In Caenorhabditis elegans, ablation of germline stem cells leads to extended lifespan and increased fat storage. Here the authors show that disrupting distinct gametogenesis programs and germline progression in C. elegans triggers molecular responses that affect fat metabolism, stress resilience, and lifespan.
This issue’s cover features work by Adrian M. Seifert & team on Nectin-4’s connection to poor outcome and immune suppression in patients with PDAC, and targeting Nectin-4 with the antibody-drug conjugate enfortumab vedotin inhibited tumor growth in PDAC organoids:
The cover image shows high Nectin-4 immunohistochemistry staining (brown) in human PDAC.
1Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
2National Center for Tumor Diseases (NCT), Dresden, Germany.
3German Cancer Research Center (DKFZ), Heidelberg, Germany.
Deep neural networks (DNNs) have become a cornerstone of modern AI technology, driving a thriving field of research in image-related tasks. These systems have found applications in medical diagnosis, automated data processing, computer vision, and various forms of industrial automation, to name a few.
As reliance on AI models grows, so does the need to test them thoroughly using adversarial examples. Simply put, adversarial examples are images that have been strategically modified with noise to trick an AI into making a mistake. Understanding adversarial image generation techniques is essential for identifying vulnerabilities in DNNs and for developing more secure, reliable systems.
They’ve been promising eternal youth since the first snake-oil salesman bottled spring water. Now a Chinese biotech startup says it might actually have the chemistry right. Lonvi Biosciences claims its new pill could stretch human life to 150 years.
The Shenzhen-based company, backed by China’s booming longevity sector, says it has developed a pill that could theoretically extend human life to 150 years. The company’s formula targets so-called “zombie cells”—aging cells that refuse to die, triggering inflammation and age-related disease. “This is not just another pill. This is the Holy Grail,” said CEO Ip Zhu, describing the capsule as a breakthrough that could make extreme longevity a reality.
The drug’s key ingredient, procyanidin C1 (PCC1), is derived from grape seeds and has shown lifespan extension in lab animals. In Lonvi’s own mouse trials, the treatment reportedly increased overall lifespan by 9.4 percent and extended life by 64 percent from the first day of treatment. “Living to 150 is definitely realistic,” said Chief Technology Officer Lyu Qinghua in an interview with The New York Times. “In a few years, this will be the reality.”
Fungal infections kill millions of people each year, and modern medicine is struggling to keep up. But researchers at McMaster University have identified a molecule that may help turn the tide—butyrolactolA, a chemical compound that targets a deadly, disease-causing fungi called Cryptococcus neoformans.
Infections caused by Cryptococcus are extremely dangerous. The pathogen, which can cause pneumonia-like symptoms, is notoriously drug-resistant, and it often preys on people with weakened immune systems, like cancer patients or those living with HIV. And the same can be said about other fungal pathogens, like Candida auris or Aspergillus fumigatus—both of which, like Cryptococcus, have been declared priority pathogens by the World Health Organization.
Despite the threat, though, doctors have only three treatment options for fungal infections.
Northwestern Medicine scientists have zeroed in on a cellular gatekeeper that may hold promise for treating abnormal protein accumulation in neurodegenerative diseases, according to a study published in Nature Communications. “In all neurodegenerative diseases, there is an accumulation of misfolded proteins,” said Robert Kalb, MD, the Joan and Paul Rubschlager Professor, chief of Neuromuscular Disease in the Ken and Ruth Davee Department of Neurology, and director of the Les Turner ALS Center, who was senior author of the study.
“We think that these misfolded proteins are a target for disease—the disease is actually driven by the accumulation of these misfolded proteins.”
In the current study, Kalb and his collaborators aimed to investigate the role of RAD23, a protein that is involved in the identification and disposal of damaged or misfolded proteins. Under normal circumstances, elimination of misfolded proteins is essential for maintaining a healthy collection of proteins in cells, a process known as protein homeostasis, or proteostasis.
Clinically suspected neurodegeneration in histiocytic neoplasms as causes of neurologic decline: a retrospective study.
ObjectivesThe aim of this study was to evaluate the causes of suspected neurodegeneration in adults with histiocytic neoplasms. MethodsPatients with histiocytic neoplasms were identified. Inclusion criteria were diagnosis of histiocytic neoplasm; the treating hematologist suspected neurodegeneration; and patients age 18 years or older. Active CNS histiocytic neoplasm was defined as new or enlarging T2 lesions, or gadolinium enhancing lesions on MRI.
To identify the critical mitochondrial protease regulating HSPC homeostasis, we performed real-time PCR to examine the expression levels of various mitochondrial proteases in EPCR+SLAM-HSCs from mouse bone marrow (BM). Among them, the m-AAA protease Afg3l2 was the most highly expressed (Figure S1 A),18 suggesting its potential significance in HSC regulation. Furthermore, we conducted a comprehensive analysis of Afg3l2 expression across the hematopoietic hierarchy by examining EPCR+ SLAM-HSCs, SLAM-LT-HSCs, SLAM-ST-HSCs, SLAM-MPPs (multipotent progenitors), LSK (Lin-Sca-1+c-Kit+) cells, Lin− cells, and mature blood cells (B cells, T cells, and myeloid cells). Our results demonstrate that Afg3l2 expression is highest in the most primitive EPCR+SLAM-HSC population and gradually decreases with differentiation, supporting its crucial role in hematopoietic stem cells (HSCs) (Figure S1 B). Afg3l2 dysfunction has been linked to neurodegenerative disorders such as spinocerebellar ataxia19,20,21; however, its role in hematopoietic cells and its broader metabolic implications remain unexplored. To systemically investigate the function of Afg3l2 in HSPCs, we generated a conditional knockout (KO) allele of the Afg3l2 gene (Afg3l2f/+), in which exons 4 and 5 were flanked by loxP sites (Figure S1 C). Afg3l2f/+ mice were then crossed with Mx1-Cre transgenic mice to obtain Afg3l2f/f;Mx1-Cre+ animals. Deletion of Afg3l2 in hematopoietic cells was induced by administering polyinosinic-polycytidylic acid (pIpC) to 6-to 8-week-old mice, and KO efficiency was confirmed by real-time PCR and western blot analysis (Figures S1 D–S1G). On day 14 after the final pIpC administration, complete blood count analysis revealed a significant reduction in white blood cell, lymphoid cell, and platelet counts in Afg3l2f/f mice (wild-type [WT]) compared to Afg3l2f/f;Mx1-Cre+ mice (KO) (Figures S1 H–S1J). Interestingly, red blood cell counts and hemoglobin levels remained comparable between WT and KO groups (Figures S1 K and S1L). Flow cytometry analysis of BM revealed a significant reduction in multiple hematopoietic populations in Afg3l2-KO mice, including LT-HSCs, ST-HSCs, MPPs, common myeloid progenitors, granulocytic/monocytic progenitors, and megakaryocyte/erythroid progenitors (Figures S1 M–S1P). Notably, the EPCR+SLAM-HSC population, a highly purified HSC subset, was also remarkably diminished (Figure S1 Q).
Consistently, functional colony-forming unit (CFU) assays showed that CFU-granulocyte, erythrocyte, macrophage, megakaryocyte (CFU-GEMM); CFU-granulocyte and macrophage (CFU-GM); and burst-forming unit-erythroid (BFU-E) were markedly decreased in Afg3l2-KO BM cells (Figures S1 R and S1S). These findings indicate that Afg3l2 deficiency causes leukopenia and impairs steady-state hematopoiesis.
To assess the in vivo function of Afg3l2 in HSPCs, we performed competitive BM transplantation. Lethally irradiated recipient mice (CD45.1) were transplanted with a 1:1 mixture of total BM cells from WT or Afg3l2-KO donor mice (CD45.2) and competitor BM cells (CD45.1/CD45.2) (Figure 1A). CD45 chimerism in peripheral blood (PB) was monitored every four weeks, and BM composition was analyzed 16 weeks post-transplantation. The percentage of donor-derived CD45.2+ cells in PB was significantly lower in recipients receiving Afg3l2-KO BM compared to those transplanted with WT BM (Figures 1B and 1C). The percentage of donor BM cells-derived CD45.2+ cells, HPCs, Lin−Sca-1+c-Kit+ (LSK) cells, HSCs, myeloid cells, B cells, and T cells was dramatically decreased in the BM of the Afg3l2-KO cell transplanted group 16 weeks after transplantation (Figures 1D and 1E).
