein interactions. Protein modules associated with positive AMPARs current increases were downregulated in SZ, while protein modules that were upregulated in SZ were associated with decreased AMPARs currents. Our results indicate that transcriptomic and proteomic alterations, frequently observed in the DLPFC in SZ, converge at the synaptic level producing a functional electrophysiological impairment of AMPARs.

Primary cilia function as cells' antennas to detect and transduce external stimuli and play crucial roles in cell signaling and communication. The vast majority of cilia genes that are causally linked with ciliopathies are also associated with neurological deficits, such as cognitive impairments. Yet, the roles of cilia dysfunctions in the pathogenesis of psychiatric disorders have not been studied. Our aim is to identify patterns of cilia gene dysregulation in the four major psychiatric disorders: schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BP), and major depressive disorder (MDD). For this purpose, we acquired differentially expressed genes (DEGs) from the largest and most recent publicly available databases. We found that 42%, 24%, 17%, and 15% of brain-expressed cilia genes were significantly differentially expressed in SCZ, ASD, BP, and MDD, respectively. Several genes exhibited cross-disorder overlap, suggesting that typical cilia signaling pathways' dysfunctions determine susceptibility to more than one psychiatric disorder or may partially underlie their pathophysiology. Our study revealed that genes encoding proteins of almost all sub-cilia structural and functional compartments were dysregulated in the four psychiatric disorders. Strikingly, the genes of 75% of cilia GPCRs and 50% of the transition zone proteins were differentially expressed in SCZ. The present study is the first to draw associations between cilia and major psychiatric disorders, and is the first step toward understanding the role that cilia components play in their pathophysiological processes, which may lead to novel therapeutic targets for these disorders.

Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer's disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.

Abstract Recent postmortem transcriptomic studies of schizophrenia (SCZ) have shown hundreds of differentially expressed genes. However, the extent to which these gene expression changes reflect antipsychotic drug (APD) exposure remains uncertain. We compared differential gene expression in the prefrontal cortex of SCZ patients who tested positive for APDs at the time of death with SCZ patients who did not. APD exposure was associated with numerous changes in the brain transcriptome, especially among SCZ patients on atypical APDs. Brain transcriptome data from macaques chronically treated with APDs showed that APDs affect the expression of many functionally relevant genes, some of which show expression changes in the same directions as those observed in SCZ. Co-expression modules enriched for synaptic function showed convergent patterns between SCZ and some of the APD effects, while those associated with inflammation and glucose metabolism exhibited predominantly divergent patterns between SCZ and APD effects. In contrast, major cell-type shifts inferred in SCZ were primarily unaffected by APD use. These results show that APDs may confound SCZ-associated gene expression changes in postmortem brain tissue. Disentangling these effects will help identify causal genes and improve our neurobiological understanding of SCZ.

Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We impose ELA by rearing rat pups in simulated poverty, assess hippocampal memory, and probe changes in gene expression, their transcriptional regulation, and the consequent changes in hippocampal neuronal structure. ELA rats have poor hippocampal memory and stunted hippocampal pyramidal neurons associated with ~140 differentially expressed genes. Upstream regulators of the altered genes include glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributes critically to the memory deficits because blocking its function transiently following ELA rescues spatial memory and restores the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augments dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function.

To image the accessible genome at nanometer scale in situ, we developed three-dimensional assay for transposase-accessible chromatin-photoactivated localization microscopy (3D ATAC-PALM) that integrates an assay for transposase-accessible chromatin with visualization, PALM super-resolution imaging and lattice light-sheet microscopy. Multiplexed with oligopaint DNA-fluorescence in situ hybridization (FISH), RNA-FISH and protein fluorescence, 3D ATAC-PALM connected microscopy and genomic data, revealing spatially segregated accessible chromatin domains (ACDs) that enclose active chromatin and transcribed genes. Using these methods to analyze genetically perturbed cells, we demonstrated that genome architectural protein CTCF prevents excessive clustering of accessible chromatin and decompacts ACDs. These results highlight 3D ATAC-PALM as a useful tool to probe the structure and organizing mechanism of the genome.

BackgroundEvidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hormone receptor (MCHR1) gene locus and schizophrenia, and the largest genome-wide association study conducted to date shows a credible genome-wide association.MethodsWe analyzed MCHR1 and pro-melanin concentrating hormone RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls. Disruptions in the melanin concentrating hormone system were modeled in the mouse brain by germline deletion of MCHR1 and by conditional ablation of melanin concentrating hormone expressing neurons using a Cre-inducible diphtheria toxin system.ResultsMCHR1 expression is decreased in the prefrontal cortex of schizophrenia samples (false discovery rate (FDR) P

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37–82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3–12). The median number of BM cycles administered was three (range, 1–22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.

The processes leading to the assembly of the Rodinia supercontinent through Grenvillian collisional orogeny are relatively well known. In contrast, accretionary orogenic processes occurring at the supercontinent periphery following Rodinia assembly are poorly understood. To fill this gap, we have identified metamorphic rocks in the Mongolia collage of the Central Asian Orogenic Belt, where numerous data testify for Meso- to Neoproterozoic magmatic reworking. The tectono-metamorphic evolution of the peri-Siberian tract of the Central Asian Orogenic Belt is mainly characterized by the late Proterozoic–early Cambrian (Baikalian) cycle. However, we document here a Tonian age metamorphism at the northern part of the Precambrian Baidrag block, previously considered as a typical example of the Baikalian metamorphic belt. This study incorporates zircon and in-situ monazite geochronology linked to P-T modelling of Grt-Sil-Ky migmatite gneiss and Grt-St micaschist. Grt-Sil-Ky gneiss records initial burial to the sillimanite stability field at ∼720 °C and 6.0 kbar followed by further burial to the kyanite stability field at ∼750 °C and ∼9 kbar and decompression to ∼650 °C and ∼8 kbar. The Grt-St schist records initial burial to the staurolite stability field at ∼620 °C and 6 kbar, followed by further burial to ∼590 °C and 8.5 kbar. The monazite data yield a continuum of 207Pb-corrected 238U/206Pb dates of ca. 926–768 Ma in the Grt-Sil-Ky gneiss, and ca. 937–754 Ma in the Grt-St schist. Based on monazite textural positon, internal zoning, and REE patterns, the time of prograde burial to 6.0 kbar under a thermal gradient of 27–32 °C/km is estimated at ca. 890–853 Ma. It is not clear whether such high-grade conditions prevailed until a phase of further burial under a geothermal gradient of 18–22 °C/km dated at ca. 835–815 Ma. The late monazite recrystallization at ca. 790 Ma is related to decompression. Additionally, monazite with dates of ca. 568–515 Ma occur as whole grains or as rims with sharp boundaries on Tonian monazite in Grt-St schist suggesting a minor Baikalian overprint. Metamorphic zircon rims with Th/U ratios of ∼ 0.01–0.06 in Grt-Sil-Ky gneiss with 877 ± 7 Ma age, together with lower intercepts of detrital zircon discordia lines in both Grt-Sil-Ky gneiss and Grt-St schist further support the Tonian age of high-grade metamorphism. The anticlockwise P-T evolution is interpreted as a result of thickening of a supra-subduction extensional and hot edifice – probably of back-arc or arc type. This kind of prograde metamorphism has so far only been described on the northern part of the Tarim block and was interpreted to be a result of initiation of peri-Rodinian subduction of the Mirovoi Ocean. The geodynamic consequences of a unique discovery of Tonian metamorphism are discussed in terms of tectonic switch related to initiation of peri-Rodinian oceanic subduction during supercontinent assembly, followed by strong mechanical coupling potentially related to onset of Rodinia dispersal.

Synaptic loss may disturb the excitatory to inhibitory balance (E/I ratio) in circuits vulnerable in Alzheimer’s disease (AD). The authors find reduced synaptic levels of PSD-95 and gephyrin and show that individuals with AD exhibit a pro-excitatory shift of postsynaptic densities and the electrophysiological synaptic E/I ratio in the parietal cortex.

Mid-Devonian high-pressure (HP) and high-temperature (HT) metamorphism represents an enigmatic early phase in the evolution of the Variscan Orogeny. Within the Bohemian Massif this metamorphism is recorded mostly in allochthonous complexes with uncertain relationship to the major tectonic units. In this regard, the Mariánské Lázně Complex (MLC) is unique in its position at the base of its original upper plate (Teplá-Barrandian Zone). The MLC is composed of diverse, but predominantly mafic, magmatic-metamorphic rocks with late Ediacaran to mid-Devonian protolith ages. Mid-Devonian HP eclogite-facies metamorphism was swiftly followed by a HT granulite-facies overprint contemporaneous with the emplacement of magmatic rocks with apparent supra-subduction affinity. New Hf in zircon isotopic measurements combined with a review of whole-rock isotopic and geochemical data reveals that the magmatic protoliths of the MLC, as well as in the upper plate Teplá-Barrandian Zone, developed above a relatively unaltered Neoproterozoic lithospheric mantle. They remained coupled with this lithospheric mantle throughout a geological timeframe that encompasses separate Ediacaran and Cambrian age arc magmatism, protracted early Paleozoic rifting, and the earliest phases of the Variscan Orogeny. These results are presented in the context of reconstructing the original architecture of the Variscan terranes up to and including the mid-Devonian HP-HT event.

The tectonic evolution of the Himalayan orogenic belt before Cenozoic convergence is important to understand its modern structural framework. There is still controversy regarding the tectonic history of the lower Lesser Himalaya Sequence (LHS) in the frame of the Paleoproterozoic geological record. In this study, integrated analysis of field geology, zircon U-Pb age, Hf isotope, and whole-rock geochemistry was conducted across the LHS and the Main Central Thrust zone in the Arun Valley, eastern Nepal, to address their Precambrian tectonic evolution and the later convergence. Two groups of metasedimentary rocks with different age spectrums of detrital zircons and Hf isotope in the Paleoproterozoic can be distinguished in an imbricated duplexing system in the study area. One group with a maximum depositional age around ca. 1800 Ma has a unimodal detrital zircon pattern and negative zircon ƐHf (t) values ranging from −8.9 to 0.9. These data can be interpreted to reflect the deposition of zircons close to a Japanese-type arc that was isolated from the northern Indian Craton. The other group of calc-silicate rocks and quartzite with multiple peaks of detrital zircons in the Paleoproterozoic show a younger maximum depositional age around ca. 1,600 Ma and variable zircon ƐHf (t) values ranging from −6.7 to 8.8, indicating their deposition in a back-arc basin of an Andean-type arc established on the northern Indian Craton. The geochemistry of an orthogneiss sample dated at 1783 ± 11 Ma indicates high potassium, peraluminous granodiorite protolith emplaced in a volcanic arc or syn-collisional tectonic setting, supporting the existence of the Paleoproterozoic Andean-type arc. We hypothesize that possibly two arc systems developed, respectively, onto and in the proximity of northern Indian Craton in the Paleoproterozoic at the final stages of the Columbia supercontinent formation. These two arcs were juxtaposed either in the Paleoproterozoic or Cenozoic time, and were finally imbricated during the Cenozoic duplexing.

Absent a drug or vaccine, containing epidemic outbreaks is achieved by means of mobility restrictions and lock-downs. Here, the authors propose an alternating quarantine strategy, in which half of the population remains under lockdown while the other half continues to be active, resulting in a dramatic reduction in transmission.

The geological map L-47-V at a scale 1:500,000 covers part of Mongolian Altaids with ophiolite fragments in southern Central Asian Orogenic Belt in SW Mongolia. This region has a basin and range topography with Neoproterozoic and Palaeozoic units exposed at NW–SE trending ranges rising along major intracontinental faults and with intermontane basins filled by Mesozoic and Cenozoic sediments in between. The map shows clear N–S tectonic zonation featuring the northerly Precambrian Baidrag microcontinent, the lower Palaeozoic Lake Zone in the centre and the southerly Palaeozoic Gobi-Altai and Trans-Altai zones. Gravity highs are located in the SW part of the map and low to intermediate Bouguer anomalies in the NE part. NW–SE trends of gravity anomalies correlate well with the contact between the Trans-Altai and the Gobi-Altai zones but the important first-order geological boundary between the Lake and Gobi-Altai zones cannot be delineated by the gravity gradients.

Abstract Background Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population. Methods Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX. Results The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX. Conclusions The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.

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