Melanoma biology and treatment: a review of novel regulated cell death-based approaches.

The incidence of melanoma, the most lethal form of skin cancer, has increased due to ultraviolet exposure. The treatment of advanced melanoma, particularly metastatic cases, remains challenging with poor outcomes. Targeted therapies involving BRAF/MEK inhibitors and immunotherapy based on anti-PD1/anti-CTLA4 antibodies have achieved long-term survival rates of approximately 50% for patients with advanced melanoma. However, therapy resistance and inadequate treatment response continue to hinder further breakthroughs in treatments that increase survival rates. This review provides an introduction to the molecular-level pathogenesis of melanoma and offers an overview of current treatment options and their limitations. Cells can die by either accidental or regulated cell death (RCD). RCD is an orderly cell death controlled by a variety of macromolecules to maintain the stability of the internal environment. Since the uncontrolled proliferation of tumor cells requires evasion of RCD programs, inducing the RCD of melanoma cells may be a treatment strategy. This review summarizes studies on various types of nonapoptotic RCDs, such as autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and the recently discovered cuproptosis, in the context of melanoma. The relationships between these RCDs and melanoma are examined, and the interplay between these RCDs and immunotherapy or targeted therapy in patients with melanoma is discussed. Given the findings demonstrating melanoma cell death in response to different stimuli associated with these RCDs, the induction of RCD shows promise as an integral component of treatment strategies for melanoma.

Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion.

Ubiquitination and deubiquitination are important forms of posttranslational modification that govern protein homeostasis. Deubiquitinating enzymes (DUBs), a protein superfamily consisting of more than 100 members, deconjugate ubiquitin chains from client proteins to regulate cellular homeostasis. However, the dysregulation of DUBs is reportedly associated with several diseases, including cancer. The tumor microenvironment (TME) is a highly complex entity comprising diverse noncancerous cells (e.g., immune cells and stromal cells) and the extracellular matrix (ECM). Since TME heterogeneity is closely related to tumorigenesis and immune evasion, targeting TME components has recently been considered an attractive therapeutic strategy for restoring antitumor immunity. Emerging studies have revealed the involvement of DUBs in immune modulation within the TME, including the regulation of immune checkpoints and immunocyte infiltration and function, which renders DUBs promising for potent cancer immunotherapy. Nevertheless, the roles of DUBs in the crosstalk between tumors and their surrounding components have not been comprehensively reviewed. In this review, we discuss the involvement of DUBs in the dynamic interplay between tumors, immune cells, and stromal cells and illustrate how dysregulated DUBs facilitate immune evasion and promote tumor progression. We also summarize potential small molecules that target DUBs to alleviate immunosuppression and suppress tumorigenesis. Finally, we discuss the prospects and challenges regarding the targeting of DUBs in cancer immunotherapeutics and several urgent problems that warrant further investigation.

Diphenyl disulfide potentiates the apoptosis of breast cancer cells through Bax proteolytic activation with accompanying autophagy.

Breast cancer is a leading cause of cancer-related death worldwide, and chemoresistance often leads to poor patient outcomes. In this study, we investigated the anticancer activity of synthetic diphenyl disulfide (DPDS) in breast cancer cell lines. DPDS inhibited cellular proliferation and viability in a dose-dependent manner and reduced colony formation, an index of clonogenicity. Annexin-V and 7-AAD double staining showed that DPDS could induce the apoptosis of breast cancer cells. Western blotting of the expression of Bax p21 and its cleaved form p18 suggested the activation of p18 Bax-induced apoptosis. Furthermore, the increased expression of the autophagy marker LC3B-II indicated autophagic lysosome accumulation induced by DPDS. Our findings suggest that DPDS has potential as a candidate for treating breast cancer, and further modifications and optimizations are warranted.

Neuronal Function and Dopamine Signaling Evolve at High Temperature in Drosophila.

Neuronal activity is temperature sensitive and affects behavioral traits important for individual fitness, such as locomotion and courtship. Yet, we do not know enough about the evolutionary response of neuronal phenotypes in new temperature environments. Here, we use long-term experimental evolution of Drosophila simulans populations exposed to novel temperature regimes. Here, we demonstrate a direct relationship between thermal selective pressure and the evolution of neuronally expressed molecular and behavioral phenotypes. Several essential neuronal genes evolve lower expression at high temperatures and higher expression at low temperatures, with dopaminergic neurons standing out by displaying the most consistent expression change across independent replicates. We functionally validate the link between evolved gene expression and behavioral changes by pharmacological intervention in the experimentally evolved D. simulans populations as well as by genetically triggered expression changes of key genes in D. melanogaster. As natural temperature clines confirm our results for Drosophila and Anopheles populations, we conclude that neuronal dopamine evolution is a key factor for temperature adaptation.

Parallel gene expression evolution in natural and laboratory evolved populations.

Ecological adaptation is frequently inferred by the comparison of natural populations from different environments. Nevertheless, inference of the selective forces suffers the challenge that many environmental factors covary. With well-controlled environmental conditions, experimental evolution provides a powerful approach to complement the analysis of natural populations. On the other hand, it is apparent that laboratory conditions differ in many ways from natural environments, which raises the question as to what extent selection responses in experimental evolution studies can inform us about adaptation processes in the wild. In this study, we compared the expression profiles of replicated Drosophila melanogaster populations which have been exposed to two distinct temperature regimes (18/28 and 10/20°C) in the laboratory for more than 80 generations. Using gene-wise differential expression analysis and co-expression network analysis, we identified 541 genes and three coregulated gene modules that evolved in the same direction in both temperature regimes, and most of these changes probably reflect an adaptation to the space constraint or diurnal temperature fluctuation that is common in both selection regimes. In total, 203 genes and seven modules evolved temperature-specific expression changes. Remarkably, we detected a significant overlap of these temperature-adaptive genes/modules from experimental evolution with temperature-adaptive genes inferred from natural Drosophila populations covering two different temperature clines. We conclude that well-designed experimental evolution studies are a powerful tool to dissect evolutionary responses.

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway.

Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.

Curcumin Metabolite Tetrahydrocurcumin in the Treatment of Eye Diseases.

Curcumin is one of the most valuable natural products due to its pharmacological activities. However, the low bioavailability of curcumin has long been a problem for its medicinal use. Large studies have been conducted to improve the use of curcumin; among these studies, curcumin metabolites have become a relatively new research focus over the past few years. Additionally, accumulating evidence suggests that curcumin or curcuminoid metabolites have similar or better biological activity than the precursor of curcumin. Recent studies focus on the protective role of plasma tetrahydrocurcumin (THC), a main metabolite of curcumin, against tumors and chronic inflammatory diseases. Nevertheless, studies of THC in eye diseases have not yet been conducted. Since ophthalmic conditions play a crucial role in worldwide public health, the prevention and treatment of ophthalmic diseases are of great concern. Therefore, the present study investigated the antioxidative, anti-inflammatory, antiangiogenic, and neuroprotective effects of THC on four major ocular diseases: age-related cataracts, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). While this study aimed to show curcumin as a promising potential solution for eye conditions and discusses the involved mechanistic pathways, further work is required for the clinical application of curcumin.

Unfolded Protein Response (UPR) in Survival, Dormancy, Immunosuppression, Metastasis, and Treatments of Cancer Cells.

The endoplasmic reticulum (ER) has diverse functions, and especially misfolded protein modification is in the focus of this review paper. With a highly regulatory mechanism, called unfolded protein response (UPR), it protects cells from the accumulation of misfolded proteins. Nevertheless, not only does UPR modify improper proteins, but it also degrades proteins that are unable to recover. Three pathways of UPR, namely PERK, IRE-1, and ATF6, have a significant role in regulating stress-induced physiological responses in cells. The dysregulated UPR may be involved in diseases, such as atherosclerosis, heart diseases, amyotrophic lateral sclerosis (ALS), and cancer. Here, we discuss the relation between UPR and cancer, considering several aspects including survival, dormancy, immunosuppression, angiogenesis, and metastasis of cancer cells. Although several moderate adversities can subject cancer cells to a hostile environment, UPR can ensure their survival. Excessive unfavorable conditions, such as overloading with misfolded proteins and nutrient deprivation, tend to trigger cancer cell death signaling. Regarding dormancy and immunosuppression, cancer cells can survive chemotherapies and acquire drug resistance through dormancy and immunosuppression. Cancer cells can also regulate the downstream of UPR to modulate angiogenesis and promote metastasis. In the end, regulating UPR through different molecular mechanisms may provide promising anticancer treatment options by suppressing cancer proliferation and progression.

Reproductive isolation arises during laboratory adaptation to a novel hot environment.

BACKGROUND: Reproductive isolation can result from adaptive processes (e.g., ecological speciation and mutation-order speciation) or stochastic processes such as "system drift" model. Ecological speciation predicts barriers to gene flow between populations from different environments, but not among replicate populations from the same environment. In contrast, reproductive isolation among populations independently adapted to the same/similar environment can arise from both mutation-order speciation or system drift. RESULTS: In experimentally evolved populations adapting to a hot environment for over 100 generations, we find evidence for pre- and postmating reproductive isolation. On one hand, an altered lipid metabolism and cuticular hydrocarbon composition pointed to possible premating barriers between the ancestral and replicate evolved populations. On the other hand, the pronounced gene expression differences in male reproductive genes may underlie the postmating isolation among replicate evolved populations adapting to the same environment with the same standing genetic variation. CONCLUSION: Our study confirms that replicated evolution experiments provide valuable insights into the mechanisms of speciation. The rapid emergence of the premating reproductive isolation during temperature adaptation showcases incipient ecological speciation. The potential evidence of postmating reproductive isolation among replicates gave rise to two hypotheses: (1) mutation-order speciation through a common selection on early fecundity leading to an inherent inter-locus sexual conflict; (2) system drift with genetic drift along the neutral ridges.

Burning down the house: Pyroptosis in the tumor microenvironment of hepatocellular carcinoma.

A high mortality rate makes hepatocellular carcinoma (HCC) a difficult cancer to treat. When surgery is not possible, liver cancer patients are treated with chemotherapy. However, HCC management and treatment are difficult. Sorafenib, which is a first-line treatment for hepatocellular carcinoma, initially slows disease progression. However, sorafenib resistance limits patient survival. Recent studies have linked HCC to programmed cell death, which has increased researcher interest in therapies targeting cell death. Pyroptosis, which is an inflammatory mode of programmed cell death, may be targeted to treat HCC. Pyroptosis pathways, executors, and effects are examined in this paper. This review summarizes how pyroptosis affects the tumor microenvironment (TME) in HCC, including the role of cytokines such as IL-1ß and IL-18 in regulating immune responses. The use of chemotherapies and their ability to induce cancer cell pyroptosis as alternative treatments and combining them with other drugs to reduce side effects is also discussed. In conclusion, we highlight the potential of inducing pyroptosis to treat HCC and suggest ways to improve patient outcomes. Studies on cancer cell pyroptosis may lead to new HCC treatments.

Effects of larval crowding on the transcriptome of Drosophila simulans.

Larval crowding is one common ecological stressor for many insect species. In Drosophila, high larval density alters multiple widely-studied phenotypes including life-history traits, morphology and behavior. Nevertheless, we still miss a holistic view of the full range of phenotypic changes and the underlying molecular mechanisms. In this study, we analyzed the adult transcriptomes of high and low larval density fly cohorts, and highlighted the molecular basis of the plastic traits. Increased cellular energy metabolism and locomotion, along with reduced reproductive investment, are key responses to high larval density. Moreover, we compared the expression changes among cohorts with different developmental delays caused by larval crowding. The majority of genes induced by larval crowding showed the strongest expression alterations in cohorts with intermediate delay. Furthermore, linear expression changes were observed in genes related to nutrition and detoxification. Comparing different high-density cohorts could provide insights into the varied responses to distinct larval crowding-induced stresses such as space competition, food degradation and waste accumulation.

The Role of Exosomes in Pancreatic Ductal Adenocarcinoma Progression and Their Potential as Biomarkers.

Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy, is an aggressive and lethal cancer with a dismal five-year survival rate. Despite remarkable improvements in cancer therapeutics, the clinical outcome of PDAC patients remains poor due to late diagnosis of the disease. This highlights the importance of early detection, wherein biomarker evaluation including exosomes would be helpful. Exosomes, small extracellular vesicles (sEVs), are cell-secreted entities with diameters ranging from 50 to 150 nm that deliver cellular contents (e.g., proteins, lipids, and nucleic acids) from parent cells to regulate the cellular processes of targeted cells. Recently, an increasing number of studies have reported that exosomes serve as messengers to facilitate stromal-immune crosstalk within the PDAC tumor microenvironment (TME), and their contents are indicative of disease progression. Moreover, evidence suggests that exosomes with specific surface markers are capable of distinguishing patients with PDAC from healthy individuals. Detectable exosomes in bodily fluids (e.g., blood, urine, saliva, and pancreatic juice) are omnipresent and may serve as promising biomarkers for improving early detection and evaluating patient prognosis. In this review, we shed light on the involvement of exosomes and their cargos in processes related to disease progression, including chemoresistance, angiogenesis, invasion, metastasis, and immunomodulation, and their potential as prognostic markers. Furthermore, we highlight feasible clinical applications and the limitations of exosomes in liquid biopsies as tools for early diagnosis as well as disease monitoring. Taking advantage of exosomes to improve diagnostic capacity may provide hope for PDAC patients, although further investigation is urgently needed.

The Pyroptotic and Nonpyroptotic Roles of Gasdermins in Modulating Cancer Progression and Their Perspectives on Cancer Therapeutics.

Gasdermins (GSDMs) are a protein family encoded by six paralogous genes in humans, including GSDMA, GSDMB, GSDMC, GSDMD, GSDME (also known as DFNA5), and DFNB59 (also known as pejvakin). Structurally, members of the GSDM family possess a C-terminus (an autoinhibitory domain) and a positively charged N-terminus (a pore-forming domain) linked with divergent peptide linkers. Recently, GSDMs have been identified as key executors of pyroptosis (an immunogenic programmed cell death) due to their pore-forming activities on the plasma membrane when proteolytically cleaved by caspases or serine proteases. Accumulating studies suggest that chemoresistance is attributed to dysregulation of apoptotic machinery and that inducing pyroptosis to bypass aberrant apoptosis can potently resensitize apoptosis-resistant cancer to chemotherapeutics. Pyroptosis is initiated by pore formation and culminates with plasma membrane rupture; these processes enable the release of proinflammatory cytokines (e.g., IL-1ß and IL-18) and damage-associated molecular patterns, which further modulate antitumor immunity within the tumor microenvironment. Although pyroptosis is considered a promising strategy to boost antitumor effects, it is also reported to cause unwanted tissue damage (e.g., gut damage and nephrotoxicity). Intriguingly, mounting evidence has uncovered nonpyroptotic roles of GSDMs in tumorigenesis, such as proliferation, invasion, metastasis, and drug resistance. Thus, this provides a rationale for GSDMs as potential therapeutic targets. Taken together, we shed unbiased light on the pyroptosis-dependent roles of GSDMs in cancer progression and highlighted how GSDMs modulate tumorigenesis in a pyroptosis-independent manner. It is evident that targeting GSDMs seems profound in cancer management; however, several problems require further investigation to target GSDMs from bench to bedside, which is elucidated in the discussion section.

Discovery of potent antimicrobial peptide analogs of Ixosin-B.

Antimicrobial peptides (AMPs) represent the first defense line against infection when organisms are infected by pathogens. These peptides are generally good targets for the development of antimicrobial agents. Peptide amide analogs of Ixosin-B, an antimicrobial peptide with amino acid sequence of QLKVDLWGTRSGIQPEQHSSGKSDVRRWRSRY, were designed, synthesized and examined for antimicrobial activities against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Within the peptides synthesized, we discovered an 11-mer peptide, KRLRRVWRRWR-amide, which exhibited potent antimicrobial activity while very little hemolytic activity in human erythrocytes was observed even at high dose level (100 µM). With further modifications, this peptide could be developed into a potent antimicrobial agent in the future.

Culprits of PDAC resistance to gemcitabine and immune checkpoint inhibitor: Tumour microenvironment components.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer with a dismal five-year survival rate of 11%. Despite remarkable advancements in cancer therapeutics, PDAC patients rarely benefit from it due to insurmountable treatment resistance. Notably, PDAC is pathologically characterized by an extensive desmoplastic reaction and an extremely immunosuppressive tumour microenvironment (TME). The PDAC TME consists of cell components (e.g., tumour, immune and stromal cells) and noncellular components (e.g., extracellular matrix), exhibiting high complexity and their interplay resulting in resistance to chemotherapeutics and immune checkpoint inhibitors. In our review, we shed light on how crosstalk of complex environmental components modulates PDAC drug resistance, and we summarize related clinical trials. Moreover, we extend our discussion on TME exploration and exosome analysis, providing new insights into clinical applications, including personalized medicine, disease monitoring and drug carriers.

The Adverse Effects of Air Pollution on the Eye: A Review.

Air pollution is inevitably the result of human civilization, industrialization, and globalization. It is composed of a mixture of gases and particles at harmful levels. Particulate matter (PM), nitrogen oxides (NOx), and carbon dioxides (CO2) are mainly generated from vehicle emissions and fuel consumption and are the main materials causing outdoor air pollution. Exposure to polluted outdoor air has been proven to be harmful to human eyes. On the other hand, indoor air pollution from environmental tobacco smoking, heating, cooking, or poor indoor ventilation is also related to several eye diseases, including conjunctivitis, glaucoma, cataracts, and age-related macular degeneration (AMD). In the past 30 years, no updated review has provided an overview of the impact of air pollution on the eye. We reviewed reports on air pollution and eye diseases in the last three decades in the PubMed database, Medline databases, and Google Scholar and discussed the effect of various outdoor and indoor pollutants on human eyes.

The Role of Nonapoptotic Programmed Cell Death - Ferroptosis, Necroptosis, and Pyroptosis - in Pancreatic Ductal Adenocarcinoma Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer, with a dismal 5-year survival rate of less than 10%. It is estimated that approximately 80% of pancreatic ductal carcinoma (PDAC) patients are diagnosed at an advanced or metastatic stage. Hence, most patients are not appropriate candidates for surgical resection and therefore require systemic chemotherapy. However, it has been reported that most patients develop chemoresistance within several months, partly because of antiapoptotic mechanisms. Hence, inducing alternative programmed cell death (PCD), including ferroptosis, necroptosis or pyroptosis, seems to be a promising strategy to overcome antiapoptosis-mediated chemoresistance. In this review, we shed light on the molecular mechanisms of ferroptosis, necroptosis and pyroptosis and suggest several potential strategies (e.g., compounds and nanoparticles [NPs]) that are capable of triggering nonapoptotic PCD to suppress PDAC progression. In conclusion, these strategies might serve as adjuvants in combination with clinical first-line chemotherapies to improve patient survival rates.

Endoglin Modulates TGFßR2 Induced VEGF and Proinflammatory Cytokine Axis Mediated Angiogenesis in Prolonged DEHP-Exposed Breast Cancer Cells.

Angiogenesis is the process of vascular network development and plays a crucial role in cancer growth, progression, and metastasis. Phthalates are a class of environmental pollutants that have detrimental effects on human health and are reported to increase cancer risk. However, the interplay between phthalate exposure and angiogenesis has not been investigated thoroughly. In this study, we investigated the effect of prolonged di (2-ethylhexyl) phthalate (DEHP) treatment on the angiogenic potential of triple-negative breast cancer. MDA-MB-231 cells were exposed to physiological concentrations of DEHP for more than three months. Prolonged DEHP exposure induced angiogenesis in breast cancer cells. Endoglin (ENG)/CD105 is a membrane glycoprotein and an auxiliary receptor of the TGFß receptor complex. In endothelial cells, ENG is highly expressed and it is a prerequisite for developmental angiogenesis. A literature review highlights endoglin as a well-known mesenchymal stem cell marker responsible for vascular development and angiogenesis. NGS analysis showed that endoglin overexpression in DEHP-exposed MDA-MB-231 cells correlated with tumor development and growth. An in vivo zebrafish xenograft assay showed that VEGFA induced sprouting of the subintestinal vein (SIV) in embryos injected with DEHP-exposed cells. Endoglin knockdown reduced SIV sprouting and VEGFA expression in zebrafish embryos. An in vitro HUVEC tube formation assay showed that endoglin depletion reversed DEHP-induced VEGF-mediated HUVEC tube formation in coculture. DEHP-induced endoglin activated TGFß/SMAD3/VEGF and MAPK/p38 signaling in MDA-MB-231 cells. A cytokine angiogenesis antibody array showed induced expression of the inflammatory cytokines IL1α, IL1ß, IL6, and IL8, along with GMCSF and VEGF. Endoglin knockdown reversed DEHP-induced activation of the TGFß/SMAD3/VEGF signaling axis, MAPK/p38 signaling, and cytokine regulation, limiting angiogenesis potential both in vivo and in vitro. Targeting endoglin might serve as a potential alternative treatment to control angiogenesis, leading to metastasis and limiting cancer progression.

Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment.

In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.

Rapid sex-specific adaptation to high temperature in Drosophila.

The pervasive occurrence of sexual dimorphism demonstrates different adaptive strategies of males and females. While different reproductive strategies of the two sexes are well-characterized, very little is known about differential functional requirements of males and females in their natural habitats. Here, we study the impact environmental change on the selection response in both sexes. Exposing replicated Drosophila populations to a novel temperature regime, we demonstrate sex-specific changes in gene expression, metabolic and behavioral phenotypes in less than 100 generations. This indicates not only different functional requirements of both sexes in the new environment but also rapid sex-specific adaptation. Supported by computer simulations we propose that altered sex-biased gene regulation from standing genetic variation, rather than new mutations, is the driver of rapid sex-specific adaptation. Our discovery of environmentally driven divergent functional requirements of males and females has important implications-possibly even for gender aware medical treatments.

Male and female animals of the same species sometimes differ in appearance and sexual behavior, a phenomenon known as sexual dimorphism. Both sexes share most of the same genes, but differences can emerge because of the way these are read by cells to create proteins ­ a process called gene expression. For instance, certain genes can be more expressed in males than in females, and vice-versa. Most studies into the emergence of sexual dimorphism have taken place in stable environments with few changes in climate or other factors. Therefore, the potential impact of environmental changes on sexual dimorphism has been largely overlooked. Here, Hsu et al. used genetic and computational approaches to investigate whether male and female fruit flies adapt differently to a new, hotter environment over several generations. The experiment showed that, after only 100 generations, the way that 60% of all genes were expressed evolved in a different direction in the two sexes. This led to differences in how the males and females made and broke down fat molecules, and in how their neurons operated. These expression changes also translated in differences for high-level biological processes. For instance, animals in the new settings ended up behaving differently, with the males at the end of the experiment spending more time chasing females than the ancestral flies. These findings demonstrate that male and female fruit flies adapt many biological processes (including metabolism and behaviors) differently to cope with changes in their environment, and that many different genes support these sex-specific adaptations. Ultimately, the work by Hsu et al. may inform medical strategies that take into account interactions between the patient's sex and their environment.