The experimental interest and developments in quantum spin-1/2 chains has increased uninterruptedly over the past decade. In many instances, the target quantum simulation belongs to the broader class ...of noninteracting fermionic models, constituting an important benchmark. In spite of this class being analytically efficiently tractable, no direct certification tool has yet been reported for it. In fact, in experiments, certification has almost exclusively relied on notions of quantum state tomography scaling very unfavorably with the system size. Here, we develop experimentally friendly fidelity witnesses for all pure fermionic Gaussian target states. Their expectation value yields a tight lower bound to the fidelity and can be measured efficiently. We derive witnesses in full generality in the Majorana-fermion representation and apply them to experimentally relevant spin-1/2 chains. Among others, we show how to efficiently certify strongly out-of-equilibrium dynamics in critical Ising chains. At the heart of the measurement scheme is a variant of importance sampling specially tailored to overlaps between covariance matrices. The method is shown to be robust against finite experimental-state infidelities.
De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a ...portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10
) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10
) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.
The combination of downward-looking airborne lidar, radar, microwave, and imaging spectrometer measurements was exploited to characterize the vertical and small-scale (down to 10 m) horizontal ...distribution of the thermodynamic phase of low-level Arctic mixed-layer clouds. Two cloud cases observed in a cold air outbreak and a warm air advection event observed during the Arctic CLoud Observations Using airborne measurements during polar Day (ACLOUD) campaign were investigated. Both cloud cases exhibited the typical vertical mixed-phase structure with mostly liquid water droplets at cloud top and ice crystals in lower layers. The horizontal, small-scale distribution of the thermodynamic phase as observed during the cold air outbreak is dominated by the liquid water close to the cloud top and shows no indication of ice in lower cloud layers. Contrastingly, the cloud top variability in the case observed during a warm air advection showed some ice in areas of low reflectivity or cloud holes. Radiative transfer simulations considering homogeneous mixtures of liquid water droplets and ice crystals were able to reproduce the horizontal variability in this warm air advection. Large eddy simulations (LESs) were performed to reconstruct the observed cloud properties, which were used subsequently as input for radiative transfer simulations. The LESs of the cloud case observed during the cold air outbreak, with mostly liquid water at cloud top, realistically reproduced the observations. For the warm air advection case, the simulated ice water content (IWC) was systematically lower than the measured IWC. Nevertheless, the LESs revealed the presence of ice particles close to the cloud top and confirmed the observed horizontal variability in the cloud field. It is concluded that the cloud top small-scale horizontal variability is directly linked to changes in the vertical distribution of the cloud thermodynamic phase. Passive satellite-borne imaging spectrometer observations with pixel sizes larger than 100 m miss the small-scale cloud top structures.
This study aimed to define the expression patterns of HENMT1 and PIWI proteins in human testis and investigate their association with transposon expression, infertility sub-type or development of ...testicular germ cell tumours (TGCTs). Testis biopsies showing normal spermatogenesis were used to identify normal localisation patterns of HENMT1 and PIWIL1 by immunolocalisation and RT-PCR after laser microdissection. 222 testis biopsies representing normal spermatogenesis, hypospermatogenesis, spermatogenic arrests, Sertoli cell-only (SCO) tumours and TGCTs were analysed by RT-qPCR for expression of
and
Additionally,
-overexpressing TCam2 seminoma cell lines were analysed for the same parameters by RT-qPCR. We found that
and
are coexpressed in pachytene spermatocytes and spermatids. Expression of
,
and
was mainly dependent on germ cell content but low levels of expression were also detected in some SCO samples. Levels of
,
and
expression were low in TGCT. Samples with
and
expression showed significantly (
< 0.05) lower transposon expression compared to samples without expression in the same histological group. HENMT1-overexpressing TCam2 cells showed lower
expression than empty vector-transfected control lines. Our findings support that the transposon-regulating function of the piRNA pathway found in the mouse is conserved in adult human testis. HENMT1 and PIWI proteins are expressed in a germ-cell-specific manner and required for transposon control.
The Arctic CLoud Observations Using airborne measurements during polar Day (ACLOUD) campaign was carried out north-west of Svalbard (Norway) between 23 May and 6 June 2017. The objective of ACLOUD ...was to study Arctic boundary layer and mid-level clouds and their role in Arctic amplification. Two research aircraft (Polar 5 and 6) jointly performed 22 research flights over the transition zone between open ocean and closed sea ice. Both aircraft were equipped with identical instrumentation for measurements of basic meteorological parameters, as well as for turbulent and radiative energy fluxes. In addition, on Polar 5 active and passive remote sensing instruments were installed, while Polar 6 operated in situ instruments to characterize cloud and aerosol particles as well as trace gases. A detailed overview of the specifications, data processing, and data quality is provided here. It is shown that the scientific analysis of the ACLOUD data benefits from the coordinated operation of both aircraft. By combining the cloud remote sensing techniques operated on Polar 5, the synergy of multi-instrument cloud retrieval is illustrated. The remote sensing methods were validated using truly collocated in situ and remote sensing observations. The data of identical instruments operated on both aircraft were merged to extend the spatial coverage of mean atmospheric quantities and turbulent and radiative flux measurement. Therefore, the data set of the ACLOUD campaign provides comprehensive in situ and remote sensing observations characterizing the cloudy Arctic atmosphere. All processed, calibrated, and validated data are published in the World Data Center PANGAEA as instrument-separated data subsets (Ehrlich et al., 2019b, https://doi.org/10.1594/PANGAEA.902603).
Abstract
BACKGROUND
Infertility is an important side effect of treatments used for cancer and other non-malignant conditions in males. This may be due to the loss of spermatogonial stem cells (SSCs) ...and/or altered functionality of testicular somatic cells (e.g. Sertoli cells, Leydig cells). Whereas sperm cryopreservation is the first-line procedure to preserve fertility in post-pubertal males, this option does not exist for prepubertal boys. For patients unable to produce sperm and at high risk of losing their fertility, testicular tissue freezing is now proposed as an alternative experimental option to safeguard their fertility.
OBJECTIVE AND RATIONALE
With this review, we aim to provide an update on clinical practices and experimental methods, as well as to describe patient management inclusion strategies used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss.
SEARCH METHODS
Based on the expertise of the participating centres and a literature search of the progress in clinical practices, patient management strategies and experimental methods used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss were identified. In addition, a survey was conducted amongst European and North American centres/networks that have published papers on their testicular tissue banking activity.
OUTCOMES
Since the first publication on murine SSC transplantation in 1994, remarkable progress has been made towards clinical application: cryopreservation protocols for testicular tissue have been developed in animal models and are now offered to patients in clinics as a still experimental procedure. Transplantation methods have been adapted for human testis, and the efficiency and safety of the technique are being evaluated in mouse and primate models. However, important practical, medical and ethical issues must be resolved before fertility restoration can be applied in the clinic.Since the previous survey conducted in 2012, the implementation of testicular tissue cryopreservation as a means to preserve the fertility of prepubertal boys has increased. Data have been collected from 24 co-ordinating centres worldwide, which are actively offering testis tissue cryobanking to safeguard the future fertility of boys. More than 1033 young patients (age range 3 months to 18 years) have already undergone testicular tissue retrieval and storage for fertility preservation.
LIMITATIONS, REASONS FOR CAUTION
The review does not include the data of all reproductive centres worldwide. Other centres might be offering testicular tissue cryopreservation. Therefore, the numbers might be not representative for the entire field in reproductive medicine and biology worldwide. The key ethical issue regarding fertility preservation in prepubertal boys remains the experimental nature of the intervention.
WIDER IMPLICATIONS
The revised procedures can be implemented by the multi-disciplinary teams offering and/or developing treatment strategies to preserve the fertility of prepubertal boys who have a high risk of fertility loss.
STUDY FUNDING/COMPETING INTEREST(S)
The work was funded by ESHRE. None of the authors has a conflict of interest.
In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 ...(Essen, Germany) and 2006 (Amsterdam, The Netherlands) Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377–1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478–496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497–513. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues.
The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.
Background
The routine genetic analysis for diagnosing male infertility has not changed over the last twenty years, and currently available tests can only determine the etiology of 4% of unselected ...infertile patients. Thus, to create new diagnostic assays, we must better understand the molecular and genetic mechanisms of male infertility. Although next‐generation sequencing allows for simultaneous analysis of hundreds of genes and the discovery of novel candidates related to male infertility, so far only a few gene candidates have enough sound evidence to support the gene–disease relationship.
Objective
Since complementary studies are required to validate genes, we aimed to analyze the presence of potentially pathogenic rare variants in a set of candidate genes related to azoospermia in a hitherto understudied South American population.
Subjects and Methods
We performed whole exome sequencing in a group of 16 patients with non‐obstructive azoospermia from Ribeirão Preto, Brazil. Based on a recent systematic review of monogenic causes of male infertility, we selected a set of 37 genes related to azoospermia, Sertoli‐Cell‐Only histology, and spermatogenic arrest to analyze. The identified variants were confirmed by Sanger sequencing, and their functional consequence was predicted by in silico programs.
Results
We identified potential pathogenic variants in seven genes in six patients. Two variants, c.671A>G (p.(Asn224Ser)) in DMRT1 and c.91C>T (p.(Arg31Cys)) in REC8, have already been described in association with azoospermia. We also found new variants in genes that already have moderate evidence of being linked to spermatogenic failure (TEX15, KLHL10), in genes with limited evidence (DNMT3B, TEX14) and in one novel promising candidate gene that has no evidence so far (SYCE1L).
Discussion
Although this study included a small number of patients, the process of rationally selecting genes allowed us to detect rare potentially pathogenic variants, providing supporting evidence for validating candidate genes associated with azoospermia.
Abstract
STUDY QUESTION
Can a systematic scoring procedure provide crucial information on the status of highly heterogeneous immature human testicular tissues in the context of cryopreservation for ...fertility preservation?
SUMMARY ANSWER
We developed a systematic histological score as a novel diagnostic tool which differentiates the patient cohort according to the status of germ cell differentiation and number of spermatogonia (normal, diminished and absent), and which could be relevant in the fertility clinic.
WHAT IS KNOWN ALREADY
Cryopreservation of testicular tissue of immature boys is currently considered the option for future fertility restoration. However, experimental techniques for the derivation of sperm as well as valid diagnostic scoring of these immature testis tissues are not yet reported.
STUDY DESIGN, SIZE, DURATION
Testicular tissues of 39 patients (aged 2-20 years) who attended our clinic for cryopreservation between 2010 and 2015 were analyzed to determine the variability of testicular tissue composition, germ cell numbers and differentiation status.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Human testicular tissue samples were divided into three groups. Group NT included patients suffering from diseases which do not directly affect the testes (n = 6; aged 6-14 years), group AT included patients suffering from diseases that directly affect the testes (n = 14; 2-17 years), and group KS (Klinefelter patients, n = 19; 12-20 years). Based on immunohistochemical stainings for MAGEA4, the differentiation status as well as the numbers of gonocytes, spermatogonia and spermatocytes were determined.
MAIN RESULTS AND THE ROLE OF CHANCE
Testicular tissue samples from the NT group contained a mean of 100.3 spermatogonia/mm3 (×103). Highly heterogeneous and significantly lower mean numbers of spermatogonia were scored in testes from boys after cytotoxic exposures or with pre-existing disease (AT group: 35.7 spermatogonia/mm3 (×103); KS group: 1.8 spermatogonia/mm3 (×103)). In addition, the germ cell differentiation status was determined and revealed tissues with either spermatogonia and gonocytes, only spermatogonia, spermatogonia and spermatocytes, or all three germ cell types were present. Based on spermatogonial numbers and differentiation status, we developed a germ cell score which we applied to each individual patient sample.
LIMITATIONS REASONS FOR CAUTION
Normal human testicular tissue samples are difficult to obtain for ethical reasons and the sample numbers were small. However, six such samples provide a valid baseline for the normal situation.
WIDER IMPLICATIONS OF THE FINDINGS
Fertility preservation of immature male tissues is an emerging field and is currently offered in many specialized centers worldwide. Our diagnostic germ cell score delivers an easily applicable tool, facilitating patient counseling and thus ensuring comparability between the centers with regard to future studies.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the Funding Initiative: Translational Research, Ministry of Innovation, Science and Research, Federal State of North Rhine Westphalia (z1403ts006). The authors declare that they do not have competing financial interests.
Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. ...This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (
TERB2
) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of
TERB2
variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in
TERB1
and one NOA patient with a rare homozygous missense variant in
MAJIN
. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.
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