Explore the vast range of titles available.

Mammalian spermatogenesis is an elaborately organized differentiation process, starting with diploid spermatogonia, which include germ-line stem cells, and ending with haploid spermatozoa. The process involves four pivotal transitions occurring in physical proximity: spermatogonial differentiation, meiotic initiation, initiation of spermatid elongation, and release of spermatozoa. We report how the four transitions are coordinated in mice. Two premeiotic transitions, spermatogonial differentiation and meiotic initiation, were known to be coregulated by an extrinsic signal, retinoic acid (RA). Our chemical manipulations of RA levels in mouse testes now reveal that RA also regulates the two postmeiotic transitions: initiation of spermatid elongation and spermatozoa release. We measured RA concentrations and found that they changed periodically, as also reflected in the expression patterns of an RA-responsive gene, STRA8; RA levels were low before the four transitions, increased when the transitions occurred, and remained elevated thereafter. We found that pachytene spermatocytes, which express an RA-synthesizing enzyme, Aldh1a2, contribute directly and significantly to RA production in testes. Indeed, chemical and genetic depletion of pachytene spermatocytes revealed that RA from pachytene spermatocytes was required for the two postmeiotic transitions, but not for the two premeiotic transitions. We conclude that the premeiotic transitions are coordinated by RA from Sertoli (somatic) cells. Once germ cells enter meiosis, pachytene spermatocytes produce RA to coordinate the two postmeiotic transitions. In combination, these elements underpin the spatiotemporal coordination of spermatogenesis and ensure its prodigious output in adult males.

IntroductionPrevious studies on patients with symptoms of spinal ligament ossification, including ossification of the posterior longitudinal ligament (OPLL) and ligamentum flavum (OLF), have not clarified whether obesity is a cause or consequence of these diseases and were limited by selection bias. Thus, we investigated the association between obesity and the prevalence of spinal ligament ossification in randomly selected asymptomatic subjects.Materials and methodsBetween April 2020 and March 2021, 622 asymptomatic Japanese subjects who underwent computed tomography of neck to pelvis for medical check-up purposes were included. All subjects were divided into the following three groups: normal weight (body mass index [BMI] < 25 kg/m2), obese I (25 ≤ BMI < 30 kg/m2), and obese II (BMI ≥ 30 kg/m2). The relationship between factors affecting the presence of each spinal ligament ossification was evaluated using multivariate logistic regression analysis.ResultsThe proportion of subjects with thoracic OPLL was significantly higher in the obese II group than in the other two groups (vs. normal weight, P < 0.001; vs. obese I, P < 0.001). BMI was associated with the prevalence of OLF, cervical OPLL, thoracic OPLL, and ossification of the anterior longitudinal ligament (OALL). BMI was most significantly associated with the prevalence of thoracic OPLL (β, 0.28; 95% confidence interval, 0.17–0.39).ConclusionBMI was associated with the prevalence of OALL, cervical OPLL, thoracic OPLL, and OLF in asymptomatic subjects, suggesting that obesity is associated with the development of heterotopic ossification of the spinal ligaments.

Although ossification of the posterior longitudinal ligament (OPLL) commonly develops in the cervical spine, it also occurs, albeit less commonly, in the thoracic spine. However, data are scarce regarding the characteristics of patients with thoracic OPLL. In the current study, we performed a cross-sectional study on a total of 133 patients with OPLL to clarify the clinical characteristics of patients with thoracic OPLL compared with those of patients with cervical OPLL. The subjects were divided into four groups according to the main region of OPLL and treatment type: C-OPLL-C, cervical OPLL treated conservatively; C-OPLL-S, cervical OPLL treated via surgery; T-OPLL-C, thoracic OPLL treated conservatively; and T-OPLL-S, thoracic OPLL treated via surgery. Symptoms developed at an earlier age in the T-OPLL-S group than in the C-OPLL groups. Current body mass index (BMI), maximum lifetime BMI, and BMI at the age of 20 years were significantly higher in the T-OPLL-S group than in the C-OPLL groups. Yearly weight gain from the age of 20 years to the age at which maximum body weight was attained was significantly greater in the T-OPLL-S group than in the C-OPLL groups. The T-OPLL group showed a higher rate of co-existence of OPLL at other regions or ossification of the ligamentum flavum compared to the C-OPLL groups. Our findings demonstrate that severe obesity, early-onset of symptoms, and diffuse ossification of spinal ligaments are distinct features of patients with myelopathy caused by thoracic OPLL.

Mammalian spermatogenesis—the transformation of stem cells into millions of haploid spermatozoa—is elaborately organized in time and space. We explored the underlying regulatory mechanisms by genetically and chemically perturbing spermatogenesis in vivo, focusing on spermatogonial differentiation, which begins a series of amplifying divisions, and meiotic initiation, which ends these divisions. We first found that, in mice lacking the retinoic acid (RA) target gene Stimulated by retinoic acid gene 8 ( Stra8 ), undifferentiated spermatogonia accumulated in unusually high numbers as early as 10 d after birth, whereas differentiating spermatogonia were depleted. We thus conclude that Stra8 , previously shown to be required for meiotic initiation, also promotes (but is not strictly required for) spermatogonial differentiation. Second, we found that injection of RA into wild-type adult males induced, independently, precocious spermatogonial differentiation and precocious meiotic initiation; thus, RA acts instructively on germ cells at both transitions. Third, the competencies of germ cells to undergo spermatogonial differentiation or meiotic initiation in response to RA were found to be distinct, periodic, and limited to particular seminiferous stages. Competencies for both transitions begin while RA levels are low, so that the germ cells respond as soon as RA levels rise. Together with other findings, our results demonstrate that periodic RA–STRA8 signaling intersects with periodic germ-cell competencies to regulate two distinct, cell-type-specific responses: spermatogonial differentiation and meiotic initiation. This simple mechanism, with one signal both starting and ending the amplifying divisions, contributes to the prodigious output of spermatozoa and to the elaborate organization of spermatogenesis. Significance As male sex cells mature into sperm, two pivotal transitions are spermatogonial differentiation (exit from the stem cell pool) and meiotic initiation. These transitions occur in physical proximity, with 8.6-d periodicity. We report that the gene Stra8 , essential for meiotic initiation, also promotes (but is not required for) spermatogonial differentiation. Moreover, injected RA induces both transitions to occur precociously. We conclude that a periodic RA signal, acting instructively through the common target Stra8 , coordinates these transitions. This RA signal intersects with two distinct windows of sex-cell competency, which both begin while RA levels are low; sex cells respond quickly to rising RA. These mechanisms help account for the elaborate organization of sperm production, and its prodigious output.

Some surgical strategies can maintain or restore thoracic kyphosis (TK); however, next-generation surgical schemes for adolescent idiopathic scoliosis (AIS) should consider anatomical corrections. A four-dimensional correction could be actively achieved by curving the rod. Thus, anatomically designed rods have been developed as notch-free, pre-bent rods for easier anatomical reconstruction. This study aimed to compare the initial curve corrections obtained using notch-free rods and manually bent, notched rods for the anatomical reconstruction of thoracic AIS. Two consecutive series of 60 patients who underwent anatomical posterior correction for main thoracic AIS curves were prospectively followed up. After multilevel facetectomy, except for the lowest instrumented segment, either notch-free or notched rods were used. Patient demographic data, radiographic measurements, and sagittal rod angles were analyzed within 1 week after surgery. Patients with notch-free rods had significantly higher postoperative TK than patients with notched rods ( P  < .001), but both groups achieved three-dimensional spinal corrections and significantly increased postoperative rates of patients with T6–T8 TK apex ( P  = .006 for notch-free rods and P  = .008 for notched rods). The rod deformation angle at the concave side was significantly lower in the notch-free rods than in the notched rods ( P  < .001). The notch-free, pre-bent rod can maintain its curvature, leading to better correction or maintenance of TK after anatomical spinal correction surgery than the conventional notched rod. These results suggest the potential benefits of anatomically designed notch-free, pre-bent rods over conventional, manually bent rods.

Infertility is a global issue, and approximately 50% of cases are due to male factors, with defective spermatogenesis being the main one. For studies of spermatogenesis, evaluating the seminiferous tubule stage is essential. However, current evaluation methods involve labor-intensive manual tasks with a lack of reproducibility owing to the subjective nature of visual evaluation by experts. Here, we propose a deep-learning-based method for automatically and objectively evaluating the seminiferous tubule stage. Our approach predicts which of 12 seminiferous tubule stages is represented in bright-field microscopic images of mouse seminiferous tubules stained by hematoxylin-PAS. The maximum prediction accuracy of our approach was 79.58% which rose to 98.33% with allowance for a prediction error of stage. Remarkably, although the model was not explicitly trained on the stage transition patterns, it inferred the patterns involved in the spermatogenesis. This method not only advances our understanding of spermatogenesis but also holds promise for improving the automated diagnosis of infertility.

The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the epididymis. Males lacking Nicol are sterile due to impaired NELL2-mediated lumicrine signalling, leading to defective epididymal differentiation and deficient sperm maturation but can be restored by NICOL expression in testicular germ cells. Our results demonstrate how lumicrine signalling regulates epididymal function for successful sperm maturation and male fertility. Mammalian sperm need to be matured in the epididymis to achieve potential for fertility. Here the authors identify NICOL as a secreted protein that acts on the epididymis to trigger its functional differentiation and induce sperm maturation.

Fertility across metazoa requires the germline-specific DAZ family of RNA-binding proteins. Here we examine whether DAZL directly regulates progenitor spermatogonia using a conditional genetic mouse model and in vivo biochemical approaches combined with chemical synchronization of spermatogenesis. We find that the absence of Dazl impairs both expansion and differentiation of the spermatogonial progenitor population. In undifferentiated spermatogonia, DAZL binds the 3' UTRs of ~2,500 protein-coding genes. Some targets are known regulators of spermatogonial proliferation and differentiation while others are broadly expressed, dosage-sensitive factors that control transcription and RNA metabolism. DAZL binds 3' UTR sites conserved across vertebrates at a UGUU(U/A) motif. By assessing ribosome occupancy in undifferentiated spermatogonia, we find that DAZL increases translation of its targets. In total, DAZL orchestrates a broad translational program that amplifies protein levels of key spermatogonial and gene regulatory factors to promote the expansion and differentiation of progenitor spermatogonia.

Osteoarthritis (OA) is a musculoskeletal disease characterized by cartilage degeneration and stiffness, with chronic pain in the affected joint. It has been proposed that OA progression is associated with the development of low-grade inflammation (LGI) in the joint. In support of this principle, LGI is now recognized as the major contributor to the pathogenesis of obesity, aging, and metabolic syndromes, which have been documented as among the most significant risk factors for developing OA. These discoveries have led to a new definition of the disease, and OA has recently been recognized as a low-grade inflammatory disease of the joint. Damage-associated molecular patterns (DAMPs)/alarmin molecules, the major cellular components that facilitate the interplay between cells in the cartilage and synovium, activate various molecular pathways involved in the initiation and maintenance of LGI in the joint, which, in turn, drives OA progression. A better understanding of the pathological mechanisms initiated by LGI in the joint represents a decisive step toward discovering therapeutic strategies for the treatment of OA. Recent findings and discoveries regarding the involvement of LGI mediated by DAMPs in OA pathogenesis are discussed. Modulating communication between cells in the joint to decrease inflammation represents an attractive approach for the treatment of OA.