Search Results (61)

The mitochondrial phosphate carrier (mPiC), encoded by the nuclear gene SLC25A3, is synthesized with an N-terminus mitochondrial targeting sequence (MTS), enabling its import into the mitochondria. mPiC imports inorganic phosphate (P_i) into the mitochondrial matrix for ATP production and other matrix phosphorylation reactions, as well as regulates mitochondrial Ca²⁺ uptake and buffering of matrix Ca²⁺. PiC also imports copper (Cu), crucial to COX subunit holoenzyme assembly. Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first year of life. We have developed a novel therapeutic approach using TAT-mPiC fusion protein for cellular delivery since the TAT peptide enables delivery of proteins across biological membranes. We designed, produced, and purified the TAT-mPiC fusion protein. The fusion protein is delivered into the mitochondria and localizes within the mIM, its natural cellular location, as a processed protein. Treatment of mPiC-knockdown cells with TAT-mPiC fusion protein increased cell growth and improved bioenergetic capabilities, as measured by oxygen consumption rate (OCR), ATP production, and reduction in lactate secretion. Most importantly, TAT-mPiC restored P_i and Cu delivery into the mitochondrial matrix. TAT-mPiC fusion protein also restored the mitochondrial activity of cells harboring various mitochondrial defects. This study presents the first successful delivery of a mitochondrial transmembrane carrier using the TAT-fusion system, offering a potential early treatment strategy for newborns with mPiC deficiency. Full article

Background: Most newly developed anticancer treatments trigger tumor cell death through apoptosis, for which involvement of caspases activity is essential. However, numerous mutations in apoptotic pathways that lead to cancer and favor resistance to apoptosis are known; most are related to caspase-dependent apoptosis pathways and thus have low efficacy. To overcome these limitations, we constructed a novel chimeric protein, GnRH-AIF, using a gonadotropin-releasing hormone (GnRH) analog as a targeting moiety and the apoptosis-inducing factor (AIF) in its cleaved form as a killing moiety, fused at the cDNA level. AIF has a crucial role in the caspase-independent apoptotic pathway. A wide variety of solid tumors overexpress GnRH-receptors (GnRH-R) that are targeted by the new GnRH-AIF chimeric protein. Methods and Results: In this study, we constructed, expressed, and highly purified GnRH-AIF chimeric proteins. We demonstrated the ability of the chimera to enter and specifically and very efficiently kill solid cancer cell lines overexpressing GnRH-R. Most importantly, upon its entry, GnRH-AIFs translocate to the nucleus where it causes DNA fragmentation leading to a direct caspase-independent apoptotic death. As AIFs lack nuclease activity, our findings also emphasize that cell death induced by GnRH-AIF is dependent on the presence of the ENDOG and PPIA proteins, known to participate in the formation of a DNA–degradosome complex. Finally, we demonstrated the high anti-tumor efficacy of the GnRH-AIF ex vivo, in a human, colon cancer organoid model. Conclusions: Our study shows the potential of using a GnRH-AIF chimeric protein as a novel approach to treat solid cancers that overexpress GnRH-R, via a caspase-independent apoptotic pathway. Full article

Background: In the 21st century, the management of groin hernias (GHs) has evolved from watchful waiting (WW) to robotic hernia repair (RHR). The present study interrogates the status of robotics in the context of current repairs and provides one author’s perspectives. Methods: A systematic review was undertaken using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for studies comparing open (OHR) to robotic hernia repair (RHR); RHR to laparoscopic hernia repair (LHR); or OHR vs. LHR vs. RHR. The historical context was extracted from previous reviews. Results: Fifty-four studies were included in the analysis. Three techniques have withstood the test of time: OHR (tissue and mesh repairs), laparo-endoscopic (TEP and TAPP), and RHR. The literature indicates that RHR is safe and effective for the management of groin hernias. Operative times and costs remain a concern when using this technique. While the number of overall complications with RHR is similar to OHR, in a minority of cases, complications are more consequential with the robotic platform. Conclusions: RHR has emerged as an unequivocally powerful technique for the management of GHs. OHR remains the technique of choice for local/regional anesthesia, posterior recurrences, and in centers that lack other platforms. In low- and middle-income countries, OHR is the most utilized technique. Centers of excellence should offer all techniques of repair including WW. Full article

Objectives: The aim of this study was to examine the adherence, changes in weight, and, waist circumference associated with the daily consumption of a culturally preferred food, namely an avocado, among Hispanic/Latina females in the Habitual Diet and Avocado Trial (HAT). Methods: HAT was a multisite, randomized controlled trial conducted between 2018 and 2020. Participants in the Avocado-Supplemented Diet Group were provided with and instructed to consume one avocado/day (~2.2 servings) for 6 months; participants in the Habitual Diet Group were instructed to follow their usual diet and limit intake to ≤2 avocados/month. Avocado consumption was assessed using three random 24 h dietary recalls administered by dietitians. This analysis focused on women who self-identified as Hispanic/Latina. Results: Within HAT, 158 females self-identified as Hispanic/Latina (median age: 42 years, IQR: 36–54). Across the dietary recalls, the Avocado-Supplemented Group (n = 80) consumed 1.9–2.1 avocado servings/day; the Habitual Diet Group (n = 78) consumed 0.04–0.09 servings/day (p < 0.001). The weight and waist circumference measurements were similar between groups. Hispanic/Latina females remained adherent to daily avocado consumption for the 6-month study period, without a significant change in their body weight or waist circumference measurements. Conclusions: Integrating a culturally preferred food into a dietary intervention enhanced adherence amongst Latina adults, with no impact significant impact on body composition. Full article

There have been increasing efforts to compute magnetic exchange coupling constants for transition metal complexes and magnetic insulators using the magnetic force theorem and Green’s function-based linear response methods. These were originally conceived for magnetic metals, yet it has not been clear how these methods fare conceptually with the conventional models based on electron-correlation interactions among so-called magnetic orbitals. We present a spinor-based theoretical analysis pertinent to the magnetic force theorem and linear response theory using Brillouin–Wigner perturbation method and Green’s function perturbation method, and we shed light on the conceptual nature of the Lichtenstein formula in its applications for calculations of the total energy and magnetic exchange coupling constants for both molecules and solids. Derivation of the magnetic force theorem in this perturbational analysis identifies the first-order energy correction terms, which are considered as the ferromagnetic component for the magnetic exchange interactions of transition metal compounds but are not included in the Lichtenstein formula. Detailed perturbational analysis of the energy components involved in the magnetic force theorem identifies the energy components that are missing in the Lichtenstein formula but are critical in the Anderson’s model for transition metal complexes and magnetic insulators where magnetic orbitals can overlap. Full article

Background: The Lichtenstein open anterior approach with static flat meshes, the most popular inguinal hernia repair technique, has raised concerns regarding mesh fixation, defect patency, and poor quality biological response. To address these issues, the 3D dynamic ProFlor scaffold promoting a fixation-free hernia defect obliteration has been developed as an alternative. Methods: The results of open inguinal hernia repair with the ProFlor approach compared with those of the Lichtenstein repair were evaluated. Results: In a time frame of 24 months, two cohorts of patients were enrolled, 95 in the ProFlor group and 93 in the Lichtenstein group. ProFlor demonstrated superior outcomes compared to the Lichtenstein technique, with shorter procedure times, decreased intraoperative complications, and lower rates of postoperative complications. Additionally, ProFlor provided enhanced postoperative pain relief, a faster return to daily activities, and no long-term discomfort. No chronic pain was reported in the ProFlor group and 11.8% reported chronic pain in the Lichtenstein group. Conclusions: The results highlight the need to reevaluate the conventional Lichtenstein approach and align it with recent scientific progress. Further consideration of the evolving understanding of inguinal pathophysiology and groin protrusion genesis is crucial for advancing surgical techniques. Full article

The Lichtenstein procedure is one of the most performed surgeries worldwide. However, proper examination to exclude a femoral hernia is often not performed, resulting in a high number of missed hernias. For patients in whom a femoral hernia is suspected pre- or intraoperatively, we describe a novel surgical technique of a femoral extension to the classic Lichtenstein repair. We aim to investigate its safety and clinical outcome. Methods: The femoral–extended Lichtenstein is applied when a femoral hernia is suspected. The fascia transversalis is opened, the lacunar ligament incised, and the hernia reduced. A self-gripping mesh covers the femoral orifice equally on all sides. In a prospective single-center study, we compared 50 consecutive femoral–extended to 50 classic Lichtenstein repairs, evaluating operative time, patient-reported pain (intensity, duration), and recurrence. Results: The technique seems feasible and safe. Apart from 3 min additional surgical time, no difference in pain scoring or hernia recurrence was observed between both groups. Conclusions: We successfully introduced a femoral-extended Lichtenstein repair for patients with suspected femoral herniation. Full article

Skeletal muscle regeneration after injury is a complex process involving inflammatory signaling and myoblast activation. Pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) are key mediators, but their effects on gene expression in proliferating myoblasts are unclear. We performed the RNA sequencing of TNF-α treated C2C12 myoblasts to elucidate the signaling pathways and gene networks regulated by TNF-α during myoblast proliferation. The TNF-α (10 ng/mL) treatment of C2C12 cells led to 958 differentially expressed genes compared to the controls. Pathway analysis revealed significant regulation of TNF-α signaling, along with the chemokine and IL-17 pathways. Key upregulated genes included cytokines (e.g., IL-6), chemokines (e.g., CCL7), and matrix metalloproteinases (MMPs). TNF-α increased myogenic factor 5 (Myf5) but decreased MyoD protein levels and stimulated the release of MMP-9, MMP-10, and MMP-13. TNF-α also upregulates versican and myostatin mRNA. Overall, our study demonstrates the TNF-α modulation of distinct gene expression patterns and signaling pathways that likely contribute to enhanced myoblast proliferation while suppressing premature differentiation after muscle injury. Elucidating the mechanisms involved in skeletal muscle regeneration can aid in the development of regeneration-enhancing therapeutics. Full article

Inguinal hernia repair represents one of the most frequent pathologies with surgical addressability. From the multitude of surgical procedures, a limited number still keep their indication in the current treatment of hernias. Open surgery, the exclusive repair method until recently, is associated with laparoscopic techniques with benefits that are at least superposable on those in open repair. We conducted a study, analyzing several types of procedures in open surgery and comparing them to each other, but also with the TAPP approach, which is still at the beginning in our service. The non-mesh procedures scored poorly in terms of recurrence, the duration of the surgical intervention, and complications of the pain type, the Lichtenstein procedure was frequently associated with non-infectious inflammatory complications, and the TAPP, which is still in the learning curve, presented a prolonged duration of the surgical intervention. The Lichtenstein procedure maintains its usefulness and represents the most frequent technique for sanctioning inguinal hernia, the non-mesh processes, less used lately, are more frequently preferred in situations where hernia strangulation is associated with a septic complication. Open surgery hernia repair remains a feasible option in the era of minimal invasiveness, especially under the conditions of performing a tension-free technique, for specific categories of patients or surgical services remaining the first intention solution. Full article

Vaccines are pivotal for control of the coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBDs) treated with antitumor necrosis factor (TNF)-α have lower serologic response after two COVID-19 vaccine doses. Data regarding a third vaccine dose are scarce. An Israeli multicenter prospective observational study recruited 319 subjects: 220 with IBD (79 treated with anti-TNFα) and 99 healthy control (HC) participants. All patients received two mRNA-BNT162b2 vaccines (Pfizer/BioNTech), 80% of whom received a third vaccine dose. Evaluation included disease activity, anti-spike (S) and nucleocapsid (N) antibody levels, anti-TNFα drug levels, and adverse events (AEs). All participants showed significant serologic response one month after receiving a third dose. However, three months later, the anti-S levels decreased significantly in patients treated with anti-TNFα compared with the non-anti-TNFα and HC groups. A correlation between serologic response to the third vaccine dose and anti-TNF drug levels was not found. No significant AE or IBD exacerbation was observed. Importantly, lower serologic response after the third vaccine dose predicted infection. A third dose of BNT162b2 is effective and safe in patients with IBD. Lower serologic response predicted infection, even in seropositive subjects. Lower serologic responses and their rapid decline suggest a fourth vaccine dose in this patient population. Full article

The Atlantic Goliath Grouper Epinephelus itajara (Lichtenstein, 1822) occurs on both sides of the Atlantic, from the Carolinas (USA) to Brazil in the western Atlantic and historically from North Senegal to North Angola off of West Africa in the eastern Atlantic. While there are relatively good data on their distribution in the western Atlantic, confirmed occurrences, population status, fishing reports, and trade data are almost non-existent for West Africa. Part of the problem is that tropical West African countries largely lack the wherewithal to fund the research needed to evaluate this species, nor do they have laws, management plans, or viable enforcement measures that might lead to effective population recovery or protection for essential juvenile mangrove habitats. Given the lack of published studies on this species in West Africa, the primary objectives of this paper are (1) to describe all known historical and current anecdotal information available on this species and (2) to encourage the increased monitoring of habitats where viable populations might still occur (i.e., mangroves, oil rigs, and oil platforms). Full article

Objective: To investigate whether cognitive inflexibility could be identified using the Wisconsin Card Sorting Test (WCST) in patients with severe and extreme anorexia nervosa (AN) compared to healthy control participants (HCs). Method: We used the WCST to assess 34 patients with AN (mean age: 25.9 years, mean body mass index (BMI): 13.2 kg/m²) 3–7 days after admission to a specialized nutrition unit and 34 HCs. The Beck Depression Inventory II and the Eating Disorder Inventory 3 were distributed. Results: The patients displayed more perseveration than HCs controlled for age and years of education, with moderate effect sizes (perseverative responses (%): adjusted difference = −7.74, 95% CI: −14.29–(−1.20), p-value: 0.021; perseverative errors (%): adjusted difference = −6.01, 95% CI: −11.06–(−0.96), p-value: 0.020). There were no significant relationships between perseveration and depression, eating disorder symptoms, illness duration, or BMI. Discussion: Patients with severe and extreme AN demonstrated lower cognitive flexibility compared to HCs. Performance was not related to psychopathology or BMI. Patients with severe and extreme anorexia nervosa may not differ from less severe patients in cognitive flexibility performance. As this study exclusively focused on patients suffering from severe and extreme AN, potential correlations might be masked by a floor effect. Full article

Dual localization or dual targeting refers to the phenomenon by which identical, or almost identical, proteins are localized to two (or more) separate compartments of the cell. From previous work in the field, we had estimated that a third of the mitochondrial proteome is dual-targeted to extra-mitochondrial locations and suggested that this abundant dual targeting presents an evolutionary advantage. Here, we set out to study how many additional proteins whose main activity is outside mitochondria are also localized, albeit at low levels, to mitochondria (eclipsed). To do this, we employed two complementary approaches utilizing the α-complementation assay in yeast to uncover the extent of such an eclipsed distribution: one systematic and unbiased and the other based on mitochondrial targeting signal (MTS) predictions. Using these approaches, we suggest 280 new eclipsed distributed protein candidates. Interestingly, these proteins are enriched for distinctive properties compared to their exclusively mitochondrial-targeted counterparts. We focus on one unexpected eclipsed protein family of the Triose-phosphate DeHydrogenases (TDH) and prove that, indeed, their eclipsed distribution in mitochondria is important for mitochondrial activity. Our work provides a paradigm of deliberate eclipsed mitochondrial localization, targeting and function, and should expand our understanding of mitochondrial function in health and disease. Full article

Objective: The main characteristics of Anorexia Nervosa (AN) in adults are restriction of energy intake relative to requirements leading to significant weight loss, disturbed body image, and intense fear of becoming fat. Traumatic experiences (TE) have been reported as common, although less is known about the relationship with other symptoms in severe AN. We investigated the presence of TE, PTSD, and the relation between TE, eating disorder (ED) symptoms, and other symptoms in moderate to severe AN (n = 97) at admission to inpatient weight-restoration treatment. All patients were enrolled in the Prospective Longitudinal all-comer inclusion study on Eating Disorders (PROLED). Methods: TE were assessed using the Post-traumatic stress disorder checklist, Civilian version (PCL-C), and ED symptoms using the Eating Disorder Examination Questionnaire (EDE-Q); depressive symptoms were assessed using the Major Depression Inventory (MDI), and the presence of Post-traumatic Stress Disorder (PTSD) was diagnosed according to ICD-10 criteria. Results: The mean score on PCL-C was high (mean 44.6 SD 14.7), with 51% having a PCL-C score at or above 44 (n = 49, suggested cut-off for PTSD), although only one individual was clinically diagnosed with PTSD. There was a positive correlation between baseline scores of PCL-C and EDE-Q-global score (r = 0.43; p < 0.01) as well as of PCL-C and all EDE-Q subscores. None of the included patients were admitted for treatment of TE/PTSD during the first 8 weeks of treatment. Conclusions: In a group of patients with moderate to severe AN, TE were common, and scores were high, although only one had a diagnosis of PTSD. TE were related to ED symptoms at baseline, but this association diminished during the weight restoration treatment. Full article