Incomplete Maturation Research Articles

Effects of Heat Stress-Induced Sex Hormone Dysregulation on Reproduction and Growth in Male Adolescents and Beneficial Foods.

Heat stress due to climate warming can significantly affect the synthesis of sex hormones in male adolescents, which can impair the ability of the hypothalamus to secrete gonadotropin-releasing hormone on the hypothalamic-pituitary-gonadal axis, which leads to a decrease in luteinizing hormone and follicle-stimulating hormone, which ultimately negatively affects spermatogenesis and testosterone synthesis. For optimal spermatogenesis, the testicular temperature should be 2-6 °C lower than body temperature. Heat stress directly affects the testes, damaging them and reducing testosterone synthesis. Additionally, chronic heat stress abnormally increases the level of aromatase in Leydig cells, which increases estradiol synthesis while decreasing testosterone, leading to an imbalance of sex hormones and spermatogenesis failure. Low levels of testosterone in male adolescents lead to delayed puberty and incomplete sexual maturation, negatively affect height growth and bone mineral density, and can lead to a decrease in lean body mass and an increase in fat mass. In order for male adolescents to acquire healthy reproductive capacity, it is recommended to provide sufficient nutrition and energy, avoid exposure to heat stress, and provide foods and supplements to prevent or repair testosterone reduction, germ cell damage, and sperm count reduction caused by heat stress so that they can enter a healthy adulthood.

Evidence for Two Subpopulations of Cerebrospinal Fluid-Contacting Neurons with Opposite GABAergic Signaling in Adult Mouse Spinal Cord.

Spinal cerebrospinal fluid-contacting neurons (CSF-cNs) form an evolutionary conserved bipolar cell population localized around the central canal of all vertebrates. CSF-cNs were shown to express molecular markers of neuronal immaturity into adulthood; however, the impact of their incomplete maturation on the chloride (Cl-) homeostasis as well as GABAergic signaling remains unknown. Using adult mice from both sexes, in situ hybridization revealed that a proportion of spinal CSF-cNs (18.3%) express the Na+-K+-Cl- cotransporter 1 (NKCC1) allowing intracellular Cl- accumulation. However, we did not find expression of the K+-Cl- cotransporter 2 (KCC2) responsible for Cl- efflux in any CSF-cNs. The lack of KCC2 expression results in low Cl- extrusion capacity in CSF-cNs under high Cl- load in whole-cell patch clamp. Using cell-attached patch clamp allowing recordings with intact intracellular Cl- concentration, we found that the activation of ionotropic GABAA receptors (GABAA-Rs) induced both depolarizing and hyperpolarizing responses in CSF-cNs. Moreover, depolarizing GABA responses can drive action potentials as well as intracellular calcium elevations by activating voltage-gated calcium channels. Blocking NKCC1 with bumetanide inhibited the GABA-induced calcium transients in CSF-cNs. Finally, we show that metabotropic GABAB receptors have no hyperpolarizing action on spinal CSF-cNs as their activation with baclofen did not mediate outward K+ currents, presumably due to the lack of expression of G-protein-coupled inwardly rectifying potassium (GIRK) channels. Together, these findings outline subpopulations of spinal CSF-cNs expressing inhibitory or excitatory GABAA-R signaling. Excitatory GABA may promote the maturation and integration of young CSF-cNs into the existing spinal circuit.

Artificial activation of sperm motility in vitro.

The sperm activation method is a modern methodological approach that is used more and more often in practice. The number of studies focused on methods of artificial activation of human sperm motility are constantly increasing. Standard sperm selection methods can fail in some cases, among other things, because very young sperm are isolated that have not yet completed their development. In these cases, artificial stimulation of their movement can have a positive effect and greatly facilitate and faster the process of selecting suitable sperm. Methylxanthines are most often used as activating agents. However, opinions on the safety of using these substances on sperm are not uniform. The aim of the thesis is to present current knowledge about artificial activation of sperm motility for in vitro fertilization and subsequent embryonic development. Research of relevant literature in Web of Science, Scopus, PubMed/Medline databases. The literature analysis shows that this method is safe and effective in the selection of immotile spermatozoa. Scientific studies have been conducted to verify the safety and reliability of this method. The conclusion of these studies is the positive impact of this method of selection, especially in cases of sperm obtained from testicular tissue after method testicular sperm extraction. In these cases, the method of artificial sperm activation facilitated and accelerated the selection of sperm before intracytoplasmic sperm injection. Undamaged spermatozoa, which are immobile due to incomplete maturation, were activated.

Associations of the placental metabolome with immune maturation up to one year of age in the Swedish NICE-cohort

IntroductionAllergies and other immune-mediated diseases are thought to result from incomplete maturation of the immune system early in life. We previously showed that infants’ metabolites at birth were associated with immune cell subtypes during infancy. The placenta supplies the fetus with nutrients, but may also provide immune maturation signals.ObjectivesTo examine the relationship between metabolites in placental villous tissue and immune maturation during the first year of life and infant and maternal characteristics (gestational length, birth weight, sex, parity, maternal age, and BMI).MethodsUntargeted metabolomics was measured using Liquid Chromatography-Mass Spectrometry. Subpopulations of T and B cells were measured using flow cytometry at birth, 48 h, one, four, and 12 months. Random forest analysis was used to link the metabolomics data with the T and B cell sub populations as well as infant and maternal characteristics.ResultsModest associations (Q2 = 0.2–0.3) were found between the placental metabolome and kappa-deleting recombination excision circles (KREC) at birth and naïve B cells and memory T cells at 12 months. Weak associations were observed between the placental metabolome and sex and parity. Still, most metabolite features of interest were of low intensity compared to associations previously found in cord blood, suggesting that underlying metabolites were not of placental origin.ConclusionOur results indicate that metabolomic measurements of the placenta may not effectively recognize metabolites important for immune maturation.

#108 : Methods of Sperm DNA Fragmentation (SDF) Testing and Interpretation: Results from the Global Andrology Forum Survey

Background and Aims: Sperm DNA fragmentation (SDF) is caused by apoptosis, oxidative stress or incomplete chromatin maturation and can result in male infertility and poor reproductive outcomes. Despite growing trends, there are no specific recommendations on specific diagnostic tests used, assay cut-offs or abstinence periods prior to SDF testing. Therefore, we conducted a global survey to evaluate the approaches used to diagnose SDF, towards a consensus in the field of SDF research and clinical management. Method: The survey collected cross-sectional global data from 55 countries following the CHERRIES protocol. 436 respondents included clinicians, researchers and reproductive biologists from academic, public and private health sectors, all of whom utilize SDF testing in their routine patient care and practice (Fig. 1). Results: Survey results showed that TUNEL (28.6%), SCSA (24.1%), SCD (19.1%) and Comet (5.3%) were most frequently used to diagnose SD (Fig. 2A). Assays were chosen primarily due to their availability (70.0%), cost (44.05%) and accuracy (35.48%). Published evidence on assays (25.71%), training of staff (25.48%), cost to patients (21.67%), assay time (18.81%), ease of interpretation (18.33%) and performance (17.38%) were taken lesser into consideration when selecting SDF diagnostic tests (Fig. 2B). Assay cut-offs of “30% or higher” (33.7%) were most frequently used to diagnose SDF (Fig. 2C). Finally, an abstinence period of 3-5 days was mostly recommended (53.6%; Fig. 2D). The results of this survey provide valuable data on SDF assays used in clinical practice as well as factors affecting assay choices such as availability of resources, personnel and complexity in assay processing. As decreased abstinence period is associated with lower SDF, testing is recommended with an abstinence period of less than five days. We observed that there was a lack of standard cut-off values, and every laboratory should establish its own reference values based on predictive values for fertility outcomes. Conclusion: We present new data associated with SDF testing in real-world practice, on a global scale. The trends and conclusions derived from the study are recommended for inclusion into the 6[Formula: see text] Edition WHO Manual, towards optimized patient care.

Verbal memory and executive components of recall in adolescent binge drinkers.

Binge drinking (BD) is a common health-risk behavior among young people. Due to the incomplete maturation of the adolescent brain, BD can lead to structural and functional changes that impact neurocognitive processes, particularly executive functioning and verbal memory. This study aimed to investigate the influence of executive components, such as mnemonic strategies and error avoidance, on performance in a verbal memory test and the potential effects of BD on this performance. A sample of 160 college students (51.55% female) with a mean age of 18.12 ± 0.32 years completed assessments for alcohol use disorders using the Alcohol Use Disorder Identification Test (AUDIT), as well as psychopathological (Symptom Checklist-90-R) and neuropsychological evaluations (Verbal Learning Test Spain-Complutense and WMS-III Logical Memory). The Intensive Drinking Evaluation Instrument (IECI) was utilized to gather detailed information about binge drinking habits, including the calculation of the highest blood alcohol concentration (BAC) during an episode of intake. Correlation and clustering analyses revealed a negative association between BAC values and verbal memory performance, as well as the use of memory strategies. The high BAC group (BD) exhibited negative values in verbal memory variables, higher accuracy errors, and less efficient strategy usage, while the low BAC group (No BD) demonstrated better memory test performance, fewer precision errors, and superior use of memory strategies. These findings support the hypothesis that, when solving tests requiring verbal memory, adolescents reporting a BD consumption pattern show fewer executive skills in their resolution and, therefore, achieved poorer performance than non-binge drinkers. Addressing excessive alcohol consumption in young individuals is crucial for safeguarding their cognitive development and overall well-being.

Reduced corticospinal drive to antagonist muscles of upper and lower limbs during hands-and-knees crawling in infants with cerebral palsy: Evidence from intermuscular EMG-EMG coherence

BackgroundThere is growing interest in understanding the central control of hands-and-knees crawling, especially as a significant motor developmental milestone for early assessment of motor dysfunction in infants with cerebral palsy (CP) who have not yet acquired walking ability. In particular, CP is known to be associated with walking dysfunctions caused by early damage and incomplete maturation of the corticospinal tract. However, the extent of damage to the corticospinal connections during crawling in infants with CP has not been fully clarified. Therefore, this study aimed to investigate the disparities in intermuscular EMG-EMG coherence, which serve as indicators of corticospinal drives to antagonist muscles in the upper and lower limbs during crawling, between infants with and without CP. MethodsThis study involved 15 infants diagnosed with CP and 20 typically developing (TD) infants. Surface EMG recordings were obtained from two pairs of antagonist muscles in the upper limbs (triceps brachii (TB) and biceps brachii (BB)) and lower limbs (quadriceps femoris (QF) and hamstrings (HS)), while the infants performed hands-and-knees crawling at their self-selected velocity. Intermuscular EMG-EMG coherence was computed in two frequency bands, the beta band (15–30 Hz) and gamma band (30–60 Hz), which indicate corticospinal drive. Additionally, spatiotemporal parameters, including crawling velocity, cadence, duration, and the percentage of stance phase time, were calculated for comparison. Spearman rank correlations were conducted to assess the relationship between EMG-EMG coherence and crawling spatiotemporal parameters. ResultsInfants with CP exhibited significantly reduced crawling velocity, decreased cadence, longer cycle duration, and a higher percentage of stance phase time compared to TD infants. Furthermore, CP infants demonstrated decreased coherence in the beta and gamma frequency bands (indicators of corticospinal drive) in both upper and lower limb muscles. Regarding limb-related differences in the beta and gamma coherence, significant disparities were found between upper and lower limb muscles in TD infants (p < 0.05), but not in infants with CP (p > 0.05). Additionally, significant correlations between coherence metrics and crawling spatiotemporal parameters were identified in the TD group (p < 0.05), while such correlations were not evident in the CP group. ConclusionsOur findings suggest that the corticospinal drive may functionally influence the central control of antagonist muscles in the limbs during typical infant crawling. This functional role could be impaired by neurological conditions such as cerebral palsy. The neurophysiological markers of corticospinal drive, specifically intermuscular EMG-EMG coherence during crawling in infants with cerebral palsy, could potentially serve as a tool to assess developmental response to therapy.

Successful pregnancy and delivery in a female with pituitary stalk interruption syndrome following in vitro fertilization and embryo transfer: A case report and literature review.

Pituitary stalk interruption syndrome (PSIS) in female patients is mainly characterized by short stature, primary amenorrhea, absent or incomplete sexual maturation, and infertility. Successful pregnancies among these patients are rare. In this report, we describe a successful pregnancy and delivery in a 28-year-old Chinese woman with PSIS following in vitro fertilization and embryo transfer. The patient exhibited typical symptoms, including multiple pituitary hormone deficiency, typical triad signs in magnetic resonance imaging (MRI), undetectable serum gonadotropins and estradiol levels, and invisible antral follicles in both ovaries. During the first attempted controlled ovarian hyperstimulation cycle, 14 oocytes were retrieved and six embryos were acquired. Artificial endometrial preparation and frozen-thawed embryo transfer were performed, resulting in a clinical pregnancy after the transfer of a day 5 blastocyst. The patient was closely monitored throughout the pregnancy and multiple hormone dosages were modulated accordingly. She delivered a healthy boy by elective cesarean section, and the newborn developed normally during a 1-year follow-up period. This is the first report of a successful live birth in a woman with PSIS achieved through in vitro fertilization and frozen-thawed embryo transfer. A literature review on this topic is also presented.

Motor control differs for increasing and decreasing force production during ankle Isometric exercises in children

BackgroundPerformance of the central nervous system (CNS) in increased and decreasing muscle force around the ankle joint is essential for upright tasks of daily living. Previous studies have shown altered CNS control when they decrease force compared with when they increase force in young and older adults. But whether such alteration exists during childhood with incomplete maturation of CNS systems remain unclear. Therefore, this study aimed to evaluate the disparities in intramuscular EMG-EMG coherence, which serve as indicators of corticospinal drive to muscles during ankle isometric increasing and decreasing force generation in children.MethodsWe measured intramuscular EMG-EMG coherence activity of the tibialis anterior (TA) and the associated ability to perform isometric efforts at the ankle in 12 typically developing children (mean ± SD age = 5.91±1.37 years) and 12 healthy young adults (mean ± SD age = 23.16±1.52 years). The participants maintained isometric contractions at 20% of their maximal voluntary contractions (MVC) during ankle dorsiflexion to match a triangle trajectory for 7 s, including ramping up in 3.5 s (increasing force phase) and then linearly ramping down to rest in 3.5 s (decreasing force phase). The variability of force control was characterized by the coefficient of variance (CoV) of force output. Intramuscular EMG-EMG coherence from TA in two frequency bands, the beta band (15–30 Hz) and gamma band (30–45) that could reflect the corticospinal drive, were calculated for the comparison. A repeated measures ANOVA with the within-subjects factor of force generation phase (increasing force vs. decreasing force)x between-subjects factor of the group (children and young adults) was used for statistical analysis.ResultsRegarding the within-subjects difference, our results exhibited significantly higher CoV of force (p < 0.01) and lower EMG-EMG coherence of TA when they decrease force compared with when they increase force in both children and young adult groups. Regarding the between-subjects difference, the CoV of force was significantly higher (p < 0.01) in children compared to young adults, while the EMG-EMG coherence in children showed a significantly lower (p < 0.01) coherence compared with young adults. Furthermore, the EMG-EMG coherence measures were negatively correlated with the CoV of force.ConclusionsThe findings suggest that the age-related development would increase the corticospinal drive to TA muscle to deal with ankle isometric dorsiflexion during childhood, which could be also modulated with the force production phases, including increasing and decreasing force.

A Subungual Nevoid Melanoma of the Right Hallux from a 65-Year-Old Man: A Case Report.

Nevoid melanoma (NeM) is a rare variant of malignant melanoma characterized by slight cellular atypia, polymorphism, and incomplete maturation. It most frequently occurs on the trunk and arms but rarely on the foot. Here, we report a subungual NeM of the right hallux. A 65-year-old man presented with severe pain of 6 months' duration to his right great toe following self-treatment for an ingrown nail. He was evaluated and treated with debridement of the toenail at an urgent medical center 3 months prior. However, this had not relieved his pain. The patient also noticed discoloration of his distal great toe over the past 3 months. Removal of part of the ingrown nail revealed a pigmented mass extending distally from the matrix. Surgical excision of the mass was performed because of the concern for malignancy. The diagnosis of NeM was based on histologic analysis along with enhanced diagnostic modalities. The patient was further treated with surgical amputation of the great toe and anti-programmed cell death-1 therapy. The patient had no relapse at 1-year follow-up. Nevoid melanoma is a rare variant of malignant melanoma on the toes, which needs to be differentiated from a nevus with atypia, with a variety of modalities including cellular and molecular profiling. The optimal treatment is amputation.

Effects of cumulus cells on the in vitro cytoplasmic maturation of immature oocytes in pigs

The exposure of cumulus cells to nuclear matured oocytes can be regulated through the forced delay of nuclear maturation or the alteration of in vitro maturation (IVM) time in cumulus-oocyte complexes (COCs). However, to date, no evidence has been presented for the enhancement of cytoplasmic maturation by them, indicating irrelevance of cumulus cells in cytoplasmic maturation. Therefore, in order to identify the requirement of cumulus cells in achieving the cytoplasmic maturation of immature oocytes, this study investigated the effects of cumulus cells on the in vitro cytoplasmic maturation of oocytes within COCs derived from porcine medium antral follicles (MAFs) post-the completion of nuclear maturation. For these, with IVM of COCs for 44 h (control), cumulus cell-free oocytes with completed nuclear maturation were in-vitro-matured additionally for 0, 6, or 12 h, and then a variety of factors representing the cytoplasmic maturation of oocytes were analyzed and compared. As the results, the IVM of COCs for 32 h showed complete nuclear maturation and incomplete cytoplasmic maturation. Moreover, after the removal of cumulus cells from COCs with the completion of nuclear maturation, IVM for an additional 6 or 12 h resulted in significant increases in the size of the perivitelline space, the proportion of oocytes with a normal intracellular mitochondrial distribution and a normal round first polar body, and the preimplantation development into the 2-cell and blastocyst stages after parthenogenetic activation. Simultaneously, they showed significant reduction in the level of intracellular reactive oxygen species and no significant differences in the total number of blastocysts. Furthermore, oocytes obtained by this approach did not significantly differ from control oocytes produced by IVM of COCs for 44 h. Our results demonstrate that the cumulus cells enclosing COCs derived from porcine MAFs are not essential for the completion of cytoplasmic maturation after complete nuclear maturation by COCs.

Academic Debt in Higher Education: An Analysis of the Causes and Opportunities to Overcome

Academic debt can cause a significant damage to the Russian economics and the higher education system in the medium term (on the horizon of 5–10 years). The purpose of the study is to identify the key problems based on the results of a comprehensive empirical analysis of the situation of the formation of massive academic debt (using the example of the “Business Informatics” direction at a Russian university) and to substantiate ways to improve the activities of universities in order to overcome them and reduce students’ academic dept. Research methods are general scientific (deduction, induction, generalization, comparative analysis, etc.), as well as special ones (correlation and regression, statistical, sociological surveys, etc.). Analytics and visualization of quantitative data were carried out using MS PowerBI software. Research results. It was revealed that: a) high incoming scores do not guarantee trouble-free education at the university; b) students with low scores (but not less than 160–170) are also able to master quite complicated university programs; c) the presence of academic debts does not depend on the type of disciplines studied (economics / information technology). The number of student dropouts in the studied sample (up to 50% of those who entered with a non-linear dependence on the total USE scores) testifies to the presence of reasons that are not related to the incoming educational potential of students. The results of the study made it possible to structure them into three groups: insufficient motivation, self-organization problems, and “incomplete maturation”. Five groups of students have been identified with an increased risk of accumulating academic debt. The article substantiates the use of indirect educational influence on the students through a special mobile application.

Age-Related Dichotic Listening Skills in Impaired and Non-Impaired Readers: A Comparative Study.

Dichotic listening is the high-level auditory process which enables the perception of different verbal stimuli delivered simultaneously to the right and left ears (binaural integration), as well as the perception of a verbal stimulus presented to one ear while ignoring a different stimulus in the other ear (binaural separation). Deficits in central auditory processing have been reported in children with learning disabilities. The present study aimed to compare dichotic listening performances in right-handed impaired readers (IR) and non-impaired readers (non-IR) according to age. For this, a cross-sectional study was conducted in 120 IR (56 males and 64 females) divided into five age groups and 120 non-IR (63 male and 57 female) matched on chronological age (8 to 9 years; 9 to 10 years; 10 to 12 years; 12 to 18 years; adult). They were tested for binaural integration and binaural separation, allowing for the calculation of dichotic aptitude (DA), ear prevalence (EP), and attentional shift index (ASI). A series of ANOVAs showed an effect of age and of the reading group for all the dichotic-related measures, except for EP. Binaural separation scores were lower in IR who also showed more intrusive responses compared to non-IR. These intrusive responses, which were more frequent on the right ear for IR, decreased with age in both groups. Overall, these results suggest that dichotic listening scores improve with age as the central auditory pathways mature. However, whatever the age, performances are lower in IR than in non-IR. This might be explained by an incomplete maturation of the auditory pathways in IR; an early start for long-term follow-up and auditory training is suggested.

Advances in imaging technologies for soybean seed analysis

Abstract: Among grain-producing species, soybean is one of the most important commodities, with increasing demand for production in coming years. Evaluation of soybean seed quality is fundamental for ensuring maximum germination and yield potential. Therefore, effective methods are necessary for examining different properties associated with physical-chemical, physiological, and seed-health changes that affect seed quality. This review focuses on the fundamental principles and on the application of techniques of radiographic imaging, magnetic resonance imaging, multispectral imagining, chlorophyll fluorescence imaging, and infrared thermography to evaluate changes related to loss of soybean seed quality, such as mechanical injury, injury caused by insects, embryonic malformation, and incomplete maturation. Computerized seedling image analysis is also presented for evaluation of seed lot vigor. The examples presented here show the potential of these image analysis techniques for identifying different types of injuries and increasing the efficiency of in-house quality control programs in soybean seed production companies.

Effects of the addition of insulin-transferrin-selenium (ITS) and/or metformin to the in vitro maturation of porcine oocytes on cytoplasmic maturation and embryo development.

One of the main problems of porcine in vitro maturation (IVM) is incomplete cytoplasmatic maturation. Nuclear and cytoplasmic maturation will determine the future success of fertilisation and embryo development. Insulin-transferrin-selenium (ITS) has insulin-like and antioxidant effects, and metformin (M) is an insulin-sensitiser and antioxidant drug. To assess the effects of adding ITS and/or M in porcine IVM media on cytoplasmic maturation and early embryo development. Cumulus -oocyte complexes (COC) were IVM with M (10-4 M), ITS (0.1% v/v), M+ITS or no adding (Control). ITS increased glucose consumption compared to Control and M (P <0.01), and M+ITS did not differ from ITS or Control. Redox balance: M, ITS and M+ITS increased glutathione (P <0.01) and decreased lipid peroxidation (P <0.005). The viability of cumulus cells by flow cytometry increased with M (P <0.005) and decreased with ITS (P <0.001); M+ITS did not differ from Control. After IVF, M increased penetration and decreased male pronucleus (P <0.05). Embryo development: cleavage increased with M (P <0.05), and blastocysts increased with ITS and M+ITS (P <0.05). The number of blastocyst cells increased with ITS (P <0.05). Adding ITS and M+ITS to porcine IVM media benefits embryo development to blastocysts, but ITS alone has better effects than M+ITS. ITS is an excellent tool to improve IVM and embryo development after IVF in pigs.

Co-occurrence of CLCN2-related leukoencephalopathy and SPG56

Family ReportTwo rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A > T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G > T, p.(Gly203Cys), classified as a variant of unknown significance. Testing of additional family members revealed homozygosity for both variants in an additional brother, whom we initially considered unaffected. Both male CLCN2 carriers were infertile, and review of the literature revealed one reported case with azoospermia, however the brother had no overt signs of SPG56. His testicular biopsy revealed incomplete maturation arrest in spermatogenesis; clinically we found mild memory impairment and hand tremor and MRI showed similar changes as his siblings. We consider CLCN2 c.607G > T pathogenic because of the neuroradiological and clinical findings, including azoospermia. ConclusionConsiderable workup may be required to determine the pathogenicity of novel variants, and to unambiguously associate phenotype with genotype. In very rare disorders, highly specific clinical or biomarker combinations provide sufficient evidence for a variant’s pathogenicity. Phenotypic variation of monogenic disorders described in the literature may be attributed to a second co-occurring monogenic disorder, especially in consanguineous families. SPG56 may have reduced penetrance.

Three-dimensional heart extracellular matrix enhances chemically induced direct cardiac reprogramming

Direct cardiac reprogramming has emerged as a promising therapeutic approach for cardiac regeneration. Full chemical reprogramming with small molecules to generate cardiomyocytes may be more amenable than genetic reprogramming for clinical applications as it avoids safety concerns associated with genetic manipulations. However, challenges remain regarding low conversion efficiency and incomplete cardiomyocyte maturation. Furthermore, the therapeutic potential of chemically induced cardiomyocytes (CiCMs) has not been investigated. Here, we report that a three-dimensional microenvironment reconstituted with decellularized heart extracellular matrix can enhance chemical reprogramming and cardiac maturation of fibroblasts to cardiomyocytes. The resultant CiCMs exhibit elevated cardiac marker expression, sarcomeric organization, and improved electrophysiological features and drug responses. We investigated the therapeutic potential of CiCMs reprogrammed in three-dimensional heart extracellular matrix in a rat model of myocardial infarction. Our platform can facilitate the use of CiCMs for regenerative medicine, disease modeling, and drug screening.

NK cells reduce anergic T cell development in early-stage tumors by promoting myeloid cell maturation.

Studies of NK cells in tumors have primarily focused on their direct actions towards tumor cells. We evaluated the impact of NK cells on expression of homing receptor ligands on tumor vasculature, intratumoral T cell number and function, and T cell activation in tumor draining lymph node. Using an implantable mouse model of melanoma, T cell responses and homing receptor ligand expression on the vasculature were evaluated with and without NK cells present during the early stages of the tumor response by flow cytometry. NK cells in early-stage tumors are one source of IFNγ that augments homing receptor ligand expression. More significantly, NK cell depletion resulted in increased numbers of intratumoral T cells with an anergic phenotype. Anergic T cell development in tumor draining lymph node was associated with increased T-cell receptor signaling but decreased proliferation and effector cell activity, and an incomplete maturation phenotype of antigen presenting cells. These effects of NK depletion were similar to those of blocking CD40L stimulation. We conclude that an important function of NK cells is to drive proper APC maturation via CD40L during responses to early-stage tumors, reducing development of anergic T cells. The reduced development of anergic T cells resulting in improved tumor control and T cell responses when NK cells were present.

Silk scaffolding drives self-assembly of functional and mature human brain organoids.

Human pluripotent stem cells (hPSCs) are intrinsically able to self-organize into cerebral organoids that mimic features of developing human brain tissue. These three-dimensional structures provide a unique opportunity to generate cytoarchitecture and cell-cell interactions reminiscent of human brain complexity in a dish. However, current in vitro brain organoid methodologies often result in intra-organoid variability, limiting their use in recapitulating later developmental stages as well as in disease modeling and drug discovery. In addition, cell stress and hypoxia resulting from long-term culture lead to incomplete maturation and cell death within the inner core. Here, we used a recombinant silk microfiber network as a scaffold to drive hPSCs to self-arrange into engineered cerebral organoids. Silk scaffolding promoted neuroectoderm formation and reduced heterogeneity of cellular organization within individual organoids. Bulk and single cell transcriptomics confirmed that silk cerebral organoids display more homogeneous and functionally mature neuronal properties than organoids grown in the absence of silk scaffold. Furthermore, oxygen sensing analysis showed that silk scaffolds create more favorable growth and differentiation conditions by facilitating the delivery of oxygen and nutrients. The silk scaffolding strategy appears to reduce intra-organoid variability and enhances self-organization into functionally mature human brain organoids.

Traumatic Retinal Tears and Retinal Detachment

Traumatic retinal detachment, which can occur in the early or late phases following open and closed globe injuries, can result in permanent loss of vision. Particularly, retinal detachments in the pediatric population are often related to trauma and can result in severe vision loss due to possible delay in diagnosis and incomplete maturation of the visual system. The optimal treatment for retinal detachments following open glob injuries is to maintain the globe integrity on day-1 and vitreoretinal surgery between day 10 and day 14; whereas retinal detachments following closed glob injuries should be treated as soon as possible. Low vision at presentation, open globe injury, presence of the intraocular foreign body, and proliferative vitreoretinopathy have been associated with poor prognosis.