Many birds are arriving earlier each spring as temperatures warm along the East Coast of the United States.  However, the farther those birds journey, the less likely they are to keep pace with the rapidly changing climate.

Scientists at Boston University and the Manomet Center for Conservation Sciences analyzed changes in the timing of spring migrations of 32 species of birds along the coast of eastern Massachusetts since 1970.  Researchers at Manomet gathered this data by capturing birds in mist nets, attaching bands to their legs, and then releasing them.  Their findings, published in Global Change Biology, show that eight out of 32 bird species are passing by Cape Cod significantly earlier on their annual trek north than they were 38 years ago.  The reason?  Warming temperatures.  Temperatures in eastern Massachusetts have risen by 1.5 degrees Celsius (2.7 degrees Fahrenheit) since 1970.

Species, such as the swamp sparrow, that winter in the southern United States are generally keeping pace with warming temperatures and earlier leafing of trees.  They migrate earlier when temperatures are warm and later when spring is cool.

Birds that winter further south, like the great crested flycatcher, which spends its winters in South America, are slow to change, though.  Their migration times are not changing, despite the warming temperatures in New England.

There appears to be good reason for the difference between the shortand long-distance migrants.  Because temperatures are linked along much of the East Coast of the United States—an early spring in North Carolina is generally an early spring in Massachusetts—the short-distance migrants can gain insight into when it will be warm further north.  They can follow the flush of leaves and insects all the way to their breeding grounds each year.  Long-distance migrants, though, do not have any good cue for whether it will be an early or late spring on the northern stretches of their migrations.  Weather in South America has little to do with weather in New England.

Being slow to change in response to warming temperatures could have serious repercussions for long-distance migrant birds.  This same research group has shown that plants are blooming earlier in Massachusetts than they did in the past.  It appears that the short-distance migrants are keeping pace with this changing environment.  However, long-distance migrants are being left behind; as temperatures continue to warm, they will probably experience environments increasingly different from the ones for which they are adapted.  Other researchers have already noted that some long-distance migrant birds returning from African wintering areas to breed in Europe are now mistimed with their insect food supply.  The inability of some birds to adapt to rapid climate change may be an important factor in some of the declines among songbird populations that have been documented in recent years.

A PhD thesis from the University of the Basque Country has concluded that there are opioid and cannabinoid receptors in human sperm and that these influence the mobility of spermatozoid.  The research by Mr Ekaitz Agirregoitia opens the door to more effective treatment of fertility problems.

Freshly released spermatozoids cannot achieve fertilisation, they must undergo some changes for this to occur.  Amongst other, such changes take place due to receptors situated in the plasmatic membrane (the layer covering the cells) and opioid and cannabinoid receptors are two of these.  On coming into contact with these, physiological reactions are generated in the body which are similar to, for example, sedation, analgesia and low blood pressure.  Moreover, according to the research undertaken to date, both substances have an influence on the process of fertilisation.  It is known that the consumption of external opiates (heroin, methadone) reduces the mobility of spermatozoids and that external cannabinoids (hachis) causes changes in the reproductive process.  Also, the body itself generates internal opioids and cannabinoids, secreted to enable us withstand pain or stress situations, and it is also known that this phenomenon affects the reproduction process.

Despite all this being previously known, there has been no thorough study of the opioid and cannabinoid receptors in the human sperm such as this one, carried out by Mr Ekaitz Agirregoitia Marcos for his PhD thesis, defended at the Faculty of Medicine and Odontology of the University of the Basque Country (UPV/EHU) and entitled in Basque, Opioide-hartzaileak eta kannabinoide-hartzaileak giza espermatozoideetan espresatzen dira eta haien mugikortasunean eragiten dute (Opioid receptors and cannabinoid receptors are expressed in human spermatozoids and influence their mobility).  The aim was to define this expression and the location of three opioid receptors and two cannabinoid receptors, as well as to analyse the influence of their activity in the mobility of spermatozoids.  Mr Agirregoitia has a degree in Biology, specialising in Health Sciences.  He is currently working as a substitute lecturer in the Department of Physiology, giving classes in Medical Biophysics and General Physiology.  His PhD work was led by Dr. Jon Irazusta Astiazaran from the same Department and was undertaken in collaboration with Dr. Carmen Ochoa of the Euskalduna Clinic and Dr. Manolo Guzmán from the Complutense University in Madrid.  Pinpointing the receptors

This PhD has shown, for the first time, that all the types of opioid and cannabinoid receptors are found in human sperm.  To date, only the MU opioid receptor has been found in equine sperm, and the presence in human sperm of the CB1 cannabinoid receptor was only discovered this year.  Dr. Agirregoitia has used a number of techniques to find three opioid receptors (DELTA, KAPPA and MU) and two cannabinoid receptors (CB1 and CB2) in the human sperm.  According to his research, all these are found at the head, the middle and the tail of the spermatozoids.  How is mobility influenced?

After defining the expression and location of the opioid and cannabinoid receptors, Dr. Agirregoitia initiated an analysis of their influence on the mobility of the spermatozoids.  These receptors act like a kind of lock catch mechanism to which the opioids and cannabinoids attach themselves.  Some of these substances (agonists) are capable of activating the cells, just like a key opening a lock.  Others (antagonists), although fitting perfectly into the “locks”, are not capable of opening them and have the effect of blocking the receptor.  Mr Agirregoitia studied both processes, incubating human sperm with agonist and antagonist synthetic substances to this end.

From this PhD thesis, presented at the UPV/EHU, it was concluded that, for the movement of the spermatozoids to be maintained, a minimum number of DELTA receptors must remain active.  On the other hand, it is pointed out that the activation of the MU opioid receptor inhibits the mobility of the spermatozoids, i.e. it causes them to slow down.  Finally, the PhD concludes that the KAPPA opioid receptor participates in another process which has nothing to do with mobility.

As regards the cannabinoid system, the activation of the CB1 y CB2 receptors causes the percentage of spermatozoids with rapid and progressive mobility to be reduced.  Even so, as a consequence of the activation of the CB1 receptor, the number of slow spermatozoids rises, while the activation of CB2 increases the number of spermatozoids with progressive but slow movement.  The most effective diagnoses and treatments

It is known that opiods and cannabinoids regulate the function of reproduction through the central nervous system and, according to this PhD thesis, they are also able to control the process through the receptors located in the spermatozoids themselves.  Thus, the type and concentration of internal opioids and cannabinoids found in the spermatozoid on its way to the egg will condition its mobility.

This work opens the door – in the medium to long term – to the diagnosis and treatment of numerous pathologies.  For example, an analysis of the components of the system of opioid and cannabinoid receptors would enable us to better understand fertility problems due to currently unknown causes, exhibited by both spermatozoids as well as the female reproductive organ.  Also, when designing treatment aimed at fomenting the mobility of spermatozoids, it will enable the prescribing of treatment that activates or inhibits the appropriate receptor in order to benefit the process of fertilisation.

The identification of five genes involve in the metastasis of breast tumours to the lung is the principal finding of a scientific team made up of two bodies from the University of Navarra, the Applied Medical Research Centre (CIMA) and the University Hospital of the University of Navarra.

Doctor Alfonso Calvo, researcher in the area of Oncology at the CIMA, led the work with the special collaboration of Doctor Ignacio Gil Bazo, cancer specialist from the University Hospital.  The study made up a significant part of Mr Raúl Catena’s PhD thesis.

For this research, recently published in the scientific journal Oncogene, a transgenic mouse model which presented a greater tendency for developing metastasis was employed.  The increase in what is known as the Vascular Endothelial Growth Factor (VEGF) in its mammary glands triggered profound changes in the tumoural structure, which enabled the malignant cells to leave the tumour and invade the lungs.

Finally, the pattern of genes responsible for this tumoural migration to the lungs was analysed and this was compared to that shown by women with breast tumours with pulmonary metastatic affectation.  It was shown that five of these genes were common to the animal model and patients with breast cancer.  Most effective ways of treatment

According to the results of this study, of the five genes identified, the Tenascina-C gene seems to be a good therapeutic target for the treatment of metastatic breast cancer.  In fact, the blocking of the expression of this gene in the animal model enabled a significant reduction, both in tumour growth and in the incidence of pulmonary metastasis.

This new discovery in the complex network that is the metastasis process of tumours provides key data on the knowledge of cancer and its spreading, at the same time identifying new targets for which new pharmaceutical medicines that contribute to more efficacious treatment of this disease can be designed.

Among the first cells of the immune system to respond to microorganisms that invade our body are neutrophils.  Although neutrophils are considered the “good guys” in such circumstances, they also contribute to the noninfectious chronic inflammation that underlies various diseases, including autoimmune diseases such as rheumatoid arthritis.  One mechanism by which neutrophils protect us is to internalize microorganisms and destroy them using proteins known as neutrophil serine proteases (NSPs), but whether NSPs have a role in noninfectious chronic inflammation has not been clearly determined.  However, using mice lacking two very similar NSPs, PR3 and NE, a team of researchers at the Max-Planck-Institute of Neurobiology, Germany, have now shown that these two NSPs have a crucial role in one form of noninfectious chronic inflammation.  Detailed analysis revealed that PR3 and NE destroy an anti-inflammatory molecule known as PGRN and in this way help to promote inflammation in the absence of invading microorganisms.  The authors therefore suggest that these data provide rationale for considering inhibitors of NSPs as anti-inflammatory drugs.

Individuals inhale measles virus particles in aerosols and it is currently thought that these particles infect the cells that line the airways (respiratory epithelial cells) before being passed to immune cells that carry the virus particles to other parts of the body and then back to the airways, which again become infected and shed virus into exhaled aerosols.  In the study, a measles virus unable to bind to and infect epithelial cells was found to cause symptoms of measles virus infection in monkeys even though it did not infect respiratory epithelial cells and was not being shed into exhaled aerosols.  These data suggest that, in fact, inhaled measles virus particles first infect lymphocytes and are only passed to respiratory epithelial cells from the lymphocytes in the tissues.  Further, they indicate that the protein that measles virus particles bind to on respiratory epithelial cells, which has yet to be identified, is likely to be found on the surface of the cells that faces the tissues rather than the surface that faces the airways, as previously assumed.  As discussed in an accompanying commentary by Makoto Takeda, at Kyushu University, Japan, the results of this study should help researchers identify this protein.

New data, generated by David Ornitz and colleagues, at Washington University School of Medicine, St. Louis, have indicated a crucial role for signaling pathways that involve the protein sonic hedgehog in maintaining the blood vessels that supply the mouse heart and keep it beating.  These data have implications for drug development as they suggest that antagonists of hedgehog signaling pathways, such as those being developed as anticancer therapeutics, might have unwanted side effects.

In the study, mice lacking the ability to mediate hedgehog signaling in cells that form part of the blood vessels that supply the heart were found to die of heart failure.  This was because in the absence of hedgehog signaling the blood vessels of the heart were lost, meaning that the heart cells were no longer supplied with enough oxygen and died.  Although these data indicate a need for caution when developing clinical antagonists of hedgehog signaling, it is possible that the degree of inhibition needed to have a clinical effect on tumor development might not have the effect on blood vessels of the heart that completely eliminating expression of the protein does.

Drugs known as HDAC inhibitors, which have antitumor activity and can be used to treat some forms of skin cancer and some types of leukemia, are also known to have anti-inflammatory properties, but the mechanisms by which they modulate the immune system have not been determined.  New data, generated by Pavan Reddy and colleagues, at the University of Michigan Cancer Center, Ann Arbor, have now indicated one mechanism by which HDAC inhibitors modulate the mouse and human immune system and the information gained has been used to develop an approach to protect mice from graft-versus-host disease after bone marrow transplantation.

In the study, two different HDAC inhibitors were shown to prevent mouse and human immune cells known as dendritic cells (DCs) from initiating proinflammatory immune responses in vitro.  Further, if Dcs treated ex vivo with HDAC inhibitors were injected into mice after they had received a bone marrow transplant, the incidence and severity of graft-versus-host disease was dramatically reduced.  Detailed analysis revealed that the HDAC inhibitors mediated their effects by inducing Dcs to express more of a molecule known as IDO, which is a suppressor of DC function.  The authors therefore hope that their data provide support for studies to determine whether HDAC inhibitors might be of benefit to individuals receiving bone marrow transplants and to those with other immune-mediated diseases.

Drugs that target members of the EGFR family of proteins have proven effective for the treatment of certain types of cancer, including breast cancer.  However, in a large number of patients for whom the treatment initially works well, the tumor recurs and is resistant to the effects of the drug.  New insight into the mechanisms of tumor resistance to a drug known as gefitinib, which targets EGFR, has now been provided by a team of researchers at Vanderbilt University Medical Center, Nashville, and Massachusetts General Hospital Cancer Center, Charlestown.  As discussed by both the authors and, in an accompanying commentary, Mark Greene and Qiang Wang, at the University of Pennsylvania Medical Center, Philadelphia, these observations help us understand why tumors become resistant to the effects of EGFR-targeted drugs, information that is essential if more effective therapies are to be developed.

The team, led by Carlos Arteaga and Jeffrey Engelman, generated cancer cells resistant to the effects of gefitinib and found that these cells were constantly sending signals from a protein on their surface known as IGF1R.  This meant that two proteins known as IRS-1 and PI3K were always associated.  If this association was disrupted then the cells once again became susceptible to the effects of gefitinib.  Further analysis showed that if mice with a human tumor were treated with gefitinib and a drug inhibiting IGF1R their tumors did not recur, whereas neither drug alone could prevent tumor recurrence.  The authors therefore suggest that drug combinations that target both EGFR and IGF1R might be of benefit to individuals with cancers that are responsive to EGFR-targeted therapies.

Individuals who are obese are at increased risk of many diseases, including type 2 diabetes and heart disease.  As 75%-95% of previously obese individuals regain their lost weight, many researchers are interested in developing treatments to help individuals maintain their weight loss.  A new study, by Michael Rosenbaum and colleagues, at Columbia University Medical Center, New York, has provided new insight into the critical interaction between the hormone leptin and the brain’s response to weight loss.

Leptin levels fall as obese individuals lose weight.  So, the authors set out to see whether changes in leptin levels altered activity in the regions of the brain known to have a role in regulating food intake.  They observed that activity in these regions of the brain in response to visual food-related cues changed after an obese individual successfully lost weight.  However, these changes in brain activity were not observed if the obese individual who had successfully lost weight was treated with leptin.  These data are consistent with the idea that the decrease in leptin levels that occurs when an individual loses weight serves to protect the body against the loss of body fat.  Further, both the authors and, in an accompanying commentary, Rexford Ahima, at the University of Pennsylvania School of Medicine, Philadelphia, suggest that leptin therapy after weight loss might improve weight maintenance by overriding this fat-loss defense.

New insight into how pollution and cigarette smoke damage airways has been provided by Pierangelo Geppetti and colleagues, at the University of Florence, Italy, who studied the effects of such chemicals on guinea pig airways.  As discussed, in an accompanying commentary, by Sidney Simon and Wolfgang Liedtke, at Duke University Medical Center, it is hoped that this information will help in the development of therapeutics to combat the effects of pollutants and perhaps help individuals with smoke-related diseases such as chronic obstructive pulmonary disease and chronic asthma.

In the study, chemicals found in cigarette smoke were shown to activate signaling in nerves that ended in the airways of guinea pigs.  These effects were abolished using a molecule that inhibited a protein known as TRPA1.  Consistent with a central role for TRPA1 in sensing chemicals in cigarette smoke, no signaling in nerves that end in the airways was observed in mice lacking TRPA1 after exposure to the chemicals in cigarette smoke.  Further analysis showed that alpha,beta-unsaturated aldehydes were the chemicals that activated TRPA1, suggesting that they might contribute to the airway damage that occurs in smoke-related diseases.

A small molecule that locks an essential enzyme in an inactive form could one day form the basis of a new class of unbeatable, species-specific antibiotics, according to researchers at Fox Chase Cancer Center.

Their findings, highlighted on the cover of the June 23 issue of the journal Chemistry & Biology, take advantage of an emerging body of science regarding “morpheeins” – proteins made from individual components that are capable of spontaneously reconfiguring themselves into different shapes within living cells.

The researchers discovered a small molecule, which they have named morphlock-1, binds the inactive form of a protein known as porphobilinogen synthase (PBGS), an enzyme used by nearly all forms of cellular life.  The functioning form of PBGS is built from eight identical component parts – in what is called an octamer configuration – and is essential among nearly all forms of life in the processes that enable cells to use energy.  The other configuration is made of six parts – or a hexamer configuration – and serves as a “standby” mode for the protein.

“As the name suggests, morphlock-1 essentially locks the hexamer configuration into place, preventing its protein subunits from reconfiguring into the active assembly,” says lead investigator Eileen Jaffe, Ph.D, a Senior Member of Fox Chase.  “Targeting morpheeins in their inactive assemblies provides an entirely new approach to drug discovery.”

While their study was performed using a pea plant-version of PBGS, the researchers have reason to believe the principle could apply to bacterial versions of PBGS as well.  “Using morphlock-1 as a base, we are seeking to fine tune the molecule so that it blocks just the bacterial version of the PBGS enzyme, ” Jaffe says.

“Because PBGS is so crucial for life, the part of the enzyme where chemistry happens is highly conserved through evolution,” Jaffe says, meaning that an all-around PBGS-inhibiting drug would harm bacteria, peas and people alike.  The area where the potential drug binds to the hexamer form of the protein, however, has been found to differ among species, depending how far the organisms have evolved from each other.

When PBGS is in its inactive hexamer form, there is a small cavity on the surface of the assembled complex.  Using computer docking techniques, Jaffe and her Fox Chase colleagues identified a suite of small molecules predicted to bind to this cavity.

The researchers then bought and tested a selection of these molecules in the lab to see if any of them stabilized the pea PBGS in its hexamer assembly.  One inhibitor in particular, given the name morphlock-1, potently drove the formation of the hexamer in pea PBGS, but not in that of humans, fruit flies, or the infectious bacteria Pseudomonas aeruginosa, or Vibrio cholerae, the latter of which causes cholera.  Morphlock-1 is a potent inhibitor of pea PBGS, but not of the PBGS from these other organisms.

Jaffe coined the term “morpheein” in 2005 after a study of the structure of PBGS revealed its shape-shifting tendencies.  While initially met with skepticism because the existence of morpheeins contradicts some classic concepts about protein structure and function, subsequent studies have reinforced that PBGS (and perhaps other proteins) exhibits this behavior.  According to Jaffe, this study is the first to make use of alternate morpheein shapes as a potential strategy for drug discovery, in general, particularly for antibiotics.

“Multi-drug resistance drives the need for developing new antibiotics,” Jaffe says.  “Since drugs that stabilize the inactive PBGS hexamer need not be chemically similar to each other, it will be difficult for the bacterium to develop complete resistance to a cocktail of such compounds.”

Researchers at the University of Cincinnati (UC) are looking for ways to reduce or prevent heart damage by starting where the problem often begins: in the genes.

Following a heart attack, cells die, causing lasting damage to the heart.

Keith Jones, PhD, a researcher in the department of pharmacology and cell biophysics, and colleagues are trying to reduce post-heart attack damage by studying the way cells die in the heart—a process controlled by transcription factors.

Transcription factors are proteins that bind to specific parts of DNA and are part of a system that controls the transfer of genetic information from DNA to RNA and then to protein.  Transfer of genetic information also plays a role in controlling the cycle of cells—from cell growth to cell death.

“We call it ‘gene regulatory therapy,’” says Jones.

So far, studies have identified the role for an important group of interacting transcription factors and the genes they regulate to determine whether cells in the heart survive or die after blood flow restriction occurs.

Often, scientists use virus-like mechanisms to transfer DNA and other nucleic acids inside the body.

The “virus” takes over other healthy cells by injecting them with its DNA.  The cells, then transformed, begin reproducing the virus’ DNA.  Eventually they swell and burst, sending multiple replicas of the virus out to conquer other cells and repeat the process.

Now, UC researchers are further investigating new, non-viral delivery mechanisms for this transfer of DNA.

“We can use non-viral delivery vehicles to transfer nucleic acids, including transcription factor decoys, to repress activation of specific transcription factors in the heart,” Jones says, adding that the researchers have made this successfully work within live animal models.  “This means we can block the activity of most transcription factors in the heart without having to make genetically engineered mice.”

Jones will be presenting these results at the International Society for Heart Research in Cincinnati, June 17-20.

He says this delivery mechanism involves flooding the cells with “decoys” which trick the transcription factors into binding to the decoys rather than to target genes, preventing them from activating those genes.

“We can use this technology to identify the target genes and then investigate the action of these genes in the biological process,” Jones says.

He says that this delivery has limitations and advantages.

“It can be used to block a factor at any point in time and is reversible,” he says.  “However, right now, a specific delivery route must be used to target the tissue or cell.”

Jones and other researchers are hoping that this new technology will allow them to directly address the effects of gene regulation in disease, as opposed to using classical drugs that treat symptoms or have significant adverse outcomes.

“So far, this seems to cause no adverse effects in animals,” he says.  “We are hopeful and are working toward pre-clinical studies.”

Polycystic ovary syndrome, or PCOS, is among the most common causes of infertility, conservatively affecting 6-8% of women.  Increasing evidence suggests symptoms of PCOS arise during the pubertal process; however, the cause or causes of PCOS remain unclear.  Although genetic predispositions likely exist, environmental causes have also been suggested.  In an article on p. 154 of this issue, Abbott and coworkers provide evidence in a primate model that prenatal exposure to androgens, which are elevated in women with PCOS during late gestation, provides an endocrine environment that leads to increased gonadotropin release both prenatally and postnatally, as well as leading to increased androgen levels in female infants.  While these changes occurred in the absence of elevations of estrogen levels in the fetuses—suggesting androgen-mediated prenatal programming may be one of the factors that can contribute to the constellation of symptoms that define PCOS—local tissue conversion of androgen to estrogen may provide additional programming.

Adding to a growing literature on the role of metabolic enzymes and ATP production in sperm function, it is now shown that one lactate dehydrogenase family member, LDHC, is required for male fertility.  Several decades of work on this glycolytic enzyme had shown that it is expressed primarily in testis, but its functional significance had been only speculative.  In an article on p. 26 Odet et al.  Report that male mice homozygous for a targeted disruption of Ldhc are severely impaired in fertility, whereas females are fertile.  The fertility defects include impaired sperm motility, reduction of capacitation-related protein phosphorylation, and fertilization defects—all probably due to compromised ATP production.  Thus, LDHC is required for glycolysis and ATP production in the sperm tail, and this finding may lead to new insights into infertility in men.

Researchers have determined that there are hundreds of biological differences between the sexes when it comes to gene expression in the cerebral cortex of humans and other primates.  These findings, published June 20th in the open-access journal PloS Genetics, indicate that some of these differences arose a very long time ago and have been preserved through evolution.  These conserved differences constitute a signature of sex differences in the brain.

Many more obvious gender differences have been preserved throughout primate evolution; examples include average body size and weight, and genitalia design.  This study, believed to be the first of its kind, focuses on gene expression within the cerebral cortex.  The cerebral cortex is involved in many of the more complex functions in both humans and other primates, including memory, attentiveness, thought processes and language.

The researchers measured gene expression in the brains of male and female primates from three species: humans, macaques, and marmosets.  To measure activity of specific genes, the products of genes (RNA) obtained from the brain of each animal were hybridized to microarrays containing thousands of DNA clones coding for thousands of genes.  The authors also investigated DNA sequence differences among primates for genes showing different levels of expression between the sexes.

“Knowledge about gender differences is important for many reasons.  For example, this information may be used in the future to calculate medical dosages, as well as for other treatments of diseases or damage to the brain,” says team leader Professor Elena Jazin, at Uppsala University, Sweden.

In addition to the results mentioned above, the researchers also report on evolutionary speeds in genes that have been identified as male or female-oriented.  This could provide clues about the power of natural selection processes during the evolution of primates.

Lead author Björn Reinius notes that the study does not determine whether these differences in gene expression are in any way functionally significant.  Such questions remain to be answered by future studies.