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The acrosome is a specialized organelle that covers the anterior part of the sperm nucleus and plays an essential role in the process of fertilization. The molecular mechanism underlying the biogenesis of this lysosome-related organelle （LRO） is still largely unknown. Here, we show that germ cell-specific Atg7-knockout mice were infertile due to a defect in aerosome biogenesis and displayed a phenotype similar to human globozoospermia; this reproductive defect was successfully rescued by intracytoplasmic sperm injections. Furthermore, the depletion of Atg7 in germ cells did not affect the early stages of development of germ cells, but at later stages of spermatogenesis, the proacroso- mal vesicles failed to fuse into a single acrosomal vesicle during the Golgi phase, which finally resulted in irregular or nearly round-headed spermatozoa. Autophagic flux was disrupted in Atg7-depleted germ cells, finally leading to the failure of LC3 conjugation to Golgi apparatus-derived vesicles. In addition, Atg7 partially regulated another giobozo- ospermia-related protein, Golgi-associated PDZ- and coiled-coil motif-containing protein （GOPC）, during acrosome biogenesis. Finally, the injection of either autophagy or lysosome inhibitors into testis resulted in a similar phenotype to that of germ cell-specific AtgT-knockout mice. Altogether, our results uncover a new role for Atg7 in the biogenesis of the acrosome, and we provide evidence to support the autolysosome origination hypothesis for the acrosome.

In mammals, the inheritance of mitochondrion and its DNA （mtDNA） is strictly maternal, despite the fact that a sperm can inject up to 100 functional mitochondria into the oocyte during fertilization. The mechanisms respon- sible for the elimination of the paternal mitochondria remain largely unknown. We report here that this paternal mitochondrial elimination process is conserved in Caenorhabditis elegans, and that the lysosomal pathway actively participates in this process. Molecular and cell biological analyses indicate that in wild-type animals paternal mito- chondria and mtDNA are destroyed within two hours after fertilization. In animals with compromised lysosomes, pa- ternal mitochondria persist until late embryonic stages. Therefore, the lysosomal pathway plays an important role in degrading paternal mitochondria introduced into the oocyte during fertilization. Our study indicates that C. elegans is an excellent animal model for understanding and dissecting this conserved biological process critical for animal de- velopment and reproduction.

Globozoospermia is a human infertility syndrome caused by spermatogenesis defects （OMIM 102530）. Acrosome plays an important role at the site of sperm-zonapellucida binding during the fertilization process. Thus, malformation of the acrosome is the most prominent feature seen in globozoospermia. Disruption of several mouse genes, including Gopc （Golgi-associated PDZ and coiled-coil motif containing protein）, Hrb （HIV-I Rev binding protein）, Csnk2α2 （casein kinase 2, α prime polypeptide） and Pick1 （protein interacting with C kinase 1）, results in a phenotype similar to globozoospermia in humans, which suggests their potential role in the disease. However, no mutations with a clear link to globozoospermia have been identified in these genes in humans. In this study, we screened the candidate genes men- tioned above in three globozoospermia type I patients and discovered a homozygous missense mutation （G198A） in exon 13 of the PICK1 gene in a Chinese family. The family member affected by this homozygous missense mutation showed a complete lack of acrosome. Using the candidate gene screening strategy, our study is the first to identify an autosomal recessive genetic mutation in PICK1 that was responsible for globozoospermia in humans.

During mammalian fertilisation, the zona pellucida （ZP） matrix surrounding the oocyte is responsible for the binding of the spermatozoa to the oocyte and induction of the acrosome reaction （AR） in the ZP-bound spermatozoon. The AR is crucial for the penetration of the ZP matrix by spermatozoa. The ZP matrix in mice is composed of three glycoproteins designated ZP1, ZP2 and ZP3, whereas in humans, it is composed of four （ZP1, ZP2, ZP3 and ZP4）. ZP3 acts as the putative primary sperm receptor and is responsible for AR induction in mice, whereas in humans （in addition to ZP3）, ZP1 and ZP4 also induce the AR. The ability of ZP3 to induce the AR resides in its C-terminal fragment. O-linked glycans are critical for the murine ZP3-mediated AR. However, N-linked glycans of human ZP1, ZP3 and ZP4 have important roles in the induction of the AR. Studies with pharmacological inhibitors showed that the ZP3-induced AR involves the activation of the Gi-coupled receptor pathway, whereas ZP1- and ZP4-mediated ARs are independent of this pathway. The ZP3-induced AR involves the activation of T-type voltage-operated calcium channels （VOCCs）, whereas ZP1- and ZP4-induced ARs involve both T- and L-type VOCCs. To conclude, in mice, ZP3 is primarily responsible for the binding of capacitated spermatozoa to the ZP matrix and induction of the AR, whereas in humans （in addition to ZP3）, ZP1 and ZP4 also participate in these stages of fertilisation.

The aim of the present study was to assess if semen quality declines during in vitro fertilization （IVF） and whether or not this phenomenon is triggered by chronic male stress. In order to test this hypothesis, we first investigated a retrospective cohort of 155 male IVF patients （testing cohort）. Subsequently, we started a prospective cohort study in men undergoing their first IVF and assessed semen quality and subjective male chronic stress using a validated tool, i.e. the Fertility Problem Inventory （FPI） questionnaire. The association between stress and sperm quality decline measured 4-6weeks before the start of IVF （T1） and at the day of oocyte retrieval （T2） was the primary outcome. Live birth rate, first trimester abortion and rate of poor responders were secondary outcomes. In the testing cohort, mean progressive motility, but not mean sperm density significantly declined. There were 78/154 （51%） men who showed a decline in semen density and 50/154 （32%） men who showed a decline in progressive motility. In the validation cohort, progressive motility declined, whereas, sperm density increased from T1 to T2. Of 78 men, 27 men had increased stress （FPI-score 〉 146）. Sperm density and progressive motility were not significantly different in men with and without stress. However, in the presence of male stress, couples had a higher rate of poor responders, miscarriages and a lower rate of live births. Subjective stress is not associated with a decline in semen quality observed during IVF but may be associated with adverse ore~nancv outcome.

It is well-known that controversies and questions exist in all fields of knowledge. Beyond doubt, they play an important role in driving the development of science and technology. It is, therefore, not surprising that controversies also arise in the area of reproductive biology, and it is our belief that thorough testing of alternative hypotheses will accelerate our understanding of this field. One of the open questions in reproduction is how the sperm activate the egg during fertilization. Over the years, different mechanisms have been proposed, which led to multiple discussions.

It is imperative to understand the molecular basis of various steps involved during fertilization. In the manuscript by Bianchi et al.1 a novel protein, Juno on egg membrane （oolemma） has been characterized that binds to sperm specific protein, Izumo-1. Monoclonal antibodies against Juno inhibited in vitro fertilization. Juno knock-out female mice failed to deliver litters on mating. It is rapidly shed from oolemma after fertilization, suggesting its role in preventing polyspermy. Taken together these studies will help in our understanding of sperm-egg recognition mechanisms and also facilitate development of new fertility treatment regimens and novel contraceptives.

Intracytoplasmic sperm injection （ICSI） is the recommended treatment in many cases of male-factor infertility. Several studies have demonstrated a positive correlation between optimal sperm morphology and positive ICSI outcomes. In fact, spermatozoa with severe abnormalities of the head are well documented to be associated with low fertilisation, implantation and pregnancy rates. However, a spermatozoon which is classified as ＇normal＇ by microscopic observation at low magnification could contain ultrastructural defects that impair both the fertilisation process and embryonic development. The intracytoplasmic morphologically selected sperm injection （IMSI） procedure changed the perception of how a spermatozoon suitable for injection should appear. Sperm selection is carried out at x 6000 magnification, allowing improved assessment of the sperm nucleus. Currently, standardized clinical indications for I MSI are lacking and the candidates are selected on the grounds of their medical history or of a careful analysis of the sperm suspension. Further prospective randomized studies are needed to confirm the advantages of IMSI in specific groups of patients. In addition to providing a brief overview of the IMSI procedure, this study aims to review the literature, which explains the theoretical basis and the clinical outcomes of this technique. Several reports show that IMSI is associated with improved implantation and clinical pregnancy rates as well as lower abortion rates when compared to ICSI. Although a possible correlation between the sperm＇s abnormal nucleus shape, increased DNA fragmentation and negative laboratory and clinical outcomes has been long investigated, the results are conflicting.

Amongst the reasons for male infertility the factor ＇stress＇ is frequently cited, however, without providing more detailed explanations. In the article ＇Decline of semen quality during IVF is not associated with subjective male stress＇ published on Asian Journal ofAndrology, Nouri et al1 describe a decline in progressive sperm motility in a retrospective cohort of 155 male in vitro fertilization （IVF） patients during a time period of 4-6 weeks prior to the first IVF cycle and the time of oocyte retrieval. In a subsequent prospective cohort study on men undergoing their first IVF semen quality and subjective male chronic stress were investigated at the same time intervals.

We thank the commentator for his valuable insights as expressed in the above commentary. We fully agree that numerous lines of evidence support the assumption that male as well as female stress and the interaction of the stressed couple plays a role in the success of assisted reproduction. Furthermore, it is common ground that in vitro fertilization （IVF）/intracytoplasmic sperm injection （ICSI） couples are an especially vulnerable patient collective in this respect. We have, however, not yet identified the optimal means of measuring stress or the relevant aspects of it during the management of couples undergoing IVF/ICSI. This fact is also highlighted by our findings,t Further work is necessary to identify efficient and reliable tools to measure and treat stress in males and females undergoing IVF/ICSI with the goal of further improving reproductive outcomes.