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Prostatic adenocarcinoma is the most common type of cancer in men, with subsequent lesions most commonly occurring in the lymph nodes, bones, and lungs.1,2 We discuss the clinical case of a 59-year-old man who presented after radical prostatectomy for prostate cancer with a unilateral metastasis in the right testis. Metastases to the testis are uncommon, occurring in less than 4% of cases.2,3 This kind of metastasis is usually unilateral, manifesting as a palpable testicular mass, and rarely involves both the testis and the epididymis.1,2 Secondary neoplasms of the testis are found in around 2.5% of autopsies, including nonneoplastic fatalities.2 Most secondary testicular metastases develop from distant primary locations, the most prevalent of which are the lung, prostate, and gastrointestinal tract.2 Testicular metastases can occur in up to 4% of all prostate cancer cases and are frequently discovered by chance following orchiectomy therapy for advanced disease.4 In general, advanced prostate cancer metastases to the pelvic lymph nodes, bones, lungs, and liver are common; however, few of these patients have clinically evident testicular metastasis.4,5 Secondary neoplasms of the testis are uncommon, with a reported rate of 0.02-2.5%, except leukemia and lymphoma infiltration.2,3 The prostate is the most common site of testicular metastases (15%), followed by the lung, melanomas, skin, colon, and kidney.1,2 However, most testicular metastases of prostate cancer were discovered after examining a significant number of testes from patients who had tumors removed during therapeutic orchiectomies.2,4 Lung cancer (43%), malignant melanoma (20%), pancreatic cancer (10%), and prostate cancer (10%) are among cancers that can spread to the testes.4,5 However, the great majority of metastases are lesions detected by chance following an autopsy or bilateral orchiectomy for Prostatic Cancer hormonal treatment.3 A testicular tumor revealing clinical recurrence is highly unusual. Bubendorf et al.1 discovered testicular metastases in just 0.5% of 1,589 prostate carcinoma autopsy reports. He also suggests a backward metastatic channel through prostate veins in addition to the typical hematogenous tumor spread via the vena cava. Overall, four routes have been hypothesized for the propagation of the lesions to the testis: retrograde venous extension, retrograde lymphatic extension, arterial embolism, and through the lumen of the vas deferens.1 Patients with symptomatic isolated post-prostatectomy testicular metastases can live for a surprisingly long time after orchidectomy without further development. This phenomenon may be linked to cytoreduction.1,2 The ability to manage the malignant process locally is an undeniable clinical benefit for patients undergoing orchiectomy. Given that this method of treatment is easy, safe, and associated with few problems, all patients with isolated prostatic cancer testicular metastases should be considered candidates for metastasectomy.4,5 The histological features of prostate cancer testicular metastases are similar to those of original prostate tumors; however, histology may show a more aggressive phenotype with a significant probability of future disease spreading and, thus, worse survival.3,4 Weitzner4 found that patients with newly diagnosed testicular metastases from prostate cancer had a median survival of roughly 12 months.1,2 Other studies, on the other hand, have documented survival of more than two years without biochemical relapses. As a result, the predictive impact of testicular metastases from prostate cancer is yet unknown, owing to the rarity of the incidence.2 Testicular metastasis from prostate carcinoma is an uncommon manifestation of advanced disease.2 It often presents with testicular pain, swelling, or a palpable mass and can mimic primary testicular neoplasms. Clinicians should maintain a high index of suspicion, especially in patients with a history of prostate carcinoma. Prompt diagnosis through imaging studies and histopathological confirmation is essential for appropriate management and prognosis.3,4 This case underscores the importance of considering testicular metastasis in the differential diagnosis of testicular masses, particularly in patients with a history of prostate carcinoma. A multidisciplinary approach is crucial for optimal management and improving patient outcomes. Early recognition and timely intervention are paramount in managing metastatic disease and improving quality of life. Figure 1 refers to a 59-year-old male patient presented to our hospital with an elevated serum prostate-specific antigen (PSA) level of >100 ng/ml. He had been on regular follow-up with urology for surveillance of prostate cancer recurrence. He had undergone a radical prostatectomy two years ago with Gleason grade group 5. Scrotal ultrasound showed a hypoechoic mass involving the right testicle with increased vascularity, suggesting a neoplastic lesion. Hence, the patient was planned for a bilateral orchidectomy. The patient underwent bilateral inguinal orchiectomy without any complications. Macroscopic examination of the right resected testis revealed a solid yellowish-white tumor of 0.5 × 0.5 cm. Histopathological analysis showed that the right testis was infiltrated by metastatic adenocarcinoma. Immunohistochemical examination revealed that tumor cells were diffusely positive for PSA and Alpha (α)-methylacyl-CoA racemase (AMACR). The patient was diagnosed with right testicular metastasis of Prostatic Carcinoma. The patient had an uneventful postoperative recovery. The patient was scheduled for regular follow-up appointments to monitor disease progression. Serial PSA levels and imaging studies were planned to look for disease status. Figure 1 A – Gross view of the right orchidectomy showing a small nodular metastatic deposit in tunica albuginea from the prostate cancer; B, C and D are photomicrographs of the tumor and testicle parenchyma; B – shows normal testicular seminiferous tubules along with presence of metastatic tumor deposit in the wall of testis (Tunica albuginea) (H&E x100); C – These tumor cells are immunopositive for prostate specific antigen (PSA 40X); D – The tumor cells are also positive for Alpha-methylacyl-CoA racemase (AMACR 200X).:

In India, the incidence of mucormycosis reached high levels during 2021–2022, coinciding with the COVID-19 pandemic. In response to this, we established a multicentric ambispective cohort of patients hospitalised with mucormycosis across India. In this paper, we report their baseline profile, clinical characteristics and outcomes at discharge. Patients hospitalized for mucormycosis during March–July 2021 were included. Mucormycosis was diagnosed based on mycological confirmation on direct microscopy (KOH/Calcofluor white stain), culture, histopathology, or supportive evidence from endoscopy or imaging. After consent, trained data collectors used medical records and telephonic interviews to capture data in a pre-tested structured questionnaire. At baseline, we recruited 686 patients from 26 study hospitals, of whom 72.3% were males, 78% had a prior history of diabetes, 53.2% had a history of corticosteroid treatment, and 80% were associated with COVID-19. Pain, numbness or swelling of the face were the commonest symptoms (73.3%). Liposomal Amphotericin B was the commonest drug formulation used (67.1%), and endoscopic sinus surgery was the most common surgical procedure (73.6%). At discharge, the disease was stable in 43.3%, in regression for 29.9% but 9.6% died during hospitalization. Among survivors, commonly reported disabilities included facial disfigurement (18.4%) and difficulties in chewing/swallowing (17.8%). Though the risk of mortality was only 1 in 10, the disability due to the disease was very high. This cohort study could enhance our understanding of the disease’s clinical progression and help frame standard treatment guidelines.

This paper demonstrates a low-profile, wide-band, two-element, frequency-reconfigurable MIMO antenna that is suitable for diverse wireless applications of 4G and 5G such as WLAN/Bluetooth (2.4–2.5 GHz), WLAN (2.4–2.484 GHz, 5.15– 5.35 GHz, and 5.725–5.825 GHz), WiMAX (3.3–3.69 GHz and 5.25–5.85 GHz), Sub6GHz band proposed for 5G (3.4–3.6 GHz, 3.6-3.8GHz and 4.4–4.99 GHz), INSAT and satellite X-band(6 to 9.6 GHz). Proposed MIMO favour effortless switching between multiple bands ranging from 2.2 to 9.4 GHz without causing any interference. Both antenna elements in a MIMO array are made up of a single module comprised of a slot-loaded patch and a defective structured ground. Two PIN diodes are placed in the preset position of the ground defect to achieve frequencyreconfigurable qualities. The suggested MIMO antenna has a size of 62 ×25 ×1.5 mm3. Previous reconfigurable MIMO designs improved isolation using a meander line resonator, faulty ground structures, or self-isolation approaches. To attain the isolation requirements of modern devices, stub approach is introduced in proposed design. Without use of stub, simulated isolation is 15dB. The addition of a stub improved isolation even more. At six resonances, measured isolation is greater than 18 dB, the computed correlation coefficient is below 0.0065, and diversity gain is over 9.8 dB.

Abstract Individuals with Autism Spectrum Disorder (ASD; autism) commonly present with gastrointestinal (GI) illness in addition to core diagnostic behavioural traits. The appendix, or cecum in mice, is important for GI homeostasis via its function as a key site for fermentation and a microbial reservoir. Even so, the role of the appendix and cecum in autism-associated GI symptoms remains uninvestigated. Here, we studied mice with an autism-associated missense mutation in the post-synaptic protein neuroligin-3 (Nlgn3 R451C ), which impacts brain and enteric neuronal activity. We assessed for changes in cecal motility using a tri-cannulation video-imaging approach in ex vivo preparations from wild-type and Nlgn3 R451C mice. We investigated cecal permeability and neurally-evoked secretion in wild-type and Nlgn3 R451C tissues using an Ussing chamber set-up. The number of cecal patches in fresh tissue samples were assessed and key immune populations including gut macrophages and dendritic cells were visualised using immunofluorescence. Nlgn3 R451C mice displayed accelerated cecal motor complexes and reduced cecal weight in comparison to wildtype littermates. Nlgn3 R451C mice also demonstrated reduced neurally-evoked cecal secretion in response to the nicotinic acetylcholine receptor agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP), but permeability was unchanged. We observed an increase in the number of cecal patches in Nlgn3 R451C mice, however the cellular morphologies of key immune populations studied were not significantly altered. We show that the R451C nervous system mutation leads to cecal dysmotility, impaired secretion, and neuro-immune alterations. Together, these results suggest that the R451C mutation disrupts the gut-brain axis with GI dysfunction in autism.

Intestinal macrophages are well-studied for their conventional roles in the immune response against pathogens and protecting the gut from chronic inflammation. However, these macrophages may also have additional functional roles in gastrointestinal motility under typical conditions. This is likely to occur via both direct and indirect influences on gastrointestinal motility through interaction with myenteric neurons that contribute to the gut-brain axis, but this mechanism is yet to be properly characterised. The CX3CR1 chemokine receptor is expressed in the majority of intestinal macrophages, so we used a conditional knockout Cx3cr1-Dtr (diphtheria toxin receptor) rat model to transiently ablate these cells. We then utilized ex vivo video imaging to evaluate colonic motility. Our previous studies in brain suggested that Cx3cr1-expressing cells repopulate by 7 days after depletion in this model, so we performed our experiments at both the 48 hr (macrophage depletion) and 7-day (macrophage repopulation) time points. We also investigated whether inhibitory neuronal input driven by nitric oxide from the enteric nervous system is required for the regulation of colonic motility by intestinal macrophages. Our results demonstrated that CD163-positive resident intestinal macrophages are important in regulating colonic motility in the absence of this major inhibitory neuronal input. In addition, we show that intestinal macrophages are indispensable in maintaining a healthy intestinal structure. Our study provides a novel understanding of the interplay between the enteric nervous system and intestinal macrophages in colonic motility. We highlight intestinal macrophages as a potential therapeutic target for gastrointestinal motility disorders when inhibitory neuronal input is suppressed.

Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3R451C mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3R451C mice bred on a mixed genetic background. Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3R451C mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3R451C mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3R451C mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABAA antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3R451C p = 0.002), but not the ileum, in both wild-type and Nlgn3R451C mice. These findings demonstrate that changes in enteric nervous system function contribute to gastrointestinal dysmotility in mice expressing the autism-associated R451C missense mutation in the Neuroligin-3 protein.

Purpose – In the management world, leadership is a quality associated with business leaders, social entrepreneurs and political figures. Doctors are rarely considered as possessing or requiring leadership skills. With doctors, one thinks of skill and knowledge, but for some strange reason, leadership is hardly associated with doctors. This paper aims to highlight the leadership aspects unique to doctors. This study highlights why leadership training is imperative for doctors, outlines current status of leadership training for doctors in India and sets out proposals for effective leadership building. Design/methodology/approach – Methodology is based on a two-pronged explanatory approach – the first is review of current literature in the context of leadership training of doctors, and the second is review of circumstances unique to the line of work undertaken by doctors that shed light on the need for leadership. Findings – This paper highlights the imperative need for leadership training for doctors in India. It recommends leadership training on a continuous basis in their career life cycle as with the other professions. It also calls for involvement of all stakeholders in the medical community to foster leadership training – medical educational institutions, hospitals, medical councils and members of the medical fraternity. Practical implications – Akin to leadership training programs conducted for IT and management professionals, this paper recommends that similar programs be conducted for doctors. Originality/value – There are very few studies conducted in the Indian context on leadership training needs for doctors. This paper explains the importance of leadership training for doctors and suggests ways it can be implemented throughout the medical education life cycle of a doctor’s career.

High glucose (HG), a hallmark of the tumour microenvironment, is also a biomechanical stressor, as it exerts hyper-osmotic stress (HG-HO), but not much is known regarding how tumour cells mechanoadapt to HG-HO. Therefore, this study aimed to delineate the novel molecular mechanisms by which tumour cells mechanoadapt to HG/HG-HO and whether phytochemical-based interference in these mechanisms can generate tumour-cell-selective vulnerability to cell death. Mannitol and L-glucose were used as hyper-osmotic equivalents of high glucose. The results revealed that the tumour cells can efficiently mechanoadapt to HG-HO only in the normoxic microenvironment. Under normoxic HG/HG-HO stress, tumour cells polySUMOylate a higher pool of mitotic driver pH3(Ser10), which translocates to the nucleus and promotes faster cell divisions. On the contrary, acute hypoxia dampens HG/HG-HO-associated excessive proliferation by upregulating sentrin protease SENP7. SENP7 promotes abnormal SUMOylation of pH3(Ser10), thereby restricting its nuclear entry and promoting the M-phase arrest and cell loss. However, the hypoxia-arrested cells that managed to survive showed relapse upon reversal to normoxia as well as upregulation of pro-survival-associated SENP1, and players in tumour growth signalling, autophagy, glycolytic pathways etc. Depletion of SENP1 in both normoxia and hypoxia caused significant loss of tumour cells vs undepleted controls. SENP1 was ascertained to restrict the abnormal SUMOylation of pH3(Ser10) in both normoxia and hypoxia, although not so efficiently in hypoxia, due to the opposing activity of SENP7. Co-treatment with Momordin Ic (MC), a natural SENP1 inhibitor, and Gallic Acid (GA), an inhibitor of identified major pro-tumourigenic signalling (both enriched in Momordica charantia), eliminated surviving tumour cells in normal glucose, HG and HG-HO normoxic and hypoxic microenvironments, suggesting that appropriate and enhanced polySUMOylation of pH3(Ser10) in response to HG/HG-HO stress was attenuated by this treatment along with further dampening of other key tumourigenic signalling, due to which tumour cells could no longer proliferate and grow.

Intestinal macrophages play a key role in the gut immune system and the regulation of gastrointestinal physiology, including gut motility and secretion. Their ability to keep the gut from chronic inflammation despite constantly facing foreign antigens has been an important focus in gastrointestinal research. However, the heterogeneity of intestinal macrophages has impeded our understanding of their specific roles. It is now becoming clear that subsets of intestinal macrophages play diverse roles in various gastrointestinal diseases. This occurs through a complex interplay between cytokine production and enteric nervous system activation that differs for each pathologic condition. Key diseases and disorders in which intestinal macrophages play a role include postoperative ileus, inflammatory bowel disease, necrotizing enterocolitis, as well as gastrointestinal disorders associated with human immunodeficiency virus and Parkinson’s disease. Here, we review the identification of intestinal macrophage subsets based on their origins and functions, how specific subsets regulate gut physiology, and the potential for these heterogeneous subpopulations to contribute to disease states. Furthermore, we outline the potential for these subpopulations to provide unique targets for the development of novel therapies for these disorders.

Women are more susceptible to functional bowel disorders than men and the severity of their symptoms such as diarrhea, constipation, abdominal pain and bloating changes over the menstrual cycle, suggesting a role for sex hormones in gastrointestinal function. Nitric oxide (NO) is a major inhibitory neurotransmitter in the gut and blockade of nitric oxide synthase (NOS; responsible for NO synthesis) increases colonic motility in male mice ex vivo. We assessed the effects of NOS inhibition on colonic motility in female mice using video imaging analysis of colonic motor complexes (CMCs). To understand interactions between NO and estrogen in the gut, we also quantified neuronal NOS and estrogen receptor alpha (ERα)-expressing myenteric neurons in estrus and proestrus female mice using immunofluorescence. Mice in estrus had fewer CMCs under control conditions (6 ± 1 per 15 min, n = 22) compared to proestrus (8 ± 1 per 15 min, n = 22, One-way ANOVA, p = 0.041). During proestrus, the NOS antagonist N-nitro-L-arginine (NOLA) increased CMC numbers compared to controls (189 ± 46%). In contrast, NOLA had no significant effect on CMC numbers during estrus. During estrus, we observed more NOS-expressing myenteric neurons (48 ± 2%) than during proestrus (39 ± 1%, n = 3, p = 0.035). Increased nuclear expression of ERα was observed in estrus which coincided with an altered motility response to NOLA in contrast with proestrus when ERα was largely cytoplasmic. In conclusion, we confirm a cyclic and sexually dimorphic effect of NOS activity in female mouse colon, which could be due to genomic effects of estrogens via ERα.

Nearly 2 decades since its discovery as one of the genes responsible for the Wolf-Hirschhorn Syndrome (WHS), the primary function of the leucine-zipper EF-hand containing transmembrane 1 (LETM1) protein in the inner mitochondrial membrane (IMM) or the mechanism by which it regulates mitochondrial Ca2+ handling is unresolved. Meanwhile, LETM1 has been associated with the regulation of fundamental cellular processes, such as development, cellular respiration and metabolism, and apoptosis. This mini-review summarizes the diversity of cellular functions impacted by LETM1 and highlights the multiple roles of LETM1 in health and disease.

Objectives: To determine the outcomes of chronically ventilated patients outside the setting of intensive care units. Design: Systematic review. Setting and participants: Studies evaluating patients on chronic invasive mechanical ventilation in different care settings. Methods: A systematic literature search of the PubMed, Embase, Cochrane Library, CINAHL (EBSCOhost), LILACS and Scopus databases from inception to March 27, 2020. Studies reporting mortality outcomes of patients ≥18 years of age on chronic invasive mechanical ventilation in intensive care units and other care settings were eligible for inclusion. Results: Sixty studies were included in the systematic review. Mortality rates ranged from 13.7% to 77.8% in ICUs (n = 17 studies), 7.8%–51.0% in non-ICUs including step-down units and inpatient wards (n = 26 studies), and 12.0%–91.8% in home or nursing home settings (n = 19 studies). Age was associated with mortality in all care settings. Weaning rates ranged from 10.0% to 78.2% across non-ICU studies. Studies reporting weaning as their primary outcome demonstrated higher success rates in weaning. Home care studies reported low incidences of ventilator failure. None of the studies reported ventilator malfunction as the primary cause of death. Conclusions and implications: Mortality outcomes across various settings were disparate due to methodological and clinical heterogeneity among studies. However, there is evidence to suggest non-ICU venues of care as a comparable alternative to ICUs for stable, chronically ventilated patients, with the additional benefit of providing specialized weaning programs. By synthesizing the global data on managing chronically ventilated patients in various care settings, this study provides health care systems and providers alternative venue options for the delivery of prolonged ventilatory care in the context of limited ICU resources.

Mitochondrial Ca2+ handling is accomplished by balancing Ca2+ uptake, primarily via the Ru360-sensitive mitochondrial calcium uniporter (MCU), Ca2+ buffering in the matrix and Ca2+ efflux mainly via Ca2+ ion exchangers, such as the Na+/Ca2+ exchanger (NCLX) and the Ca2+/H+ exchanger (CHE). The mechanism of CHE in cardiac mitochondria is not well-understood and its contribution to matrix Ca2+ regulation is thought to be negligible, despite higher expression of the putative CHE protein, LETM1, compared to hepatic mitochondria. In this study, Ca2+ efflux via the CHE was investigated in isolated rat cardiac mitochondria and permeabilized H9c2 cells. Mitochondria were exposed to (a) increasing matrix Ca2+ load via repetitive application of a finite CaCl2 bolus to the external medium and (b) change in the pH gradient across the inner mitochondrial membrane (IMM). Ca2+ efflux at different matrix Ca2+ loads was revealed by inhibiting Ca2+ uptake or reuptake with Ru360 after increasing number of CaCl2 boluses. In Na+-free experimental buffer and with Ca2+ uptake inhibited, the rate of Ca2+ efflux and steady-state free matrix Ca2+ [mCa2+]ss increased as the number of administered CaCl2 boluses increased. ADP and cyclosporine A (CsA), which are known to increase Ca2+ buffering while maintaining a constant [mCa2+]ss, decreased the rate of Ca2+ efflux via the CHE, with a significantly greater decrease in the presence of ADP. ADP also increased Ca2+ buffering rate and decreased [mCa2+]ss. A change in the pH of the external medium to a more acidic value from 7.15 to 6.8∼6.9 caused a twofold increase in the Ca2+ efflux rate, while an alkaline change in pH from 7.15 to 7.4∼7.5 did not change the Ca2+ efflux rate. In addition, CHE activation was associated with membrane depolarization. Targeted transient knockdown of LETM1 in permeabilized H9c2 cells modulated Ca2+ efflux. The results indicate that Ca2+ efflux via the CHE in cardiac mitochondria is modulated by acidic buffer pH and by total matrix Ca2+. A mechanism is proposed whereby activation of CHE is sensitive to changes in both the matrix Ca2+ buffering system and the matrix free Ca2+ concentration.

The intrinsic nervous system of the gut interacts with the gut-associated lymphoid tissue (GALT) via bidirectional neuroimmune interactions. The caecum is an understudied region of the gastrointestinal (GI) tract that houses a large supply of microbes and is involved in generating immune responses. The caecal patch is a lymphoid aggregate located within the caecum that regulates microbial content and immune responses. People with Autism Spectrum Disorder (ASD; autism) experience serious GI dysfunction, including inflammatory disorders, more frequently than the general population. Autism is a highly prevalent neurodevelopmental disorder defined by the presence of repetitive behavior or restricted interests, language impairment, and social deficits. Mutations in genes encoding synaptic adhesion proteins such as the R451C missense mutation in neuroligin-3 (NL3) are associated with autism and impair synaptic transmission. We previously reported that NL3R451C mice, a well-established model of autism, have altered enteric neurons and GI dysfunction; however, whether the autism-associated R451C mutation alters the caecal enteric nervous system and immune function is unknown. We assessed for gross anatomical changes in the caecum and quantified the proportions of caecal submucosal and myenteric neurons in wild-type and NL3R451C mice using immunofluorescence. In the caecal patch, we assessed total cellular density as well as the density and morphology of Iba-1 labeled macrophages to identify whether the R451C mutation affects neuro-immune interactions. NL3R451C mice have significantly reduced caecal weight compared to wild-type mice, irrespective of background strain. Caecal weight is also reduced in mice lacking Neuroligin-3. NL3R451C caecal ganglia contain more neurons overall and increased numbers of Nitric Oxide (NO) producing neurons (labeled by Nitric Oxide Synthase; NOS) per ganglion in both the submucosal and myenteric plexus. Overall caecal patch cell density was unchanged however NL3R451C mice have an increased density of Iba-1 labeled enteric macrophages. Macrophages in NL3R451C were smaller and more spherical in morphology. Here, we identify changes in both the nervous system and immune system caused by an autism-associated mutation in Nlgn3 encoding the postsynaptic cell adhesion protein, Neuroligin-3. These findings provide further insights into the potential modulation of neural and immune pathways.

Regulation of mitochondrial free Ca2+ is critically important for cellular homeostasis. An increase in mitochondrial matrix free Ca2+ concentration ([Ca2+]m) predisposes mitochondria to opening of the permeability transition pore (mPTP). Opening of the pore can be delayed by cyclosporin A (CsA), possibly by inhibiting cyclophilin D (Cyp D), a key regulator of mPTP. Here, we report on a novel mechanism by which CsA delays mPTP opening by enhanced sequestration of matrix free Ca2+. Cardiac-isolated mitochondria were challenged with repetitive CaCl2 boluses under Na+-free buffer conditions with and without CsA. CsA significantly delayed mPTP opening primarily by promoting matrix Ca2+ sequestration, leading to sustained basal [Ca2+]m levels for an extended period. The preservation of basal [Ca2+]m during the CaCl2 pulse challenge was associated with normalized NADH, matrix pH (pHm), and mitochondrial membrane potential (ΔΨm). Notably, we found that in PO43− (Pi)-free buffer condition, the CsA-mediated buffering of [Ca2+]m was abrogated, and mitochondrial bioenergetics variables were concurrently compromised. In the presence of CsA, addition of Pi just before pore opening in the Pi-depleted condition reinstated the Ca2+ buffering system and rescued mitochondria from mPTP opening. This study shows that CsA promotes Pi-dependent mitochondrial Ca2+ sequestration to delay mPTP opening and, concomitantly, maintains mitochondrial function.