<![CDATA[Estrogen shapes schizophrenia in women: onset peaks, dosing shifts, and relapse risk from periods to pregnancy, postpartum, and menopause.]]>
Scaling Stem-Cell Manufacturing for Therapies
Human pluripotent stem cells (hPSCs) have long been viewed as one of regenerative medicine’s most promising raw materials. Now, as more than 100 clinical trials evaluate hPSC-derived therapies for diseases ranging from Parkinson’s disease to heart failure and type 1 diabetes, attention is turning toward a crucial challenge: how to manufacture these cells reliably and economically at industrial scale.
According to Kevin Cyrys and Robert Zweigerdt, PhD, both of Hannover Medical School in Germany, the field has entered a new phase. Rather than simply demonstrating that stem cells can be grown in bioreactors, researchers are increasingly focused on creating robust production platforms that can deliver consistent quality across facilities and patient populations.
“Human pluripotent stem cells can serve as an unlimited, renewable ‘raw material’ for essentially any therapeutic cell product,” the authors wrote, highlighting the technology’s potential to overcome limitations associated with donor-derived tissues and organs.
The manufacturing challenge is substantial. While some therapies, such as treatments for age-related macular degeneration, require only tens of thousands of cells per dose, others may demand billions of cells for a single patient treatment. Conventional laboratory-scale methods are unlikely to meet such requirements efficiently.
To address this gap, developers are increasingly adopting three-dimensional suspension cultures in bioreactors. Compared with traditional two-dimensional cell culture systems, bioreactors provide tighter control over temperature, oxygen levels, pH, and carbon dioxide while supporting automated, closed-system manufacturing compatible with good manufacturing practice (GMP) standards.
The field has already demonstrated notable progress across multiple therapeutic areas. Researchers have developed scalable processes for producing cardiomyocytes, pancreatic islet cells, hepatocyte-like cells, neural tissues, and immune effectors derived from hPSCs. Some cardiac manufacturing platforms have reported production of billions of cardiomyocytes in liter-scale bioreactors, while immune-cell manufacturing programs have successfully expanded induced pluripotent stem cell-derived natural killer cells in 1–10 L systems while maintaining product quality.
Yet scaling production involves more than increasing cell yields. “Industrial-scale success depends on more than headline totals,” Cyrys and Zweigerdt note, citing the importance of volumetric productivity, production time, reproducibility, and integration of expansion, differentiation, and downstream processing into a coherent GMP-ready workflow.
Looking ahead, Cyrys and Zweigerdt argue that the next generation of stem-cell manufacturing will be defined by data-driven process control. They predict that AI-enabled systems will help move the industry from retrospective quality analysis toward real-time decision support, ultimately improving comparability between batches and strengthening product definitions across manufacturing networks.
Despite ongoing challenges involving cost, quality control, and regulatory compliance, the authors conclude that stem-cell bioprocessing has already crossed an important threshold. Scalable culture systems are no longer the primary obstacle. Instead, the focus has shifted toward engineering reliable industrial processes capable of transforming complex stem-cell biology into reproducible therapeutic products.
The post Scaling Stem-Cell Manufacturing for Therapies appeared first on GEN – Genetic Engineering and Biotechnology News.
Pramipexole vs Placebo Treatment in Bipolar Disorder With Anhedonic Depression
Conditions: Bipolar Disorder (BD)
Interventions: Drug: Pramipexole
Sponsors: Daniel Lindqvist
Not yet recruiting
Interventions: Drug: Pramipexole
Sponsors: Daniel Lindqvist
Not yet recruiting
Local brain connectome parameters across the spectrum of clinical cognitive decline
Neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and autism disrupt the brain’s structural and functional organization, particularly in specific regions, and ultimately lead to cognitive impairments. In Alzheimer’s disease-related dementia, neuronal degeneration impairs structural connectivity between brain regions, which in turn leads to functional breakdowns. This phenomenon, referred to as disconnection syndrome, manifests as connectivity breakdowns in affected regions, with these localized changes indirectly influencing the entire brain network. As the disease progresses, patterns consistent with compensatory-type reorganization have been described in the literature, accompanied by structural and functional changes that have been hypothesized to transiently mitigate cognitive decline during early stages. This study examines the structural and functional reorganization of the brain across the clinical spectrum of Alzheimer’s disease by analyzing local nodal changes using measures such as degree, strength, clustering coefficient, and betweenness centrality. Our findings show that early-stage nodal patterns are consistent with this hypothesized reorganization, whereas later-stage changes are dominated by progressive structural decline alongside persistent functional reorganization. Because the present study is cross-sectional and group-level, the compensatory interpretation should be regarded as a working hypothesis rather than a confirmed mechanism, and these exploratory patterns require validation in independent and longitudinal cohorts before clinical translation.
Pakistan’s Massive Genetic Database Reveals Millions of Unique Variants
The Pakistan Genome Resource (PGR), one of the largest genomic studies ever conducted in South Asia, has revealed novel insights into gene function, disease susceptibility, and the translatability of preclinical findings to humans. Published in a Nature article, a collaboration between Novartis, Columbia University Irving Medical Center, and the Center for Non-Communicable Diseases, Karachi, Pakistan, examined 173,303 PGR participants, constituting 0.07% of the population of Pakistan, the fifth most populous country in the world.
The numbers alone are impressive, as the scientists identified more than 6.6 million coding genetic variants, with nearly half of them absent from existing global databases. But the PGR is particularly powerful not just because of its size but also because of the unique genetic structure of the population being studied with high levels of familial relatedness.
The study identified naturally occurring homozygous loss-of-function (LoF) variants in 6,476 genes, about one-third of all human protein-coding genes. The researchers confirmed several well-known genetic associations. For example, individuals carrying LoF variants in the APOC3 gene had significantly lower triglyceride levels, while variants in PCSK9 were linked to lower LDL cholesterol. While both genes are already important targets in cardiovascular medicine, the findings shore up the dataset’s credibility.
New links between genes and biological traits provide clues about conditions ranging from obesity and diabetes to liver disease and neurodegeneration. In one striking example, individuals lacking a functional version of the gene CIDEB, which has become a major target in metabolic research because rare mutations that inactivate the gene provide significant protection against liver diseases, appeared to have a lower risk of liver disease, strengthening the case for therapies that target this pathway.
Some findings provided new context to genes already being widely studied, such as LRRK2—a gene currently targeted by experimental Parkinson’s disease treatments. LoF mutations in LRRK2 showed signs of kidney dysfunction. It’s an observation that raises important safety questions and highlights why human genetic studies matter so much. Sometimes biology sends a warning before a drug reaches the market.
The research also challenged assumptions based on animal studies. A gene called PRDM9 is considered essential for fertility in mice. Yet several people in the PGR with completely inactive copies of the gene had healthy children.
Ultimately, the Pakistan Genome Resource is much more than a national database. It’s a reminder that human genetic diversity remains vastly underexplored. By studying populations that have historically been overlooked, researchers are uncovering entirely new biology that could lead to better treatments, safer drugs, and a more profound understanding of what makes us human.
The post Pakistan’s Massive Genetic Database Reveals Millions of Unique Variants appeared first on Inside Precision Medicine.
Transcranial magnetic stimulation and motor overflow: a systematic review in neurological disorders
Motor overflow, a neuromotor phenomenon characterized by involuntary activation of muscles during voluntary movement, reflects impairments in interhemispheric and intracortical inhibition and is commonly observed in conditions such as stroke, cerebral palsy, dystonia, and Parkinson’s disease. Transcranial Magnetic Stimulation (TMS) is a non-invasive neuromodulatory technique with potential to modulate the cortical excitability underlying overflow-related dysfunctions. This systematic review aimed to evaluate the efficacy of TMS in reducing motor overflow across neurological populations. Seven randomized controlled trials (RCTs) were included, encompassing participants with stroke, cerebral palsy, Parkinson’s disease, and focal hand dystonia. Protocols varied in frequency (1–10 Hz), target area (M1, SMA, PSC, PMC), and design (e.g., crossover, combined protocols with constraint-induced therapy or cerebellar stimulation; Motor overflow was directly assessed in only two studies, one involving Parkinson’s disease and one involving dystonia, thereby limiting cross-study comparisons. Therefore, evidence supporting a direct effect of TMS on motor overflow remains preliminary and condition-specific. In dystonia, high-frequency rTMS (10 Hz) targeting the primary somatosensory cortex led to significant reductions in overflow, demonstrated by handwriting kinematics. In Parkinson’s disease, although physiological modulation (reduced IHI) was observed after SMA stimulation, mirror movements remained unchanged. In stroke and cerebral palsy populations, overflow was not directly evaluated, though improvements in motor function, spasticity, and cortical excitability were consistently reported. Risk of bias was low in most included studies, although gaps in allocation reporting and standardization of outcome measures were noted. This review highlights the potential of TMS, particularly high-frequency protocols, to modulate motor overflow in focal dystonia. However, the lack of targeted assessment in other neurological conditions suggests a critical need for future trials with standardized protocols and specific outcome measures focused on overflow to clarify the therapeutic role of TMS in rehabilitation.
Neuroprotective effects of paederoside against mitochondrial dysfunction in rotenone-induced cell models of Parkinson’s disease
IntroductionParkinson’s disease (PD) is the second most prevalent neurodegenerative disorder and is one of the leading causes of neurological disability. Although there are currently no cures or treatments for this disease, many patients with PD may therapeutically benefit from preventing or mitigating mitochondrial dysfunction. This study aimed to investigate the protective effects of paederoside against rotenone-induced neuronal damage in Neuro-2A (N2A) cell models of PD.MethodsFirst, the cytotoxic effects of rotenone on N2A cells were assessed using the cell counting kit-8 assay to establish a cell model of PD. Second, the effects of paederoside on mitochondrial complex I activity, mitochondrial swelling, and caspase-3 activity in the rotenone-induced cellular model were investigated. Finally, the impact of paederoside on tyrosine hydroxylase-positive cells in a rotenone-induced co-culture of N2A cells and BV-2 cells (N2A/BV-2) was studied.ResultsN2A cells were significantly damaged by rotenone in a time- and concentration-dependent manner; a 48 h rotenone treatment at 20 nM was used to create a cell model of PD. Pretreatment with 1 μM paederoside notably increased mitochondrial complex I activity in N2A cells with rotenone-induced impairment, leading to 42.85% increase. Additionally, pretreatment with 0.1, 1, and 10 μM paederoside considerably alleviated rotenone-induced mitochondrial swelling as indicated by the optical density (OD) (10 min)/OD(0 min) ratio, which increased by 1.21-, 1.33-, and 1.37-fold, respectively. Notably, pretreatment with 10 μM paederoside significantly inhibited caspase-3 activation triggered by rotenone in this cellular setting, resulting in a 39.93% decrease in enzyme activity. Moreover, pretreatment with 10 μM of paederoside markedly enhanced the number of TH-positive cells in a co-culture system consisting of N2A/BV-2 cells induced by rotenone, with increases of 82.79%.ConclusionPretreatment with paederoside may protect against mitochondrial dysfunction in cell models of PD induced by rotenone.
Alcohol and cannabis use severity in relation to compulsive sexual behavior and problematic pornography use in a non-clinical sample: a cross-sectional study
IntroductionCompulsive Sexual Behavior Disorder (CSBD) and problematic pornography use (PPU) frequently co-occur with substance use disorders, yet their associations with specific substances in non-clinical populations remain poorly understood. The present study examined associations between alcohol and cannabis use severity and CSBD and PPU symptoms in a non-clinical adult sample.MethodsEligible adults were invited to complete an anonymous online survey between May and October 2025. Alcohol and cannabis use severity scores were assessed using AUDIT and CUDIT-R questionnaires, respectively. Participants compulsive sexual behavior disorders (CSBD) and problematic pornography use (PPU) scores were assessed using CSBI-13 and BPS questionnaires. Associations between substance use severity and compulsive sexual behaviors were assessed using linear adjusted regression.ResultsA total of 158 adults (61.4% women) aged 18–60 years were analysed with a mean alcohol and cannabis use severity scores of 16.29 (± 4.53) and 15.49 (± 5.08), respectively among current users, and a mean compulsive sexual behavior disorders of 21.14 (± 7.74), with a mean PPU score of 6.99 (± 2.55). In unadjusted regression models, increases in alcohol and cannabis use severity were associated with increases in CSBD and PPU scores. However, no significant increase of both outcomes was observed for alcohol use severity (CSBD: B = 0.18, 95% CI [-0.13; 0.49], p = .251; PPU: B = 0.04, 95% CI [-0.05; 0.13], p = .381) and cannabis use severity (CSBD: B = 0.09, 95% CI [-0.13; 0.31], p = .409; PPU: B = 0.03, 95% CI [-0.03; 0.09], p = .325) after controlling for age and gender.ConclusionOur study showed a positive but non-significant association between alcohol and cannabis use severity with both CSBD and PPU after controlling for age and gender, suggesting the underlying associations may be explained by sociodemographic differences in the study population. However, longitudinal studies and advanced analysis approaches including those that handle zero inflated data or latent dependant variable are needed to validate these findings.
Early biopsychological changes during masculinizing gender-affirming hormone therapy in AFAB transgender individuals: a 4-month prospective study
ObjectiveTransgender individuals frequently experience elevated levels of psychological distress, including anxiety and trauma-related symptoms. Gender-affirming hormone therapy (GAHT) has been associated with improvements in mental health and quality of life; however, early biopsychological changes occurring during the initial phase of masculinizing hormone therapy remain insufficiently understood. The present exploratory longitudinal study investigated early endocrine and psychological changes in transgender individuals assigned female at birth undergoing masculinizing GAHT.MethodsWe conducted a 4-month prospective observational study involving 30 transgender individuals assigned female at birth initiating masculinizing GAHT. Participants were assessed at baseline (prior to treatment initiation), after 2 months, and after 4 months of therapy. Hormonal parameters (estradiol, testosterone, prolactin) and psychological measures including anxiety (HAM-A), trauma-related symptoms (TSC-40), and quality of life (MANSA) were evaluated. Due to the exploratory character of the study and the relatively small sample size, analyses were performed primarily using non-parametric statistical methods, including repeated-measures analyses.ResultsDuring follow-up, expected endocrine changes were observed, including decreased estradiol levels and increased testosterone concentrations. These changes were accompanied by reductions in anxiety and trauma-related symptoms and by improvements in quality of life measures over time. Repeated-measures analyses demonstrated significant longitudinal improvements in psychological outcomes across follow-up assessments (p < 0.05). Exploratory associations between hormonal and psychological variables appeared more pronounced after 4 months of treatment, particularly for estradiol in relation to anxiety and quality of life. Earlier assessments demonstrated weaker and less consistent associations. Psychological improvements were not directly proportional to the magnitude of hormonal changes alone, suggesting that psychosocial and treatment-related factors may also contribute to early adaptation during GAHT.ConclusionEarly masculinizing GAHT in transgender individuals assigned female at birth was associated with favorable endocrine and psychological changes during the first 4 months of treatment. The findings support a complex and potentially time-dependent relationship between hormonal alterations and psychological adaptation during early transition. Given the exploratory nature and limited sample size of the present study, further longitudinal research with larger cohorts and comparison groups is needed to clarify the underlying biopsychological mechanisms of GAHT.
Mini Brains Help Identify Treatment for Rare Form Parkinson’s Disease
Brain organoids created in the lab using patient cells have allowed researchers based at the Wilhelmina Children’s Hospital in Utrecht to find out more about the progression of an ultra-rare type of childhood Parkinson’s disease.
Notably, as reported at the European Society of Human Genetics meeting in Gothenburg this week, the study also identified that an affordable and readily available form of vitamin B3 could help improve symptoms in these children.
Irena Muffels, MD, PhD, a clinical genetics resident at the Wilhemina Children’s Hospital, was working at the Icahn School of Medicine at Mount Sinai, New York, when the study began. Two parents contacted the lab where she was working to ask if they could look into the condition their children had been diagnosed with, a rare form of early Parkinson’s caused by mutations in the DHDDS gene.
“They contacted Professor Eva Morava, for whom I was then working. We started creating mini-brains—tiny blobs of brain tissue grown in the lab from patients’ own cells—thus avoiding the need to take samples directly from the children’s brains,” she explained.
Muffels and colleagues observed these mini brains in the lab and found there were significant signs of deterioration after four months mirroring that seen in the brains of children with this rare condition.
In healthy cells, DHDDS helps make dolichol, a small fat-like molecule that acts as a platform for attaching sugars to proteins. When DHDDS doesn’t work properly, dolichol levels fall. As a result, cells struggle to attach sugar chains, called glycans, to proteins in the usual way.
Those glycans are important because they help proteins fold correctly, reach the right place in the cell, and function as they should. In the patient‑derived mini brains, the team could see that these sugar chains were formed incorrectly.
Low dolichol also disrupts overall lipid regulation and causes cholesterol to build up in astrocytes, the brain’s supportive cells. “This accumulation builds over time, and this is why we think the disease progresses,” said Muffels, “since the accumulation of cholesterol leads to mitochondrial dysfunction, leading in turn to reduced energy production.”
Perlara, a rare‑disease biotech public benefit corporation that runs phenotypic screens in simple ‘patient avatar’ organisms, helped Muffels and colleagues identify nicotinamide mononucleotide, a naturally occurring type of vitamin B3, in a yeast‑based assay as a potential modifier of DHDDS‑driven cellular stress.
The vitamin appeared to have positive effects on the mini brains, and when the families of patients heard about it, they began using the supplement as it is readily available without a prescription and known to be safe. Within a few weeks, the patient’s walking got better and they had more energy and less tremors.
“The word about nicotinamide mononucleotide reached more DHDDS patients, and we currently have 12 patients taking it. We recently received funding from Congenital Disorders of Glycosylation UK… to start an international trial for nicotinamide mononucleotide supplementation in DHDDS-related disease,” said Muffels.
“Patients will take nicotinamide mononucleotide for a year and will be evaluated every three months. Although I have now left the U.S., I hope that the Wilhemina Hospital in Utrecht will be one of the official sites and that I may continue to work with these patients.”
The post Mini Brains Help Identify Treatment for Rare Form Parkinson’s Disease appeared first on Inside Precision Medicine.